Neuroscience and Biobehavioral Reviews 30 (2006) 215238

www.elsevier.com/locate/neubiorev

Review
The mesolimbic dopamine system: The final common pathway
for the reinforcing effect of drugs of abuse?
R. Christopher Piercea,*, Vidhya Kumaresana,b
a
Departments of Pharmacology and Psychiatry, Boston University School of Medicine, 715 Albany Street, L603 Boston, MA 02118, USA
b
Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, 171 Meeting Street, Providence, RI 02912, USA

Abstract
In this review we will critically assess the hypothesis that the reinforcing effect of virtually all drugs of abuse is primarily dependent on
activation of the mesolimbic dopamine system. The focus is on five classes of abused drugs: psychostimulants, opiates, ethanol, cannabinoids
and nicotine. For each of these drug classes, the pharmacological and physiological mechanisms underlying the direct or indirect influence on
mesolimbic dopamine transmission will be reviewed. Next, we evaluate behavioral pharmacological experiments that specifically assess the
influence of activation of the mesolimbic dopamine system on drug reinforcement, with particular emphasis on animal experiments using drug
self-administration paradigms. There is overwhelming evidence that all five classes of abused drugs increase dopamine transmission in limbic
regions of the brain through interactions with a variety of transporters, ionotropic receptors and metabotropic receptors. Behavioral
pharmacological experiments indicate that increased dopamine transmission is clearly both necessary and sufficient to promote
psychostimulant reinforcement. For the other four classes of abused substances, self-administration experiments suggest that although
increasing mesolimbic dopamine transmission plays an important role in the reinforcing effects of opiates, ethanol, cannabinoids and nicotine,
there are also dopamine-independent processes that contribute significantly to the reinforcing effects of these compounds.
q 2005 Elsevier Ltd. All rights reserved.

Keywords: Amphetamine; Cocaine; Heroin; Morphine Nicotine; Alcohol; Nucleus; Accumbens; Ventral tegemental area; Self administration

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
1.1. Dopaminergic modulation of the limbic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216
2. Psychostimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
2.1. Evidence of abuse in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
2.2. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217
2.3. Dopamine and psychostimulant reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
2.4. Dopamine receptors and psychostimulant reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
2.5. Dopamine receptors in limbic nuclei and psychostimulant reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219
2.6. Cocaine self-administration in DAT knockout mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
2.7. Norepinephrine, serotonin and cocaine reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220
3. Opiates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3.1. Evidence of abuse in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3.2. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3.3. Dopamine and opiate reinforcement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
3.4. Dopamine and opiate self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221

* Corresponding author. Tel.: C1 617 638 4327; fax: C1 617 638 5649.
E-mail address: rcpierce@bu.edu (R.C. Pierce).

0149-7634/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.neubiorev.2005.04.016
216 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238

3.5. Caveats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222

4. Ethanol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
4.1. Evidence of abuse in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
4.2. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
4.3. Effects of ethanol on mesolimbic dopamine transmission . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222
4.4. Dopamine and ethanol self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
4.5. Dopamine receptors and ethanol self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
4.6. Caveats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
5. Cannabinoids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223
5.1. Evidence of abuse in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
5.2. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
5.3. Cannabinoid-dopamine interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
5.4. Cannabinoid self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
5.5. Opioid-dopamine interactions and cannabinoid self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
5.6. Caveats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
6. Nicotine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.1. Evidence of abuse in humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.2. Mechanisms of action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.3. Nicotine-dopamine interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
6.4. Dopamine and nicotine self-administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
6.5. Caveats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
7. Summary/conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

