Dopamine Theory

The dopamine hypothesis proposes that schizophrenia occurs as a result of a functional overactivity of the neurotransmitter dopamine and has remained the most accepted theory. 

There are four main dopaminergic neuronal pathways in the ce​ntral nervous system and the dopamine cell bodies exist in two major areas in the brain; the midbrain and the hypothalamus (Figure 2).

 

 

The midbrain consists of: 

 

​• The nigrostriatal pathway which accounts for approximately 75% of the dopamine in the brain. The axons of dopamine cell bodies in the substantia nigra are projected to the dorsal striatum, which is located in the basal ganglia. The nigrostriatal pathway is known to facilitate the initiation of motor activities.

 

 

• Cell bodies from the ventral tegmental area innervate the frontal cortex and the limbic system (especially the nucleus accumbens and the amygdaloid nucleus), these are the mesocortical and mesolimbic pathways respectively. The mesolimbic pathway is associated with controlling reward, motivation and pleasure (positive symptoms), whereas the mesocortical pathway is known to play a part in volition and cognition (negative symptoms).

The hypothalamus consists of:

 

• The tuberohypophyseal pathway in which dopamine controls prolactin release from the pituitary gland. The release of dopamine can be seen to inhibit prolactin secretion.

























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There are five dopamine receptor subtypes, which can be categorised into two functional classes:

 

• The D1 receptor type consists of D1 and D5
• The D2 receptor type, consists of D2, D3 and D4.

The origin of the dopamine theory came from the early observation of the pharmacological action of dopamine agonists, such as amphetamine, at the dopamine receptor sites. It was shown that there was a strong correlation between the release of dopamine in the brain and the observed stereotyped behaviour seen in schizophrenic patients. Therefore, the theory postulates that symptoms of schizophrenia may result from an excess of dopaminergic neurotransmission.

In addition, the importance of the D2-receptor activity in schizophrenia has become significant over the years. Potent D2-receptor agonists, such as apomorphine, produce effects similar to amphetamine and also exacerbate the symptoms of schizophrenia.



The theory is further supported by the action of dopamine antagonists that block neuronal dopamine receptors, such as the antipsychotics reserpine and chlorpromazine. These drugs are effective in controlling the positive symptoms of schizophrenia, and in preventing amphetamine- induced behavioural changes. Furthermore, there has shown to be a robust correlation between clinical antipsychotic potency and the affinity for D2 receptors.

There have been several shortcomings in the dopamine hypothesis. In particular, it was postulated that patients with schizophrenia should have an increased dopamine receptor density. However, this evidence was not consistent with post- mortem studies, and more importantly from neuroimaging studies, which consists of binding radio-labelled antipsychotic drugs to receptors. 

Moreover, evidence for dopaminergic abnormalities in schizophrenia has been achieved through imaging studies. The studies have determined the release of dopamine, in vivo, by measuring the displacement of the radioligand raclopride which is a specific D2 receptor antagonist. Injection of amphetamine in patients with acute schizophrenia resulted in the release of dopamine and consequently the displacement of raclopride. The amount of dopamine that competitively displaced the raclopride at dopamine receptors was then determined. It was demonstrated that there was a two-fold greater reduction in raclopride binding and a corresponding three-fold greater increase in dopamine in the patients with schizophrenia as opposed to the control subjects.