What is the neuropharmacological basis of drug

addiction?
Many drugs seem to have addictive effects1. These include nicotine, ethanol, the
cannabinoids, the opiates and psychostimulants. These have a number of differing
psychological effects, but their common effect is to produce a feeling of hedonia.
People then want to repeat these sensations. If a rat is allowed to self administer an
addictive drug, they will continuously do this. The rat, like the person, can be said to
be addicted. This becomes a problem when the behaviour of the person becomes
deleterious to him/herself and/or to society as a whole. Despite the seeming diversity
of these drugs, they coincide on the same mechanism: the dopamine reward pathway
with the dopamine neurons projecting from area A10 of the ventral tegmental area to
the nucleus accumbens. The D2 receptor seems the most important receptor, since the
rewarding effects of for example amphetamine (increase DA release in inhibit its
reuptake) are blocked by these drugs. If this so-called mesolimbic dopamine reward
pathway is self stimulated by rats, they will continually activate it, even refusing food
and water, until they collapse from exhaustion.

Three terms that need to be defined are tolerance, dependence and withdrawal.
“Tolerance” describes a decrease in pharmacological effect on administration of the
drug, so that the user needs to take increasing doses of the drug in order to achieve the
same effect. “Dependence” is the state in which drug taking becomes compulsive,
taking over other needs. It is usual to distinguish physical dependence and
psychological dependence. Drugs which tend to induce euphoria – raising levels of
dopamine in the brain – will tend to induce dependence. The degree of euphoria
achieved will be related to the rapidity of the onset of euphoria after the drug has been
taken, and so will be related to how quickly the drug crosses the blood brain barrier.
Finally, “withdrawal” describes the adverse physical and psychological effects of no
longer using a drug. Using this framework, a number of effects can contribute to
addiction: in behaviourist terms there are positive reinforcing effects due to the
reward of euphoria, and there are the negative effects experience upon withdrawal.
Genetics may play a role – polymorphisms in the D2 receptor seems to have a role in
risk taking behaviour and possibly susceptibility to addiction although there is as yet
no “alcoholic gene” – while societal conditioning may play some role, since while
some drugs are frowned upon as “drugs of abuse”, others, such as alcohol and
nicotine in tobacco smoke, are widely practiced and accepted2.

Several pharmacological strategies have been developed to combat addiction (Rang

and Dale). Most of these seem more concerned with acting at the level of the
addictive drug rather than interfering with the reward pathways themselves:
presumably doing this would have excessively general effects. These include
substitution of the drug to alleviate withdrawal symptoms. Examples include
methadone (a partial opiate agonist, at least in the sense that responses to it, including
addiction, are weaker than those to morphine) used to blunt opiate withdrawal, and
1
In fact humanity seems far better at identifying these than at identifying drugs that are useful
therapeutically.
2
Chewing khat is acceptable in the Yemen and in parts of the East Africa and the Middle East, and
there are apparently low rates of addiction in these countries. In the USA, however, people do get
addicted and the possession of khat is normally a criminal offence.
benzodiazepines for recovering alcoholics. An example of the long term use of such a
replacement is the widely publicised use of nicotine patches to help stop smoking.
Here, we are not so worried about the deleterious effects of nicotine, or of nicotine
seeking behaviour, but rather that of the 2000 or so carcinogens in cigarette smoke. In
Sweden, there are smoke free cigarettes that contain only nicotine. Apparently there
are people who are happy to smoke them, and Sweden’s rates of lung cancer have
dropped dramatically. The action of the drug can be blocked. An example would be
using naloxone to block the response to opiates, or mecylamine to block the effects of
nicotine. Aversive therapies can be used, an example is the use of the aldehyde
dehydrogenase enzyme inhibitor disulfiram to discourage people from drinking
alcohol. Finally, drugs such as antidepressants, α2 adrenoceptor agonists (clonidine),
NMDA receptor antagonists and naloxone (also of value in treating other addictions)
can be given to reduce cravings for the drug.

All the addictive drugs to be discussed in this essay act to cause addiction at least to
some extent via the mesolimbic dopamine reward pathways. These pathways are
stimulated, leading to euphoria. This euphoric effect is essential if a drug is to be
addictive, acting as a positive reinforcer. It is reasonable to consider whether they
might not also share common mechanisms at the neuronal level. One idea is that
many of these drugs increase the expression of a number of genes. Among them
might be the increased expression of the adenylyl cyclase gene. Thus, there is
increased activation of the cAMP response element binding protein CREB. This will
increase expression of the fos and jun transcription factors. This provides one putative
mechanism by which chronic administration of a drug would alter gene expression,
thus possibly leading to at least tolerance (via a change in receptor number and
sensitivity of ensuing signal transduction mechanisms), if not dependence as well.