1. Introduction ganglia, a circuit of nuclei that is responsible for the

Drug addiction is a chronically relapsing disorder
characterized by compulsion to use one or more drugs of
abuse, the inability to control drug intake and continued drug
use despite negative consequences (Leshner, 1997; Deroche-
Gamonet et al., 2004). Although many factors contribute to
drug addiction, drugs of abuse function as reinforcers, which
by definition causes repetition of drug taking, a necessary
precondition for the neuronal adaptations that constitute
addiction. The complex changes in the brain that underlie
addiction are just now beginning to be understood and there
are many excellent review articles addressing this topic (Koob,
2000; Hyman and Malenka, 2001; Nestler, 2002; Wolf, 2002;
Kalivas, 2004; Kauer, 2004; Kelley, 2004; Volkow et al.,
2004; Wise, 2004). Here, we focus on the reinforcing effects of
five major classes of abused drugs (psychostimulants, opiates,
ethanol, cannabinoids and nicotine), which we argue are at
least partly due to increased dopamine transmission in limbic
regions of the brain. Although these classes of drugs of abuse
have different primary sites and mechanisms of action, a
greater appreciation of the similarities among the effects of
different abused drugs will help to focus research on genetic/
physiological predispositions for drug abuse and the develop-
ment of potential treatment interventions for individuals at
high risk of addiction.
1.1. Dopaminergic modulation of the limbic system
Drugs of abuse produce their reinforcing effects
through actions in the limbic component of the basal
influence of motivational, emotional, contextual and
affective and information on behavior (see Fig. 1). Limbic
nuclei including the amygdala, hippocampus and medial
prefrontal cortex (mPFC) send major glutamatergic
projections to the nucleus accumbens, which is subdivided
in to limbic and motor subregions known as the shell and
core, respectively (Heimer et al., 1997). The nucleus
accumbens has two main outputs, which are GABAergic
projections to the ventral pallidum and ventral tegmental
area (VTA)/substantia nigra. Both the ventral pallidum
and VTA send GABAergic efferents to the medial dorsal
thalamus. Glutamatergic projections from the medial
dorsal thalamus to the mPFC close this limbic circuit
(for reviews see Alexander et al., 1990; Pierce and
Kalivas, 1997; Kalivas and Nakamura, 1999; Groenewe-
gen and Uylings, 2000; Zahm, 2000; Heimer, 2003).
Dopaminergic neurons in the VTA innervate the nucleus
accumbens, amygdala, hippocampus, mPFC and ventral
pallidum, and changes in dopaminergic transmission play
a critical role in modulating the flow of information
through the limbic circuit comprising these interconnected
nuclei (Napier and Maslowski-Cobuzzi, 1994; Carr et al.,
1999; Kalivas and Nakamura, 1999; Wise, 2002; Jay,
2003; Sesack et al., 2003).
The notion that brain dopamine systems play a critical
role in drug reinforcement is not new. In fact, the
dopamine hypothesis of drug reinforcement dates to the
late 1970s (Fibiger, 1978; Wise, 1978). Although a
number of caveats have been applied to this hypothesis
over the years, an overwhelming body of evidence
 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
Fig. 1. Limbic circuitry. Red arrows indicate glutamatergic pathways; black arrows indicate GABAergic pathways; blue arrows indicate dopaminergic
pathways. See text for additional details.
indicates that dopamine contributes at least partially to the
reinforcing effects of many abused drugs (Wise and
Bozarth, 1987; Wise, 2004). In the following sections we
will review the role of dopamine in the reinforcing effects
of five major classes of abused drugs: psychostimulants,
opiates, ethanol, cannabinoids and nicotine. There are
thousands of research articles focusing on the issue of
dopamine and drug reinforcement; therefore, our review
will not be comprehensive. The focus of this review is on
animal studies utilizing drug self-administration, which is
the most homologous model of human drug taking. In
self-administration studies, animals are trained to emit an
operant response (lever press, nose poke, wheel turn, etc.)
in order to obtain a drug reinforcer (typically administered
intravenously, but also in preparations that can be eaten,
smoked, etc.). In some instances, critical hypotheses have
been addressed only using paradigms that assess various
effects of abused drugs, such as conditioning to
environmental cues (studied with conditioned place
preference), subjective effects (drug discrimination),
intra-cranial self-stimulation or behavioral hyperactivity,
in which case evidence from these paradigms will be
presented.
217
2. Psychostimulants
2.1. Evidence of abuse in humans
Currently, the most widely abused psychostimulants
are cocaine, methamphetamine, and so-called club drugs
such as (G)3,4-methylenedioxymethamphetamine
(MDMA). In 2002, the number of U.S. citizens over the
age of 12 who used cocaine, methamphetamine or
MDMA during the previous month was estimated to be
2 million, 597,000 and 676,000, respectively (SAMHSA,
2003). Notably, there has been a particularly dramatic
increase in MDMA use in recent years, with new users
increasing from 168,000 in 1992 to 1.8 million in 2001
(SAMHSA, 2003).
2.2. Mechanisms of action
Psychostimulants produce euphoria, elation, mood
elevation, alertness, attention focusing, fatigue reduction
and appetite suppression through interactions with
biogenic amine transporters (Ritz et al., 1990; Johnson
et al., 1991; Rudnick and Wall, 1992). While cocaine
218 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
blocks the activity of dopamine, norepinephrine and
serotonin transporters, most amphetamine derivatives
promote the release of these biogenic amines by reverse
transport (Ritz et al., 1990; Seiden et al., 1993; Sulzer
et al., 1993). With either mechanism, the final result is to
increase extracellular levels of dopamine, serotonin and
norepinephrine.
2.3. Dopamine and psychostimulant reinforcement
Among the biogenic amine transporters, psychostimu-
lants do not have the highest affinity for the dopamine
transporter. The relative monoamine transporter affinity of
cocaine is serotoninOdopamineOnorepinephrine, whereas
d-amphetamine is norepinephrineOdopamineOserotonin
(Ritz and Kuhar, 1989). However, the reinforcing potency
of cocaine is correlated with its affinity at dopamine but not
serotonin or norepinephrine transporters (Ritz et al., 1987);
there is a similar, but less definitive, correlation with
d-amphetamine (Ritz and Kuhar, 1989). Moreover, selec-
tive dopamine re-uptake inhibitors are self-administered by
rodents and non-human primates (Ritz et al., 1987; Bergman
et al., 1989; Howell and Byrd, 1991; Roberts, 1993; Stafford
et al., 2001; Woolverton et al., 2001). In humans,
intravenous administration of cocaine at commonly abused
doses produced effective DAT inhibition, with a positive
correlation between levels of DAT occupancy and the
subjective effects (high) produce by cocaine (Volkow
et al., 1997). Taken together, these data strongly suggest that
increased dopamine transmission contributes significantly
to the reinforcing effects of psychostimulants.
Increased dopamine transmission in the nucleus accum-
bens in particular appears to play a critical role in the
maintenance of psychostimulant self-administration beha-
vior. Dopamine-depleting lesions in the nucleus accumbens,
but not the neostriatum, markedly attenuate self-adminis-
tration of cocaine or d-amphetamine (Lyness et al., 1979;
Roberts et al., 1980; Pettit et al., 1984; Caine and Koob,
1994a,b; Gerrits and Van Ree, 1996). In contrast, depletion
of forebrain norepinephrine does not influence cocaine self-
administration (Roberts et al., 1977). In vivo microdialysis
experiments demonstrate that the extracellular levels of
dopamine in the striatal complex (including the nucleus
accumbens) of rats and monkeys are increased during a
cocaine or d-amphetamine self-administration session, and
that during post-session extinction dopamine levels rapidly
return to baseline levels (Hurd et al., 1989; Pettit and
Justice, 1989; Di Ciano et al., 1995; Wise et al., 1995a,b;
Parsons et al., 1996; Hemby et al., 1997; Ranaldi et al.,
1999; Bradberry et al., 2000; Czoty et al., 2000). During
psychostimulant self-administration sessions, accumbal
dopamine levels reach a peak and then decline between
cocaine infusions. The decrease in accumbal dopamine
between injections triggers responding for cocaine or
amphetamine self-administration, presumably to maintain
extracellular dopamine above a threshold level (Wise et al.,
1995a,b; Ranaldi et al., 1999).
2.4. Dopamine receptors and psychostimulant
reinforcement
There are five dopamine receptors, designated D1
through D5. The dopamine receptors were classified as
D1-like (D1 and D5) or D2-like (D2, D3 and D4) based on
sequence homology and pharmacology (Civelli et al., 1993;
Seeman and Van Tol, 1993; Missale et al., 1998). Full D1-
like agonists are self-administered by rats (Self and Stein,
1992b, Self et al., 1996 but see also Caine et al., 1999a) and
monkeys (Weed and Woolverton, 1995; Grech et al., 1996;
Weed et al., 1997), with a correlation among compounds
tested between D1 agonist affinity and reinforcing potency
(Weed et al., 1997). Self-administration studies have
consistently shown that systemically administered D1-like
antagonists decrease the reinforcing efficacy of cocaine
(Woolverton, 1986; Koob et al., 1987; Bergman et al., 1990;
Spealman, 1990; Britton et al., 1991; Corrigall and Coen,
1991b; Hubner and Moreton, 1991; Caine and Koob, 1994a,
b; Winger, 1994; Platt et al., 2000). Similar to D1-like
dopamine receptors, D2-like agonists are self-administered
by rats (Wise et al., 1990; Caine et al., 1999b) and monkeys
(Woolverton et al., 1984; Sinnott et al., 1999; Ranaldi et al.,
2001) and D2-like antagonists reduce cocaine reinforcement
(Woolverton, 1986; Bergman et al., 1990; Britton et al.,
1991; Corrigall and Coen, 1991b; Hubner and Moreton,
1991; Caine and Koob, 1994a,b; Winger, 1994; Nader and
Mach, 1996; Caine et al., 2002) and d-amphetamine
reinforcement (Amit and Smith, 1992; Fletcher, 1998).
Taken together, these results indicate that both D1-like and
D2-like dopamine receptors play critical roles in psychos-
timulant reinforcement (for reviews of dopamine receptor
pharmacology and psychostimulant reinforcement see
Mello and Negus, 1996; Platt et al., 2002).
To date, no agonists or antagonists have been developed
that effectively distinguish between D1 and D5 receptors.
This lack of pharmacological specificity among D1-like
