DOPAMINE AND

PSYCHOSIS
Leonardi A. Goenawan
Dopamine (DA)
C6H3(OH)2-CH2-CH2-NH2
Neurohormone and neurotransmitter
Responsible for pleasure or reward system,
inhibition prolactin release.
5 types of dopamine receptors: D1, D2, D3, D4 &
D5
Produced in several areas of the brain, including
the substantia nigra & ventral tegmental area.
As a medication that acts on the sympathetic
nervous system.
Functions in the Brain
Behavior & cognition
Motor activity
Motivation & reward
Prolactin inhibitor
Sleep, mood, attention & learning
Dopaminergic Pathways
Dopaminergic pathways are neural pathways
in the brain which transmit the
neurotransmitter dopamine from one region
of the brain to another.
There are EIGHT dopaminergic pathways, but
the FOUR major ones are:
Mesolimbic pathway
Mesocortical pathway
Nigrostriatal pathway
Tuberoinfundibular pathway

Mesolimbic pathway
Transmits dopamine from the ventral tegmental
area (VTA - midbrain) to the nucleus accumbens
(striatum of limbic system).
It is thought to be involved in producing
pleasurable feeling, and often associated with
feelings of reward & desire (n. accumbens) ~
heavily imlicated in neurobiological theories of
addiction.
The mesolimbic pathway may contribute to the
positive symptoms of schizophrenia

Positive Symptoms
1. Delusions
2. Auditory hallucinations
3. Thought disorder: a pattern of disordered
language use that is presumed to reflect
disordered thinking.
pressure of speech (speaking incessantly and
quickly),
derailment or flight of ideas (switching topic mid-
sentence or inappropriately),
thought blocking,
rhyming,
'word salad
Mesocortical pathway
Transmits dopamine from VTA to the frontal
cortex.
Essential to the normal cognitive function of
the dorsolateral prefrontal cortex, and it is
thought to be involved in motivation and
emotional response.
The mesocortical pathway may be
responsible for the negative symptoms of
schizophrenia.
Negative Symptoms
1. Avolition: general lack of desire, drive, or
motivation to pursue meaningful goals.
2. Flat affect: a lack of emotional reactivity on the
part of an individual (blunted of affect).
3. Alogia: a general lack of additional,
unprompted content seen in normal speech.
4. Anhedonia: an inability to experience pleasure
from normally pleasurable life events such as
eating, exercise, and social or sexual
interaction.
Meadows G., Singh, B., & Griggs, M. (2007). Mental Health in Australia, Collaborative
Community Practice 2nd Ed. Oxford University Press, Oxford. Chapter 25, p539.
Nigrostriatal pathway
Transmits dopamine from the substantia
nigra to the striatum.
This pathway is associated with motor
control and degeneration of this pathway is
related to Parkinsons disease.
Also implicated in producing tardive
dyskinesia.
Tuberoinfundibular pathway
Transmits dopamine from the hypothalamus
(arcuate nucleus) to the pituitary gland.
This pathway influences the secretion of
certain hormones, including prolactin
(anterior pituitary).
Dopamine Subtypes
Subtype Proposed Clinical Relevance
D1 D
1
and D
2
receptor stimulation synergistic;
required for stimulant effects of cocaine
D2 Target of therapeutic and extrapyramidal
effects of dopamine receptor antagonists
(atypical antipsychotics)
D3 Unknown
D4 Target of serotonin-dopamine antagonists
(atypical antipsychotics)
D5 Unknown
Dopamine hypotesis of
Schizophrenia
Model attributing symptoms of schizophrenia to
a disturbed and hyperactive dopaminergic
signal transduction.
Evidence 1: Amphetamine
The effect of drugs such as amphetamine and
cocaine. These drugs (and others like them)
increase levels of dopamine in the brain and can
cause psychosis (psychotomimetic), particularly
after large doses or prolonged use.
Up to 75% of patients with schizophrenia have
increased signs and symptoms of their psychosis
upon challenge with moderate doses of
methylphenidate or amphetamine or other
dopamine-like compounds

Evidence 2: Phenotiazines
An accidental discovery that a group of drugs
called the phenothiazines, including
antipsychotics such as chlorpromazine,
antagonized dopamine binding (particularly
at receptors known as D
2
dopamin receptors)
and reduced positive psychotic symptoms.
The affinity of antipsychotic drugs for the D
2

dopamine receptor family seemed to be
inversely proportional to their therapeutic
dose.
1,2


1. P. Seeman et al. (1975): Proceedings Nat. Acad. Sci., USA 72: 4376-4380; Nature
261: 717-719
2. P. Seeman (2002): Canad. J. Psychiat. 47: 27-38
Evidence 3: L-Dopa
Those treated with dopamine enhancing
Levodopa for Parkinson's disease can
experience psychotic side effects mimicking
the symptoms of Schizophrenia.
Evidence 4: Imaging
Evidence for the co-existence of sub cortical
dopamine excess and cortical dopamine deficit
in the schizophrenic brain is presented.
Neuroreceptor-imaging techniques, such as
SPECT and PET, have been used to provide that
evidence.
Some functional neuroimaging studies have also
shown that, after taking amphetamine, patients
diagnosed with schizophrenia show greater
levels of dopamine release (particularly in the
striatum) than non-psychotic individuals.

Anissa Abi-Dargham: Do we still believe in the dopamine hypothesis? New data
bring new evidence. The International Journal of Neuropsychopharmacology
(2004), 7 : S1-S5 Cambridge University Press
Evidence 5: Genes
Genetic evidence has suggested that there
may be genes, or specific variants of genes,
that code for mechanisms involved in
dopamine function, which may be more
prevalent in people experiencing psychosis or
diagnosed with schizophrenia. Dopamine
related genes linked to psychosis in this way
include COMT, DRD4, AKT1
Arguello PA, Gogos JA (June 2008). "A signaling pathway AKTing up in
schizophrenia". J. Clin. Invest. 118 (6): 201821
Evidence Against the
Dopamine Hypothesis 1
Studies showed that some patients had over
90% of their D
2
receptors blocked by
antipsychotic drugs, but showed little
reduction in their psychoses.
Although dopamine inhibiting medications
modify dopamine levels within minutes, the
associated improvement is usually not visible
for at least several days, indicating that if
nothing else, dopamine may not be directly
responsible for the illness.
1

1. R. Thompson, The Brain, ISBN: 0716714620
A new generation of antipsychotic drugs were
found to be just as effective as older typical
antipsychotic drugs in controlling psychosis
despite the fact that they blocked fewer
dopamine receptors (60-70%).
1
Amphetamines do more than increase
dopamine levels. They also alter other
neurotransmitter levels.

Evidence Against the
Dopamine Hypothesis 2
1. P. Seeman (2002): Canad. J. Psychiat. 47: 27-38
Other (inconclusive)
Biochemical factors
Serotonin: serotonin excess as a cause of both positive and
negative symptoms in schizophrenia
Norepinephrine: anhedonia ~ NE selective degeneration
GABA: loss of GABAergic neurons in the hippocampus.
Neuropeptides, such as substance P and neurotensin, are
localized with the catecholamine and indolamine
neurotransmitters and influence the action of these
neurotransmitters. Alteration in neuropeptide mechanisms
could facilitate, inhibit, or otherwise alter the pattern of
firing these neuronal systems.
Glutamate has been implicated because ingestion of
phencyclidine, a glutamate antagonist, produces an acute
syndrome similar to schizophrenia.
Acetylcholine & Nicotine: Postmortem studies ~ decrease
receptors.