The opiates are some of the most addictive drugs. Examples include morphine and
heroin. Naloxone is an antagonist. Centrally, they produce the effects of analgesia and
intense euphoria, along with a feeling of sedation. Side effects are respiratory
depression, cough suppression, nausea and vomiting. The respiratory depression is
potentially quite dangerous, and can be lethal upon a heroin overdose. They act via μ,
δ and κ receptors, which are all G protein coupled receptors, coupled to Gi and a
reduction in cAMP. The μ receptors are the most important for both the analgesic
effects (major clinical use) and the euphoric effects (addiction), but the δ receptors
also contribute to the sensation of euphoria. These receptors both inhibit potassium
channels, and possibly voltage gated calcium channels as well. Thus the overall
effect, at least of the important and well characterized μ receptors is to inhibit
transmitter release and neuronal excitability. The κ receptor actually mediates a
sensation of dysphoria, but normally response is dominated by the other two
receptors. Recent research has been directed into finding centrally acting analgesics
that are not addictive, but these efforts have so far been unsuccessful. Perhaps we
have simply not been looking hard enough, but it is not impossible that the two effects
are inextricably linked.

The opiate effects on dependence have been the most thoroughly studied. The number
of opioid receptors seems to stay the same after chronic administration of the drug,
but their sensitivity is decreased. That is to say, there is an increase in the expression
of the adenylyl cyclase enzyme, with a gradual return of intracellular cAMP levels to
normal (i.e. pre-opiate application). Then when the morphine is withdrawn, there is a
surge in levels in cAMP. This explains the mechanisms of both tolerance and
withdrawal. Tolerance occurs because there is an increase in adenylyl cyclase. Doses
of heroin 10 times what would cause respiratory depression and death in an
unsensitized individual are tolerated and indeed needed by the addicted user. Any
opiate will cause tolerance to any other since the changes occur occur downstream of
the receptor: this is the phenomenon of cross tolerance, and explains why gradually
reducing amounts of methadone are given to counteract the withdrawal symptoms.
Some opiate receptors are located in the locus coeruleus, and perhaps normally serve
to inhibit sympathetic activity. So after the opiate is withdrawn, there is a sharp
increase in sympathetic activity. This explains the opiate induced withdrawal
symptoms of pupillary dilatation, hyperthermia, sweating, piloerection. In addition,
there is also yawning, and more seriously, nausea, diarrhoea (application of opiates
causes constipation), anxiety and insomnia. In addition to this, neurons with inhibitory
opioid receptors project to GABA fibres which in turn inhibit mesolimbic dopamine
neurons in the VTA. Thus, addition of opiate causes an inhibition of the GABAergic
inhibition, and thus an increase in firing of the dopamine neuron. This explains the
sensation of euphoria, which is so vital for inducing addiction.

Nicotine exerts its effects via the α4β2 subtype of nicotinic receptor, which are widely
expressed in the brain including cortical and hippocampal regions. These are
excitatory ligand ion channels found both pre and post synaptically, which cause
neuronal excitation and enhanced transmitter release. Chronic administration of
nicotine causes a profound desensitisation, (and there is an upregulation in the number
of nicotinic receptors in response) which probably accounts for the tolerance effects.
The withdrawal symptoms include increased irritability, aggressiveness, sleep
disturbances and poor psychomotor function. The mechanism by which nicotine
induces these effects and indeed the initial addiction is poorly understood, but the
nicotinic receptors are firmly indicated. Animals can be trained to smoke cigarettes. If
these contain nicotine, they will continue to do so, but if there is no nicotine they will
desist. This can be blocked with the nicotinic antagonist mecamylamine, which is also
used to treat smoking addicted humans. It is worth mentioning that the nicotine
patches on their own are not effective. At the beginning of the essay the cognitive
deficits that were inherent in addiction were discussed, and it seems that these patches
are only effective if combined with counselling.