receptor ligands has significantly hindered the differen-
tiation of the respective roles of D1 and D5 dopamine
receptors in psychostimulant reinforcement. Although D1
and D5 knockout mice have been created, to date cocaine
self-administration has not been assessed in either of these
strains of transgenic animals. However, cocaine-induced
behavioral hyperactivity is attenuated in D1 dopamine
receptor knockout mice (Xu et al., 1994) and these animals
display increased thresholds for intra-cranial self-stimu-
lation (Tran et al., 2005). In D5 dopamine receptor knockout
mice, the behavioral hyperactivity produced by cocaine
(Elliot et al., 2003) and a D1/D5 agonist (Holmes et al.,
2001) is attenuated. In contrast, the discriminative stimulus
properties of cocaine are intact in D5 knockout mice (Elliot
et al., 2003). These results are not consistent with
experiments in which D5 dopamine receptor expression
 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
was decreased in adult rats with antisense oligodeoxynu-
cleotides (antisense ODNs). Thus, D5 receptor antisense
ODNs administered into the ventricles enhanced the
rotations induced by a D1/D5 agonist in unilateral dopamine
depleted rats (Dziewczapolski et al., 1998) and intra-
accumbal administration of D5 receptor antisense ODNs
disprupted the ability of rats to discriminate cocaine from
saline (Filip et al., 2000). Clearly, much work remains to be
done in order to differentiate the respective roles of D1 and
D5 dopamine receptors in psychostimulant reinforcement
(for a review of behavioral studies performed in various
dopamine receptor knockout mice see Holmes et al., 2004).
Similar problems have plagued research examining the
differential involvement of D2, D3 or D4 receptors in the
reinforcing effects of psychostimulants. There is evidence
that dopamine receptor agonists that are most selective for
D3 receptors are self-administered (Caine and Koob, 1993;
Nader and Mach, 1996; Sinnott et al., 1999) and modulate
cocaine reinforcement to a greater extent than D2 receptor-
selective compounds (Caine et al., 1997; Nader et al., 1999).
However, it has been suggested that none of these D2-like
dopamine agonists effectively distinguish between D2 and
D3 receptors in vivo (Burris et al., 1995). Moreover, neither
the D3/D4 selective antagonist L-745,829 nor the selective
D3 antagonist SB-277011-A influences cocaine self-
administration in rats (Caine et al., 2002; Di Ciano et al.,
2003). The highly selective D4 antagonist L-745,870 also
has no effect on cocaine self-administration (Caine et al.,
2002). Taken together these results indicate that D2
dopamine receptors play a primary role in cocaine
reinforcement with no conclusive evidence thus far linking
D3 or D4 receptors to the reinforcing effects of cocaine.
Recently, cocaine self-administration was assessed in D2
dopamine receptor knockout mice. Not only did the D2
receptor knockout mice readily self-administer cocaine,
their rates of consumption of higher doses of cocaine were
actually higher than wildtype controls (Caine et al., 2002).
Given the important role of D1-like receptors in cocaine
reinforcement, as outlined above, it is not surprising that D2
receptor knockout mice retain the ability to self-administer
cocaine. The increased intake of higher doses of cocaine in
mice lacking D2 receptors is likely due to compensatory
adaptations during development.
2.5. Dopamine receptors in limbic nuclei and
psychostimulant reinforcement
The behavioral pharmacological data presented above
indicate that both D1-like and D2 dopamine receptors play
critical roles in psychostimulant reinforcement. Several
dopaminoreceptive nuclei, particularly the nucleus accum-
bens, have been shown to be involved in psychostimulant
reinforcement. Thus, cocaine (McKinzie et al., 1999) and
d-amphetamine (Hoebel et al., 1983; Phillips et al., 1994) are
self-administered directly into the rat nucleus accumbens.
Moreover, cocaine is self-administered into the shell (limbic
219
portion), but not the core (striatal region), of the nucleus
accumbens (Goeders and Smith, 1983; Carlezon et al., 1995;
Rodd-Henricks et al., 2002; Ikemoto, 2003). Cocaine also is
self-administered directly into the olfactory tubercle (Ike-
moto, 2003). The reinforcing effect of intra-accumbal
cocaine appears to be due to increased dopamine trans-
mission. Thus, the selective dopamine reuptake inhibitor
nomifensine (Carlezon et al., 1995) or a combination of D1
and D2 dopamine receptor agonists (Ikemoto et al., 1997a)
were self-administered directly into the shell, but not the
core, of the nucleus accumbens (Ikemoto and Wise, 2004).
Moreover, intra-accumbal self-administration of cocaine and
amphetamine is blocked by co-infusion of D1-like or D2-like
dopamine receptor antagonists (Phillips et al., 1994; Rodd-
Henricks et al., 2002). Consistent with these findings,
microinjection of a D1-like antagonist into the nucleus
accumbens (Maldonado et al., 1993; McGregor and Roberts,
1993; Caine et al., 1995), but not the neostriatum (Caine et
al., 1995), attenuates the reinforcing effects of intravenously
self-administered cocaine.
The medial prefrontal cortex (mPFC) also appears to be
an important locus for cocaine reinforcement since rodents
can be trained to self-administer cocaine directly into the
mPFC (Goeders and Smith, 1983). In addition, adminis-
tration of a D1 receptor antagonist into the mPFC decreases
cocaine reinforcement (McGregor and Roberts, 1993). In
contrast to these findings, it was shown that rats will work
harder to receive cocaine following destruction of dopa-
minergic afferents to the mPFC with 6-OHDA (McGregor et
al., 1996). Similarly, self-administration of normally
subthreshold doses of cocaine were observed following
depletion of mPFC dopamine in rats (Schenk et al., 1991 but
see also Martin-Iverson et al., 1986). Collectively, these
data indicate that dopamine in the mPFC appears to
modulate cocaine reinforcement; however, the precise role
of mPFC dopamine in cocaine self-administration remains
to be fully elucidated.
Finally, there is some evidence that increased dopamine
transmission in the amygdala and VTA contributes to
cocaine reinforcement. Thus, d-amphetamine is self-
administered into the central nucleus of the amygdala
(Chevrette et al., 2002) and administration of a D1 receptor
antagonist directly into the amygdala decreases cocaine
reinforcement (McGregor and Roberts, 1993; Caine et al.,
1995). However, lesions of dopaminergic input to the
amygdala appears to enhance cocaine reinforcement
(Deminiere et al., 1988; McGregor et al., 1994). In terms
of the VTA, administration of a D1-like receptor antagonist
into this nucleus reduced cocaine reinforcement in rats
(Ranaldi and Wise, 2001)
Taken together, these results indicate that altering
dopamine transmission in several nuclei modifies cocaine
self-administration behavior. Although there is considerable
evidence that the mPFC and amygdala contribute to cocaine
reinforcement, there are several inconsistencies among the
studies focused on these nuclei that have yet to be resolved.
220 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
In contrast, the experiments examining the nucleus
accumbens have produced data that are consistent with
increased dopamine transmission in this structure playing a
critical role in cocaine reinforcement.
2.6. Cocaine self-administration in DAT knockout mice
Given the overwhelming evidence from numerous
behavioral pharmacological, neurochemical and biochemi-
cal studies indicating that psychostimulant action at the
DAT is the primary mechanism underlying psychostimulant
reinforcement, it is very surprising that mutant mice lacking
the DAT are able to self-administer cocaine even though
cocaine has no effect on extracellular dopamine levels in the
neostriatum of these mice (Rocha et al., 1998). However, as
reviewed above, increased dopamine transmission in the
nucleus accumbens rather than the neostriatum is linked to
cocaine reinforcement. Subsequently, cocaine was shown to
increase extracellular dopamine levels in the nucleus
accumbens of DAT knockout mice (Carboni et al., 2001;
Mateo et al., 2004). Since the NET is known to clear
dopamine (Carboni et al., 1990; Tanda et al., 1997b) and the
NET is expressed in the nucleus accumbens shell but not the
core or neostriatum (Berridge et al., 1997), it was suggested
that cocaine-induced NET inactivation increases dopamine
transmission in the nucleus accumbens shell of DAT
knockout mice (Carboni et al., 2001). Consistent with this
hypothesis, administration of a selective NET inhibitor
increased extracellular dopamine levels in the nucleus
accumbens shell of DAT knockout but not wildtype mice
(Carboni et al., 2001), which suggests that there is a
compensatory change in NET regulation of extracellular
dopamine in the accumbens shell of mice lacking the DAT.
Others, however, failed to demonstrate elevations in
accumbal dopamine in DAT knockout mice following
administration of a NET inhibitor (Mateo et al., 2004).
Pharmacological inhibition of the SERT, in contrast,
increased extracellular dopamine in the nucleus accumbens
of DAT knockout mice to a similar extent as cocaine, which
was suggested to result from adaptations in serotonin
regulation of dopaminergic neuronal activity in the VTA of
these mutant mice (Mateo et al., 2004). Although these are
compelling hypotheses, it remains to be determined which
neuronal adaptations occur in DAT knockout mice to allow
cocaine to increase accumbal dopamine (for review see
Gainetdinov and Caron, 2003). It is important to emphasize
that while cocaine self-administration in DAT knockout
mice was initially interpreted as a major blow to the
dopamine hypothesis of the reinforcing properties of
cocaine, results from experiments using these mutant mice
ultimately support a major tenet of the dopamine hypothesis
- that increased dopamine transmission in the limbic system,
and the nucleus accumbens shell in particular, underlies
cocaine reinforcement.
2.7. Norepinephrine, serotonin and cocaine reinforcement
The fact that dopamine plays a central role in
psychostimulant reinforcement does not rule out contri-
butions from the norepinephrine and serotonin systems. The
available evidence indicates that although increased
norepinephrine transmission may be involved in the
discriminative stimulus effects of cocaine (Spealman,
1995), norepinephrine does not contribute significantly to
the reinforcing effects of this psychostimulant (Woolverton,
1987; Mello et al., 1990). The role of serotonin in cocaine
reinforcement is complex. Selective SERT inhibitors do not
maintain self-administration (Gold and Balster, 1991;
