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. Delusions2. Auditory hallucinations3. 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 Symptoms1. 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 Parkinson’s 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 D1 and D2 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 D2 dopamin receptors) and reduced positive psychotic symptoms.

The affinity of antipsychotic drugs for the D2 dopamine receptor family seemed to be inversely proportional to their therapeutic dose. 1,21. 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, AKT1Arguello PA, Gogos JA (June 2008). "A signaling pathway AKTing up

in schizophrenia". J. Clin. Invest. 118 (6): 2018–21

Evidence Against the Dopamine Hypothesis 1 Studies showed that some patients had

over 90% of their D2 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.

Thank You