The cannabinoid drugs have been in the news much recently. They are a class of
psychomimetic, of which the best known is cannabis (active ingredient: THC). They
have analgesic effects, and it is suggested that they are useful in MS, among other
things. Of more interest here, however, is that they possibly induce dependence. The
receptors for the cannabinoids – CB1 and CB2 – have been cloned, and now we are
merely awaiting the discovery of the endogenous cannabinoids! Of these receptors,
the CB1 receptor (Gi coupled to a decrease in cAMP) is more important here. How
cannabinoids induce addiction is not understood at all, although it is known that they
interact with dopaminergic neurons. Indeed, CB1 knock out mice have extreme
poverty of movement, due to reduction of dopaminergic input to the basal ganglia
(Leonard 2003). Tolerance has been observed in regular users of cannabis, since these
people again take up about ten times as much THC as would be lethal in a person who
had not taken cannabis. Withdrawal symptoms to cannabis have also been described.
Alcohol is thought to act by enhancing GABAA receptors, as well as by an inhibition
of voltage gated Ca channels and inhibition of NDMA receptor function. On chronic
use of alcohol, there is a decrease in the function of GABAA receptors, increased
NMDA function, and increased expression of Ca channels, which could account for
the withdrawal effects. Alcohol also has direct effects on the cell lipid membranes,
thus producing its sedative effects in possibly the same manner as the general
anaesthetics. Tolerance has been explained in terms of a gradually altered
composition of neuronal cell membranes, so that alcohol has fewer effects. The effect
on the GABAA receptors explains the use of benzodiazepines, which have the same
mechanism of action, in weaning alcoholics off alcohol. It has been suggested that the
inverse benzodiazepine agonists could be used clinically to inhibit the effects of
alcohol, but these would not have any effects on Ca channels or NMDA receptors,
and so this has not been carried out. The use of disulfiram (Antabuse) to wean people
off alcohol was explained at the beginning of this essay. After alcohol withdrawal
there are, as one would expect, increased levels of levels of glutamate in the nucleus
accumbens, and decreased mesolimbic dopaminergic activity. Presumably, taken with
the increased NMDA receptor function, there could be a risk of neuroexcitoxicity, and
there is certainly increased neural excitability. The NMDA antagonist acamposoate is
an anti craving drug that seems to decrease levels of extracellular glutamate in
addition to its protective effects at the NMDA receptor. It also decreases calcium
channel upregulation in mice that have been withdrawn from alcohol.

The final addictive drugs I shall be discussing are the psychostimulants, such as
amphetamines, cocaine and the methylxanthines. These cause euphoria, increased
wakefulness, reduced fatigue and a decreased appetite. Cocaine and amphetamines
both inhibit dopamine reuptake, and amphetamines also increase dopamine release.
Since this occurs in the mesolimbic pathway, this explains their addictive and
euphoric effects. Withdrawal can lead to craving, anxiety, depression and anhedonia,
which in the case of cocaine is termed “cocaine crash”. Tolerance is also rapidly
induced, but oddly enough only to some of the effects of cocaine. For example, the
euphoric “rush” that one experiences after cocaine is vulnerable to tolerance, but other
effects are not. In general, however, people are much less likely to become addicted to
the psychostimulants than they are to opiates. Caffeine is not addictive, and if a
regular cocaine user could force him/herself to abstain for a few days, after initial
withdrawal symptoms one could expect the mood to return to normal. In the USA, the
TCA desipramine is used to treat these withdrawal symptoms, but its mechanism of
action is reduced.

At the same time, this dopaminergic tale has perhaps not been the entire story of
addiction. For example, brain imaging studies have shown that the subjective
responses to cocaine in humans do not correlate with its effects on the dopamine
transporter. There must be systems other than dopamine that are involved. Hnasko et
al. 2005 claimed that morphine has a rewarding effect in D2 receptor knock out mice,
also implying that dopamine cannot be the whole story of reward. This result is in fact
surprising, since D2 antagonists such as the classical neuroleptic chlorpromazine will
abolish the reward sensation. Clearly, more research is needed. Also, although many
people use potentially addictive drugs, not everyone ends up abusing, for example,
alcohol or nicotine. The brain must normally keep these reward mechanisms firmly
under control, and perhaps addiction reflects the failure of these previously
unrecognised controlling systems. In the rat, the reward regions of the brain are
separate from the craving regions. Stimulation of the ventral subiculum, an area of the
hippocampus, leads to craving for cocaine. Presumably the hippocampus is important
as the site of memory of the euphoric effects of the drug, and this link should perhaps
be investigated further in humans. This separation of craving, memory and euphoric
regions is potentially very important, since it opens the way for drugs to be developed
which abolish the craving, with inducing total apathy.