Vanover et al., 1992; Roberts et al., 1999). In fact, direct
and indirect serotonin agonists have been shown to attenuate
cocaine reinforcement (Richardson and Roberts, 1991;
Grottick et al., 2000a; Czoty et al., 2002) and cocaine-
induced increases in striatal dopamine (Czoty et al., 2002).
As reviewed above, psychostimulants increase serotonin
transmission in the brain, including the VTA and the
nucleus accumbens (Parsons et al., 1995; Reith et al., 1997).
Stimulation of 5-HT2C receptors in the VTA decreases the
firing rate of dopaminergic neurons and reduces extracellu-
lar dopamine levels in the nucleus accumbens (Di Matteo
et al., 2000; Gobert et al., 2000; Di Giovanni et al., 2001).
Collectively, these results suggest that cocaine-induced
increases in serotonin transmission in the VTA inhibit the
neurochemical and behavioral effects of cocaine via
stimulation if 5-HT2C receptors on dopaminergic neurons.
Consistent with this hypothesis, cocaine reinforcement and
cocaine-induced increases in accumbal dopamine were
enhanced in 5-HT2C knockout mice (Rocha et al., 2002).
In direct contrast to the results with 5-HT2C receptors,
administration of 5-HT1B receptor agonists enhances
cocaine-induced reinforcement (Parsons et al., 1998) and
increases in extracellular accumbal dopamine (Parsons et al.,
1999). Since 5-HT1B receptors are found on GABAergic
terminals in the VTA and stimulation of these receptors
decreases GABA release, it was suggested that stimulation of
5-HT1B receptors in the VTA increases the firing rate of
dopaminergic neurons in the VTA through disinhibition
resulting in increased dopamine release in the nucleus
accumbens (Parsons et al., 1999). Consistent with this notion,
elevated expression of 5-HT1B receptors in GABAergic
neurons that project from the nucleus accumbens to the VTA
increases cocaine-induced behavioral hyperactivity and
cocaine-conditioned place preference (Neumaier et al.,
2002). Taken together these data indicate that increased
serotonin transmission in the VTA influences cocaine
reinforcement, with opposing effects of 5-HT1B and
5-HT2C receptors, which are by far the best characterized
of the serotonin receptors in terms of interactions with
dopamine systems. It is important to emphasize that the
effects of increased serotonin transmission on cocaine
reinforcement result from modulation of mesoaccumbal
 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
dopamine transmission, which provides further support for
the dopamine hypothesis of psychostimulant reinforcement.
3. Opiates
3.1. Evidence of abuse in humans
The abuse of opiates (morphine-like drugs) remains
a significant public health problem. Indeed, since the
mid-1990s, the use of heroin increased among both youths
and young adults (SAMHSA, 2003). In 2002, there were an
estimated 4.4 million regular users of opiates for non-
medical purposes in the U.S. and the number of new heroin
users reached levels not seen since the late 1970s
(SAMHSA, 2003). Although heroin (diacetyl morphine) is
the most widely abused opiate, in recent years abuse of
OxyContin, the controlled release form of oxycodone, has
increased markedly (SAMHSA, 2003).
3.2. Mechanisms of action
Opiates are direct opioid receptor agonists, mimicking
the effects of the endogenous opioids (endorphins,
enkephalins, dynorphins, endomorphins) at m, k and/or d
opioid receptors (DeVries and Shippenberg, 2002). Stimu-
lation of these opioid receptors leads to a variety of effects,
including euphoria, analgesia, sedation, diuresis, miosis,
constipation and/or respiratory depression (Gutstein and
Akil, 2001). Of the opioid receptors, stimulation of m opioid
receptors is mainly responsible for the reinforcing effects of
morphine-like opiates, although d opioid receptors also may
contribute to opiate reinforcement (Self and Stein, 1992a,
Mello and Negus, 1996; DeVries and Shippenberg, 2002). m
opioid receptors are widely distributed in the CNS,
including relatively heavy expression in the VTA and
nucleus accumbens (German et al., 1993; Mansour et al.,
1995; Svingos et al., 1996).
3.3. Dopamine and opiate reinforcement
The meso-accumbens dopamine pathway appears to play
an important role in opiate reinforcement since rats will self-
administer opioids directly into the VTA (Bozarth and
Wise, 1981; Devine and Wise, 1994) or nucleus accumbens
(Olds, 1982; Goeders et al., 1984). Moreover, kainic acid
lesions of accumbal cell bodies disrupt opiate self-
administration (Zito et al., 1985; Dworkin et al., 1988b).
Opioid self-administration directly into the nucleus accum-
bens appears to occur without influencing dopamine release
in this nucleus. Thus, pretreatment with the D2/D3
dopamine receptor antagonist, sulpiride, had no effect on
intra-accumbal morphine self-administration (David et al.,
2002). Rather, the reinforcing effect of opioids administered
into the nucleus accumbens appears to result from either
direct inhibition of GABAergic accumbal output neurons
221
(Hakan and Henriksen, 1989; Lee et al., 1999) or inhibition
of transmitter release from accumbal glutamatergic term-
inals (Jiang and North, 1992).
In contrast, a substantial literature suggests that opiate
self-administration into the VTA relies on the activation of
the meso-accumbens dopamine system. In the VTA, only a
very small percentage of dopaminergic neurons express m
opioid receptors (Dilts and Kalivas, 1989; Garzon and
Pickel, 2001). Therefore, m opioid receptors in the VTA
most likely influence dopaminergic transmission indirectly.
A growing body of evidence indicates that stimulation of m
opioid receptors inhibits GABA release in the VTA, which
disinhibits dopaminergic neurons resulting in enhanced
dopamine release in the nucleus accumbens. Consistent with
this hypothesis, (i) m opioid receptors in the VTA are found
mainly on the axon terminals of inhibitory neurons, many of
which synapse onto dopaminergic neurons (Garzon and
Pickel, 2001; Svingos et al., 2001; Garzon and Pickel,
2002), (ii) opioids have no direct effect on dopaminergic
neurons, but hyperpolarize GABAergic interneurons
(Johnson and North, 1992), (iii) the local administration of
m opioid receptor agonists into the VTA increases the firing
rate of dopaminergic neurons (Gysling and Wang, 1983;
Matthews and German, 1984), (iv) administration of opiates
directly into the VTA promotes dopamine release in the
nucleus accumbens (Spanagel et al., 1992) and (v)
administration of a GABAergic agonist impairs dopamine
release in the nucleus accumbens initiated by intra-VTA
administration of a m opioid receptor agonist (Kalivas et al.,
1990).
3.4. Dopamine and opiate self-administration
Studies using the self-administration paradigm indicate
that dopamine plays an important role in opiate reinforce-
ment. Destruction of dopaminergic inputs to the nucleus
accumbens impairs the acquisition of heroin self-adminis-
tration (Singer and Wallace, 1984) and decreases morphine
reinforcement (Smith et al., 1985). Consistent with these
findings, intra-VTA morphine self-administration was
disrupted by administration of the D2/D3 receptor antag-
onist, sulpiride (David et al., 2002). In addition, morphine
self-administration was not observed in D2 dopamine
receptor knockout mice (Elmer et al., 2002).
The hypothesis that opiate reinforcement is at least
partially due to the disinhibition of dopaminergic neurons in
the VTA also was confirmed in experiments using the self-
administration paradigm. Thus, during heroin self-adminis-
tration there is an increase in the firing rate of dopaminergic
neurons in the VTA (Kiyatkin and Rebec, 1997; Kiyatkin
and Rebec, 2001) and an increase in dopamine release in the
nucleus accumbens (Wise et al., 1995a,b). Moreover,
pharmacological increase in GABA transmission in the
VTA impair the both the reinforcing effect of heroin and
heroin-induced increases in accumbal dopamine (Xi and
Stein, 1999; Xi and Stein, 2000). Finally, rodents can be
222 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
trained to self-administer a GABAA antagonist directly into
the VTA (David et al., 1997; Ikemoto et al., 1997d), an
effect that is extinguished by pretreatment with a D2
dopamine receptor antagonist (David et al., 1997).
3.5. Caveats
Despite this evidence, the viewpoint that opiate reward
is at least partially dopamine-dependent is not universally
embraced. For example, several reports indicate that
dopamine receptor antagonists do not consistently alter
opiate self-administration behavior (Ettenberg et al., 1982;
Van Ree and Ramsey, 1987; Gerber and Wise, 1989;
Gerrits et al., 1994). Similarly, multiple studies showed no
effect of nucleus accumbens dopamine depletion on heroin
or morphine self-administration behavior in rats (Pettit et
al., 1984, Dworkin et al., 1988a, Gerrits and Van Ree,
1996). In addition, an in vivo microdialysis study
demonstrated that noncontingent heroin administration
increased extracellular dopamine levels in the nucleus
accumbens, whereas self-administered heroin had no
effect (Hemby et al., 1995). It could be argued that self-
administration behavior under these experimental circum-
stances was maintained by m opioid receptor stimulation
in the nucleus accumbens that, as reviewed above, is
reinforcing in a dopamine-independent manner. In other
words, dopamine-dependent opiate reinforcement may be
demonstrated under specific experimental circumstances,
but opiate reinforcement does not rely completely on
activation of the mesolimbic dopamine system.
Recent evidence indicates that cannabinoids also play a
role in opiate reinforcement. Administration of a CB1
cannabinoid receptor antagonist attenuates heroin self-
administration (Navarro et al., 2001; Caille and Parsons,
2003; De Vries et al., 2003) and mice lacking CB1 receptors
do not acquire morphine self-administration (Ledent et al.,
1999; Cossu et al., 2001). Based on these findings, it seemed
possible that cannabinoid receptors exerted their influence
on opiate reinforcement via interactions with the mesoac-
cumbal dopamine system since CB1 agonists increase the
firing rate of dopaminergic neurons in the VTA and enhance
extracellular dopamine levels in the nucleus accumbens
(French, 1997; Tanda et al., 1997a). However, a recent study
showed that a CB1 antagonist reduced heroin self-
administration but had no influence on heroin-induced
increases in accumbal dopamine (Caille and Parsons, 2003),
which indicates that cannabinoids modulate opiate self-
administration in a dopamine-independent manner.
4. Ethanol
4.1. Evidence of abuse in humans
Ethanol is by far the most widely used drug in the world
today. In the U.S. the use of ethanol is greater than all other
drugs of abuse (including tobacco) combined (SAMHSA,
2003), which undoubtedly is due to the fact that ethanol use
is not regulated among adults in this country. Although most
ethanol users can be characterized as casual drinkers, the
abuse rate of ethanol is substantial. It is estimated that 7.9%
of the U.S. population age 12 or older is in need of treatment
for alcoholism, more than twice the percentage of the
population estimated to require treatment for the abuse of all
illicit drugs collectively (SAMHSA, 2003).
4.2. Mechanisms of action
Ethanol produces a wide range of effects on both
excitatory and inhibitory systems in the brain, which
combine to produce the characteristic mood elevating,
anxiolytic, sedative and ataxic effects of ethanol. Ethanol
positively modulates GABAA receptors, inhibits NMDA
and kainate glutamate receptors, has both inhibitory and
excitatory effects at nicotinic acetylcholine receptors,
enhances the activity of calcium-activated potassium
channels, inhibits N- and P/Q-type calcium channels, and
modulates inwardly rectifying potassium channels (Fleming
et al., 2001; Davies, 2003).
4.3. Effects of ethanol on mesolimbic dopamine
transmission
A growing body of evidence indicates that ethanol
enhances dopamine release in the nucleus accumbens (Di
Chiara and Imperato, 1988; Yim and Gonzales, 2000;
Gonzales et al., 2004). However, administration of
concentrations of ethanol into the nucleus accumbens
comparable to those that would be expected following
moderate intoxication had no effect on extracellular
dopamine levels (Yim et al., 1998; Budygin et al., 2001),
which suggests that ethanol may facilitate dopamine release
in the nucleus accumbens by increasing the firing rate of
dopaminergic neurons in the VTA (Gessa et al., 1985;
Brodie et al., 1990; Bunney et al., 2001). There are several
potential means through which ethanol might influence the
firing rate of dopaminergic neurons. The best studied are the
actions of ethanol on potassium channels and GABAA
receptors in the VTA. In terms of potassium channels, the
excitation of dopaminergic neurons in the VTA by ethanol
appears to be due to the reduction of potassium currents
leading to the attenuation of afterhyperpolarizations
following spontaneous action potentials (Brodie et al.,
1999; Appel et al., 2003). In contrast, stimulation of
GABAA receptors in the VTA appears to affect dopamin-
ergic neuronal activity indirectly. GABAA receptors are
found on GABAergic interneurons in the VTA and it has
been suggested that stimulation of these receptors by lower
doses of ethanol or a GABAA agonist disinhibits dopamin-
ergic neuronal activity (Mereu and Gessa, 1985; Kalivas
et al., 1990; Klitenick et al., 1992 but see also Stobbs et al.,
2004). However, GABAA receptors also are expressed by
 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
dopaminergic cells in the VTA (Okada et al., 2004) and
these neurons are inhibited by the local administration of
higher doses of a GABAA agonist (Westerink et al., 1996).
Taken together, these results suggest that, in the VTA,
GABAergic interneurons are more sensitive to the effects of
GABAA agonists than dopaminergic cells, a proposition that
is supported by electrophysiological studies (Grace and
Bunney, 1979). The differential sensitivity of GABAergic
and dopaminergic neurons in the VTA to GABAA agonists
is consistent with the fact that lower doses of ethanol
produce CNS stimulation, whereas higher doses induce
CNS depression.
4.4. Dopamine and ethanol self-administration
These results, collectively, suggest that ethanol-induced
increases in the firing rates of dopaminergic neurons in the
VTA and the subsequent increased release of dopamine in
the nucleus accumbens may underlie the reinforcing
properties of this drug. There are several lines of evidence
that are consistent with this proposition. For example,
ethanol is self-administered directly into the VTA by rats
(Gatto et al., 1994; Rodd-Henricks et al., 2000), an effect
that is blocked by the stimulation of dopaminergic
autoreceptors in the VTA (Rodd et al., 2004). In addition,
ethanol self-administration results in enhanced dopamine
release in the nucleus accumbens of rodents (Weiss et al.,
1993; Weiss et al., 1996; Gonzales and Weiss, 1998; Nurmi
et al., 1998; Olive et al., 2000; Melendez et al., 2002;
Hungund et al., 2003) and rhesus monkeys (Bradberry,
2002).
Very few studies have addressed the role of GABA-
dopamine interactions in the VTA in ethanol self-
administration, and the available evidence is contradictory.
Thus, administration of a GABAA agonist directly into the
VTA had no influence ethanol self-administration (Hodge
et al., 1996). However, intra-VTA injection of a GABAA
antagonist decreased ethanol consumption in rats (Nowak
et al., 1998) perhaps by increasing dopamine release in the
nucleus accumbens (Ikemoto et al., 1997b). Clearly,
additional research is required to determine the precise
physiological substrates (potassium channels, GABAA
receptors, others), neurochemical interactions and the
critical dose range that, combined, result in ethanol-induced
activation of the mesoaccumbal dopamine system, which
plays an important role in maintainance of ethanol self-
administration.
4.5. Dopamine receptors and ethanol self-administration
A number of studies indicate that ethanol self-adminis-
tration is modified by pretreatment with D1-like and D2-like
dopamine receptor agonists and antagonists (Pfeffer and
Samson, 1988; Weiss et al., 1990; Hubbell et al., 1991; Dyr
et al., 1993; Rassnick et al., 1993a, Ng and George, 1994;
Silvestre et al., 1996; Cohen et al., 1998; Cohen et al., 1999;
223
Boyce and Risinger, 2002; DSouza et al., 2003; Zocchi
et al., 2003). Moreover, administration of D1-like (Hodge
et al., 1997) or D2-like (Rassnick et al., 1992; Samson et al.,
1993; Hodge et al., 1997; Samson and Chappell, 2003)
dopamine receptor antagonists directly into the nucleus
accumbens reduces ethanol self-administration in rats. More
recently, ethanol self-administration was assessed in mice in
which dopamine receptor expression had been modified.
Ethanol self-administration was reduced in mice with
genetic deletion of D1 (El-Ghundi et al., 1998) or D2
(Phillips et al., 1998; Risinger et al., 2000; Risinger et al.,
2000) dopamine receptors relative to wildtype controls. In
contrast, D3 dopamine receptor knockout mice displayed
normal levels of ethanol self-administration (Boyce-Rustay
and Risinger, 2003; McQuade et al., 2003). Consistent with
the findings from D2 knockout mice, antisense olginucleo-
tide-induced decreases in D2 dopamine receptor expression
in the nucleus accumbens suppress ethanol self-adminis-
tration (Myers and Robinson, 1999). Curiously, using a two-
bottle choice paradigm similar to Myers and Robinson
(1999), overexpression of D2 dopamine receptors by an
adenoviral vector injected into the nucleus accumbens also
reduced ethanol self-administration (Thanos et al., 2001;
Thanos et al., 2004). Collectively, these data indicate that
accumbal D1 and D2 dopamine receptors play critical roles
in ethanol reinforcement. Interestingly, alcoholics have
reduced levels of striatal D2 dopamine receptors (Volkow
et al., 1996), which may result in compensatory increases in
ethanol intake (Blum et al., 1996; Volkow et al., 1996).
4.6. Caveats
The dopamine hypothesis of the reinforcing effects of
ethanol is not, however, supported by lesion studies.
Destruction of dopaminergic afferents to the nucleus
accumbens has no influence on the maintenance of ethanol
self-administration in rats (Lyness and Smith, 1992;
Rassnick et al., 1993b, Ikemoto et al., 1997c, Koistinen
et al., 2001). Similarly, not all reports have shown consistent
effects of dopaminergic ligands on ethanol self-adminis-
tration (Goodwin et al., 1996; Silvestre et al., 1996). It has
been suggested, in fact, that increases in accumbal
dopamine transmission are responsible only for the CNS
stimulant effects of lower doses of ethanol (Weiss and
Porrino, 2002).
Ethanol reinforcement is particularly difficult to model in
animals since humans consume ethanol for its positive
reinforcing (CNS stimulation) or negative reinforcing
(anxiety reducing) effects, or both. Moreover, the physio-
logical substrates for these effects are likely to be different
and potentially multidimensional given the diverse phar-
macological effects of ethanol (see above). Indeed, a wide
variety of neurotransmitters, including opioids (Koob et al.,
2003), cannabinoids (Mechoulam and Parker, 2003),
serotonin (McBride et al., 1989), and norepinephrine
(Amit and Brown, 1982; Corcoran et al., 1983), in addition
224 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
to GABA (Chester and Cunningham, 2002) and dopamine
(Weiss and Porrino, 2002), as well as various interactions
among these transmitter systems, have been implicated in
ethanol reinforcement. Although ethanol reinforcement may
be particularly complex, the preponderance of the available
evidence indicates that activation of the mesoaccumbal
dopamine system contributes significantly to the mainten-
ance of ethanol self-administration.
5. Cannabinoids
5.1. Evidence of abuse in humans
Marijuana, which is derived from the hemp plant
Cannabis sativa, is the most commonly used illicit drug
(SAMHSA, 2003). In 2002, it was estimated that 14.6
million Americans (or 6.2% of the U.S. population) had
used marijuana at least once in the month prior to being
surveyed. Approximately one third of these were heavy
users, reporting marijuana intake on twenty or more days
during the previous month. A similar number (4.29 million)
of U.S. citizens were characterized as marijuana abusers
(SAMHSA, 2003).
5.2. Mechanisms of action
Marijuana smoke contains numerous compounds, includ-
ing around sixty cannabinoids (Ameri, 1999). However,
there is general consensus that D9-tetrahydrocannabinol (D9-
THC) is primarily responsible for the psychoactive effects of
marijuana, which include euphoria, enhanced sensory
perception, increased appetite, analgesia, memory impair-
ment, anxiety, paranoia and, at higher doses, sedation
(Ameri, 1999; van der Stelt and Di Marzo, 2003).
Cannabinoids appear to mimic the action of endogenous
cannabinoids (endocannabinoids) in the brain. Although
anandamide and 2-arachidonoylglycerol are the best
characterized of the endocannabinoids, this class of
compounds also includes 2-arachidonoylglycerol ether,
N-arachidonoyldopamine and O-arachinonylethanolamine
(van der Stelt and Di Marzo, 2003). Both exogenous and
endogenous cannabinoids produce their physiological effects
by interacting with cannabinoid receptors, which include
CB1 and CB2 subtypes. CB1 receptors are expressed in the
brain and in certain peripheral tissues; CB2 receptors, in
contrast, are found only in the immune system (Howlett et al.,
1990; Pertwee, 1997). Therefore, the psychoactive effects of
D9-THC are due to interactions with CB1 receptors.
5.3. Cannabinoid-dopamine interactions
Unlike classical neurotransmitters, endocannabinoids are
not stored in vesicles but are synthesized and released on
demand (van der Stelt and Di Marzo, 2003). In the CNS,
endocannabinoids act as retrograde messengers, inhibiting
the release of classical neurotransmitters via the stimulation
of presynaptic CB1 receptors following release from the
postsynaptic neuron (Ralevic, 2003). The CB1 receptor is
one of the most abundant and widely distributed neuro-
transmitter receptors in the brain (Ameri, 1999). There is
moderate expression of CB1 receptors in the VTA and
nucleus accumbens (Herkenham et al., 1991; Julian et al.,
2003), with significantly greater abundance of CB1 positive
terminals in the nucleus accumbens shell relative to the core
(Pickel et al., 2004).
CB1 receptors are not, however, found on dopaminergic
terminals or cell bodies (Herkenham et al., 1991; Mailleux
and Vanderhaeghen, 1992; Julian et al., 2003). Nonetheless,
the systemic administration of D9-THC or CB1 receptor
agonists has been shown to increase dopamine release in the
nucleus accumbens (Chen et al., 1991; Tanda et al., 1997a,
Cheer et al., 2004). Moreover, cannabinoid-induced
increases in accumbal dopamine are restricted to the shell
subregion of the nucleus accumbens (Tanda et al., 1997a),
which may explain a lack of effect of D9-THC on accumbal
dopamine release in studies that did not distinguish between
the accumbens shell and core (Castaneda et al., 1991). It has
been suggested that, similar to opioids (see above),
stimulation of CB1 receptors on GABAergic terminals in
the VTA disinhibits dopaminergic neuronal activity
resulting in increased dopamine release in the nucleus
accumbens. Consistent with this hypothesis, systemic
cannabinoid administration increased the firing rate of
dopaminergic neurons in the VTA, an effect that was
blocked by CB1 antagonists (French et al., 1997; French,
1997; Gessa et al., 1998; Cheer et al., 2000; Wu and French,
2000; Cheer et al., 2003). Interestingly, the cannabinoid-
induced increase in dopaminergic neuronal activity was
blocked by a GABAA receptor antagonist (Cheer et al.,
2000). Moreover, GABAA receptor-mediated inhibitory
postsynaptic currents in VTA dopaminergic neurons were
decreased following administration of a cannabinoid
receptor agonist (Szabo et al., 2002). These results,
collectively, indicate that cannabinoids increase the firing
rates of dopaminergic neurons by decreasing inhibitory
GABAergic tone on these cells. However, it should be noted
that cannabinoids also inhibit glutamatergic transmission in
the VTA via a presynaptic mechanism (Melis et al., 2004),
which could counterbalance the disinhibitory effect of
cannabinoid-induced decreases in GABA release on
dopaminergic neuronal activity in the VTA.
5.4. Cannabinoid self-administration
Demonstration of reliable self-administration of D9-THC
in animal models has proven difficult. Indeed, numerous
studies performed over the past thirty years have failed to
show robust self-administration of D9-THC or cannabinoid
agonists in animal models (as reviewed by Maldonado and
Rodriguez de Fonseca, 2002; Tanda and Goldberg, 2003).
There are several potential reasons for the failure of
 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
cannabinboids to support self-administration. For example,
the pharmacokinetics of cannabinoids are not suited for
operant studies. Cannabinoids have a slow onset of action,
thus impairing the association between the operant response
and the reinforcing effect, which is necessary for the operant
response to be repeated. The psychotropic effects of
cannabinoids also are long lasting, which decreases the
overall rate of self-administration. These pharmacokinetic
characteristics are directly opposed to drugs that are readily
self-administered by animals. Cocaine, for example, readily
and rapidly gains access to the brain and this drug has a
relatively short half-life, which facilitates the rapid
acquisition and maintenance of cocaine self-administration
across a variety of species. The development of a reliable
animal model of cannabinoid self-administration is further
complicated by the fact that higher doses of cannabinoids
produced sedation and may be aversive (for review see
Maldonado and Rodriguez de Fonseca, 2002; Tanda and
Goldberg, 2003).
Despite these technical difficulties, cannabinoid self-
administration has been demonstrated, with early studies
dating to the late 1970s (Takahashi and Singer, 1979;
Takahashi and Singer, 1980). These and more recent
demonstrations of cannabinoid self-administration by
rodents (Martellotta et al., 1998; Ledent et al., 1999; Braida
et al., 2001; Fattore et al., 2001; Navarro et al., 2001) are
problematic since food or water deprivation were required
for cannabinoid self-administration to be maintained. A
recent study using squirrel monkeys as subjects demon-
strated D9-THC self-administration in the absence of food
restriction (Tanda et al., 2000). In this study, D9-THC self-
administration was abolished by treatment with a CB1
receptor antagonist (Tanda et al., 2000). However, the
monkeys used in this study had a previous history of cocaine
self-administration (Tanda et al., 2000), which could have
resulted in neuroadaptations that facilitated the subsequent
self-administration of D9-THC (Maldonado, 2002). Sub-
sequently, however, robust self-administration of D9-THC
was demonstrated in drug nave squirrel monkeys with
free access to food and water (Justinova et al., 2003;
Justinova et al., 2004). The overall lack of consistent self-
administration of cannabinoids in animal models suggests
that D9-THC may not be as reinforcing as other drugs of
abuse, such as cocaine or heroin. However, as reviewed
above, marijuana abuse is prevalent in humans. The fact that
unambiguous cannabinoid self-administration has thus far
only been demonstrated in monkeys may point to
differences in pharmacokinetics and/or pharmacodynamics
between rodents and primates (Maldonado and Rodriguez
de Fonseca, 2002). It should also be noted, finally, that the
experiments in which D9-THC was self-administered by
monkeys, a number of variables were systematically varied
in order to obtain reliable self-administration (Tanda et al.,
2000). Thus, procedural differences between primate and
rodent studies may account for the general lack of robust
cannabinoid self-administration in rats and mice. Indeed, it
225
has been suggested that the doses of cannabinoids used in
many self-administration studies are in a range that would
be expected to produce aversive and/or anxiogenic effects
(Carriero et al., 1998; Tanda and Goldberg, 2003).
5.5. Opioid-dopamine interactions and cannabinoid
self-administration
A growing body of evidence indicates that there are
functional interactions between cannabinoid and opioid
systems in several physiological processes, including the
regulation of the activity of the mesoaccumbal dopamine
system (Manzanares et al., 1999). For example, systemic
or intra-VTA administration of an opiate antagonist
attenuates the ability of D9-THC to increase accumbal
dopamine (Chen et al., 1990; Tanda et al., 1997a). These
results imply that opiates and cannabinoids cooperate in
the regulation of dopaminergic neuronal activity in the
VTA. As reviewed previously, cannabinoid and opioid
receptors are expressed by GABAergic terminals in the
VTA and stimulation of these receptors disinhibits
dopaminergic neuronal activity. However, D9-THC-
induced increases in dopaminergic neuronal activity in
the VTA were not influenced by pretreatment with an
opioid antagonist (French, 1997). Although the precise
mechanisms underlying cannabinoid-opioid interactions in
the mesoaccumbal dopamine system remain unclear,
behavioral studies indicate that opioids contribute to
cannabinoid reinforcement. Thus, administration of an
opioid receptor antagonist impaired the self-administration
of CB1 receptor agonists (Braida et al., 2001; Navarro
et al., 2001) or D9-THC (Tanda et al., 1997a, Justinova
et al., 2004). Moreover, an opioid antagonist significantly
decreased the intra-cerebroventricular self-administration
of D9-THC in rats (Braida et al., 2004).
5.6. Caveats
The data presented above suggest that cannabinoids
increase dopamine release in the nucleus accumbens by
enhancing the firing rate of dopaminergic neurons in the
VTA. However, not all results are consistent with this
conclusion. For example, intravenous administration of
D9-THC has no influence on the firing rate of dopaminergic
neurons in this nucleus (Gifford et al., 1997). Moreover,
administration of D9-THC directly into the nucleus
accumbens, but not the VTA, increases dopamine release
in the nucleus accumbens (Chen et al., 1993). These results,
collectively, suggest that a local action of cannabinoids in
the nucleus accumbens enhances dopamine release in this
structure (Gardner and Vorel, 1998). Since dopaminergic
terminals in the nucleus accumbens do not express CB1
receptors (Herkenham et al., 1991), the mechanism whereby
local cannabinoid application increases accumbal dopamine
must be indirect, possibly involving the modulation of
226 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
accumbal glutamatergic and/or GABAergic transmission
(Szabo et al., 1998; Robbe et al., 2001).
Although there is general agreement that activation of the
mesolimbic dopamine system plays an important role in
cannabinoid reinforcement (Maldonado and Rodriguez de
Fonseca, 2002; Tanda and Goldberg, 2003; Lupica et al.,
2004), critical experiments confirming this hypothesis have
not yet been performed because of the lack of a reliable
animal model of cannabinoid self-administration. Important
experiments that remain to be performed include: (i)
determining the effects of dopamine agonists and antagon-
ists, administered either systemically or directly into the
VTA or nucleus accumbens, on cannabinoid self-adminis-
tration; (ii) evaluating the effect of self-administered
cannabinoids on the firing rates of dopaminergic neurons
in the ventral midbrain; and (iii) assessing changes in
dopamine transmission in the nucleus accumbens and other
limbic nuclei during cannabinoid self-administration.
6. Nicotine
6.1. Evidence of abuse in humans
It is estimated that 71.5 million Americans (or
approximately 30% of the U.S. population over age 12)
are regular consumers of a tobacco product, including
cigarettes, cigars, pipes and smokeless tobacco (SAMHSA,
2003). The risk of addiction, defined as the percentage of
people ultimately characterized as addicts among those that
have ever tried a specific drug, is particularly high for
tobacco relative to all other abused substances (OBrien,
2001). Although this high addiction risk may be related to
the fact that tobacco use is legal among American adults, the
addiction risk of tobacco also is over twice that of alcohol
(31.9% relative to 15.4%) (OBrien, 2001). Tobacco use
increases the risk of cardiovascular diseases, stroke and
cancer. Indeed, world-wide, the number of deaths attributed
to smoking is second only to malaria (Mansvelder and
McGehee, 2002).
6.2. Mechanisms of action
Tobacco contains at least 4,000 separate chemical
compounds. However, the principal psychoactive com-
pound found in tobacco is nicotine, which is responsible for
mediating its reinforcing effects (Di Chiara, 2000; Man-
svelder and McGehee, 2002; Picciotto, 2003). The
psychoactive effects of nicotine, which include mood
elevation, decreased anxiety, decreased appetite, muscle
relaxation, increased arousal, improved attentiveness and
cognitive enhancement, are derived from the stimulation of
nicotinic acetylcholine receptors in the CNS (Picciotto,
2003). Indeed, the nicotinic acetylcholine receptor was
named for its prototype agonist, nicotine. There are
numerous nicotinic receptor subtypes, which are composed
of five subunits. To date, twelve different nicotinic receptor
subunits have been identified in the brain (a2-a10, b2-b4).
Nicotinic receptors in the brain are typically composed of
combinations of five a and b subunits, although a7 subunits
also can form pentameric homomers (Corringer et al., 2000;
Le Novere et al., 2002; Laviolette and van der Kooy, 2004).
6.3. Nicotine-dopamine interactions
Nicotinic receptors are abundantly expressed in the VTA
and nucleus accumbens and the systemic administration of
nicotine promotes dopamine release in the nucleus
accumbens. In the VTA, nicotinic receptors are found on
dopaminergic cell bodies (a4a5b2, a4a6a5b2, a7),
GABAergic cell bodies (a4b2a5, a7) and terminals
(a4b2*) as well as glutamatergic terminals (a7) (Klink
et al., 2001; Champtiaux et al., 2003; Picciotto, 2003;
Wonnacott et al., 2005). Nicotinic receptors in the nucleus
accumbens are found on dopaminergic terminals (a4b2,
a4a5b2, a6b2b3, a4a6b2b3) as well as GABAergic and
glutamatergic terminals (a4b2*) (Wonnacott et al., 2000;
Champtiaux et al., 2003; Picciotto, 2003; Luetje, 2004;
Wonnacott et al., 2005). The systemic administration of
nicotine increases extracellular dopamine levels in the
nucleus accumbens (Damsma et al., 1989; Benwell et al.,
1993; Nisell et al., 1994; Pontieri et al., 1996; Shoaib and
Shippenberg, 1996; Picciotto et al., 1998), particularly in the
shell subregion of this structure (Pontieri et al., 1996).
Moreover, local infusion of nicotine into either the VTA
(Nisell et al., 1994; Ferrari et al., 2002) or the nucleus
accumbens (Mifsud et al., 1989; Ferrari et al., 2002)
increases dopamine release in the nucleus accumbens.
Dopamine release in the nucleus accumbens following
the local administration of nicotine mainly results from the
direct stimulation of nicotinic receptors on dopaminergic
terminals (Di Chiara, 2000; Picciotto, 2003), although
nicotine-induced glutamate release may also contribute to
this process (Wonnacott et al., 2000). In experiments
performed in striatal synaptosomes, it was demonstrated
that there are four major nicotinic receptors on dopamin-
ergic terminals (a4b2, a4a5b2, a6b2b3, a4a6b2b3) that
contribute to nicotine-induced dopamine release (Champ-
tiaux et al., 2003; Cui et al., 2003; Salminen et al., 2004).
Experiments performed in vivo indicate that although
nicotine-induced dopamine release is attenuated by intra-
accumbal administration of nicotinic antagonists targeting
receptors containing a7 subunits (Fu et al., 2000b), other
nicotinic antagonists are without effect (Nisell et al., 1994;
Fu et al., 2000b). Since accumbal dopaminergic terminals
do not appear to express nicotinic receptors containing a7
subunits, these receptors must influence dopamine release
indirectly, perhaps by enhancing accumbal glutamate
release (Fu et al., 2000a).
Nicotine also increases the firing rates of dopaminergic
neurons (Calabresi et al., 1989; Pidoplichko et al., 1997;
Grillner and Svensson, 2000) and administration of a
 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
nicotinic receptor antagonist into the VTA almost com-
pletely blocks the ability of systemically administered
nicotine to produce dopamine release in the nucleus
accumbens (Nisell et al., 1994; Fu et al., 2000b). Moreover,
nicotinic antagonist administration into both the VTA and
nucleus accumbens produced greater inhibition of nicotine-
induced dopamine release in the nucleus accumbens than
infusion into the nucleus accumbens alone (Fu et al., 2000a).
Taken together, these results suggest that stimulation of
nicotinic receptors in the VTA is the primary mechanism
underlying nicotine-induced increases in accumbal dopa-
mine (Di Chiara, 2000), whereas stimulation of nicotinic
receptors in the nucleus accumbens modulates the ampli-
tude of this response (Fu et al., 2000a).
There appear to be multiple mechanisms whereby
nicotine increases dopaminergic neuronal activity. Stimu-
lation of nicotinic receptors on dopaminergic neurons
increases their firing rates, but these receptors desensitize
rapidly (Pidoplichko et al., 1997; Dani et al., 2000; Yin and
French, 2000). In contrast, nicotine-induced dopamine
release in the nucleus accumbens can persist for over one
hour (Di Chiara and Imperato, 1988; Schilstrom et al.,
1998b). Nicotine also increases glutamate and GABA
transmission in the VTA (Yin and French, 2000;
Mansvelder et al., 2002). Moreover, whereas the nicotine-
induced increase in GABA transmission rapidly desensi-
tizes (Yin and French, 2000; Mansvelder et al., 2002), the
glutamate response does so to a much lesser extent
(Mansvelder et al., 2002). Thus, following nicotine
administration there appears to be a net shift in the balance
of excitatory and inhibitory inputs to dopaminergic neurons
in the VTA such that inhibitory GABAergic transmission is
decreased and excitatory glutamatergic transmission is
increased (Mansvelder et al., 2002). Consistent with this
notion, ionotropic glutamate receptor antagonists attenuate
nicotine-induced increases in dopaminergic neuronal
activity (Grillner and Svensson, 2000) and dopamine release
in the nucleus accumbens (Schilstrom et al., 1998a,
Kosowski et al., 2004). Furthermore, intra-VTA adminis-
tration of a nicotinic antagonist that targets a7 subunits
decreases accumbal dopamine release induced by nicotine
(Schilstrom et al., 1998b). Since glutamatergic terminals in
the VTA mainly express nicotinic receptors including a7
subunits (Mansvelder and McGehee, 2000; Picciotto, 2003),
it has been proposed that these a7 subunit-containing
receptors in the VTA desensitize more slowly than other
nicotinic receptors resulting prolonged glutamate release
and stimulation of dopaminergic neuronal activity in the
VTA (Schilstrom et al., 2000; Mansvelder et al., 2002;
Wooltorton et al., 2003). However, a7 subunit-containing
receptors in the VTA are not solely responsible for nicotine-
induced dopamine release in the striatal complex since this
effect is attenuated in mutant mice lacking nicotinic
receptors containing b2 (Picciotto et al., 1998) or a4
subunits (Marubio et al., 2003).
227
6.4. Dopamine and nicotine self-administration
Nicotine self-administration has been demonstrated in a
number of non-human species, including primates, dogs,
rats and mice (Goldberg et al., 1981; Corrigall, 1999). As
expected, administration of nicotinic receptor antagonists
reduces nicotine self-administration (Martellotta et al.,
1995; Rauhut et al., 2002). A growing number of self-
administration studies indicate that activation of the
mesoaccumbal dopamine system plays a critical role in
nicotine reinforcement. For example, lesion-induced
depletion of accumbal dopamine disrupted the acquisition
(Singer et al., 1982) or maintenance (Corrigall et al.,
1992) of nicotine self-administration. Moreover, the
systemic administration of D1-like or D2-like dopamine
receptor antagonists reduces nicotine self-administration
(Corrigall and Coen, 1991a). The neurochemical findings
reviewed above indicate that nicotine-induced increases in
accumbal dopamine are primarily due to stimulation of
nicotinic receptors in the VTA. Consistent with these
findings, administration of a nicotinic receptor antagonist
directly into the VTA attenuated nicotine reinforcement,
whereas intra-accumbal administration was without effect
(Corrigall et al., 1994). Collectively, these results indicate
that the reinforcing effects of nicotine are due to
activation of the mesoaccumbal dopamine system (for
reviews of the role of dopamine in nicotine self-
administration studies see Corrigall, 1999; Di Chiara,
2000; Picciotto, 2003; Laviolette and van der Kooy,
2004).
Neurochemical studies suggest that the prolonged
stimulation of dopaminergic neuronal activity in the VTA
is due to decreases in GABAergic and increases in
glutamatergic transmission (Mansvelder and McGehee,
2002). Modulation of GABA transmission has been shown
to influence nicotine self-administration (Dewey et al.,
1999; Fattore et al., 2002; Paterson and Markou, 2002;
Paterson et al., 2004). Moreover, modulation of GABA
transmission in the VTA in particular reduces nicotine self-
administration (Corrigall et al., 2000). GABAergic neurons
in the VTA express b2-containing nicotinic receptors and
nicotine self-administration as well as nicotine-induced
increases in VTA dopaminergic neuronal activity and
striatal dopamine release were attenuated in mice lacking
the b2 subunit of the nicotinic receptor (Picciotto et al.,
1998; Epping-Jordan et al., 1999). Similarly, an antagonist
of high affinity nicotinic receptors (including the a4b2
subtype) decreased nicotine reinforcement (Watkins et al.,
1999; Grottick et al., 2000b). These results, collectively,
suggest that nicotine-induced decreases in VTA GABA
transmission disinhibits dopaminergic neuronal activity,
which promotes nicotine reinforcement.
Glutamate also has been linked to nicotine reinforcement
(Kenny et al., 2003; Paterson et al., 2003; Tessari et al.,
2004). It has been proposed the effect of nicotine on
glutamate transmission in the VTA is due to interactions
228 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238

with a7-containing nicotinic receptors (Schilstrom et al.,

2000; Mansvelder et al., 2002; Wooltorton et al., 2003).
Consistent with this hypothesis, an a7-selective nicotinic
receptor antagonist significantly reduced nicotine self-
administration (Markou and Paterson, 2001). However, in
another study, the same a7-selective nicotinic receptor
antagonist had no effect on nicotine self-administration in
rats (Grottick et al., 2000b). Thus, although it seems likely
that both GABA and glutamate play important roles in
nicotine reinforcement, the precise interactions among
GABA, glutamate and dopamine in the VTA that combine
to support nicotine reinforcement remain to be determined.

6.5. Caveats

Although these data clearly indicate that interactions

among dopamine, GABA and glutamate play a critical role
in nicotine reinforcement, emerging evidence suggests that
other transmitter systems are involved as well. In particular,
bupropion, the only non-nicotine-based smoking cessation
pharmacotherapy approved in the U.S., influences nicotine
self-administration by modulating both dopamine and
norepinephrine transmission in the CNS (Bruijnzeel and
Markou, 2003; Rauhut et al., 2003), which suggests a
potential role for norepinephrine in nicotine reinforcement.
Cannabinoids also have been linked to nicotine reinforce-
ment. Although CB1 cannabinoid receptor knockout mice
self-administer nicotine to a similar extent as wildtypes
(Cossu et al., 2001), pharmacological studies indicate that
CB1 receptors may contribute to nicotine reinforcement.
Thus, the CB1 receptor antagonist SR141716A attenuates
nicotine reinforcement as well as nicotine-induced dopa-
mine release in the nucleus accumbens (Cohen et al., 2002),
which has led to clinical studies designed to assess the
efficacy of this drug as a smoking cessation therapy (Cryan
et al., 2003).
7. Summary/conclusions
There is clear evidence that psychostimulants, opiates,
ethanol, cannabinoids and nicotine increase dopamine
transmission in limbic nuclei, and the nucleus accumbens
in particular. Psychostimulants such as amphetamine and
cocaine increase extracellular dopamine levels in limbic
nuclei by interacting with the dopamine transporter (DAT).
Opiates stimulate m opioid receptors on GABAergic
interneurons in the VTA, which disinhinits dopaminergic
neuronal activity resulting in increased dopamine release in
the nucleus accumbens. Ethanol disinhibits dopaminergic
neuronal activity in the VTA by positive modulation of
GABAA receptors located on GABAergic interneurons.
Ethanol also increases the firing rates of dopaminergic
neurons by decreasing potassium currents in these cells.
Cannabinoids increase dopaminergic neuronal activity in
the VTA through inhibition of GABA release following
Fig. 2. Direct and indirect influence of drugs of abuse on mesoaccumbal
dopamine transmission. Some drugs of abuse, such as cocaine, increase
nucleus accumbens (NAc) dopamine transmission by blocking the
dopamine transporter (DAT). Others, such as nicotine and ethanol, increase
the firing rates of dopaminergic neurons by modulating receptors or ion
channels located on these cells. Nicotine and ethanol, as well as D9-THC,
also increase the activity of dopaminergic neurons by decreasing
GABAergic transmission in the ventral tegmental area (VTA).
stimulation of presynaptic CB1 cannabinoid receptors in
the VTA. Nicotine excites dopaminergic neurons in the
VTA, through activation of nicotinic acetylcholine
receptors located on dopaminergic cells in addition to
increasing glutamate and decreasing GABA transmission
in the VTA. Thus, these five classes of abused drugs all
increase dopaminergic neuronal activity and/or dopamine
release via interactions with a number of ionotropic
receptors, metabotropic receptors, ion channels and
transporters.
Behavioral pharmacological experiments utilizing self-
administration paradigms indicate that increased dopamine
transmission in the nucleus accumbens plays at least a
partial role in the reinforcing effect of psychostimulants,
opiates, ethanol, cannabinoids and nicotine. Of these drugs
of abuse, the role of dopamine in psychostimulant
reinforcement has been studied to the greatest extent by
far. It is now clear that increased dopamine transmission is
primarily responsible for psychostimulant reinforcement
Fig. 2. There also is strong support for the dopamine
hypothesis of the reinforcing effects of ethanol and nicotine,
 R.C. Pierce, V. Kumaresan / Neuroscience and Biobehavioral Reviews 30 (2006) 215238
although these drugs not been studied as comprehensively
as the psychostimulants (and cocaine in particular). With
regard to the opiates, although there clearly is a dopamine-
dependent component of opiate reinforcement, there is a
significant dopamine-independent constituent as well.
Finally, the lack of a reliable cannabinoid self-adminis-
tration model (at least until recently) has hampered research
into the mechanisms underlying cannabinoid reinforcement.
In conclusion, dopamine appears to play at least a partial
role in psychostimulant, opiate, ethanol, cannabinoid and
nicotine reinforcement. One could argue, however, that the
dopamine hypothesis of drug reinforcement is self-fulfilling
in that an enormous research effort has focused on dopamine
to the exclusion of other neurotransmitters. Although there
is merit to this argument, it is notable that evidence in favor
of the dopamine hypothesis of drug reinforcement continues
to accumulate. In some instances evidence that initially
casts serious doubt on the dopamine hypothesis (such as
cocaine self-administration in DAT knockout mice)
ultimately is shown to be an interesting exception that
proves the rule. Moreover, in some cases of dopamine-
independent reinforcement (e.g. opiates), the drug may
support self-administration by mimicking the effect of
dopamine in brain areas such as the nucleus accumbens.
Although much work still remains to be done, more than a
quarter century after it was originally formulated (Fibiger,
1978; Wise, 1978) the hypothesis that increased dopamine
transmission plays an important role in drug reinforcement
remains valid.
Acknowledgements
The authors thank Ruth Reeves and Sharon Anderson for
their input on earlier versions of this manuscript. We also
thank Brian Inderwies for assistance creating the figures.
The authors were supported by grants from the U.S.
National Institutes of Health (RO1 DA15214, RCP;
Brown University Center of Biomedical Research Excel-
lence Grant P20 RR1578, VK).
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