A MODIFIED DOPAMINE HYPOTHESIS

Dr. Ravi Pisharodi

Consultant Psychiatrist, Tripunithura
Schizophrenia is the heartland of Psychiatry and the core of its clinical practice. A major landmark in the history of the understanding and treatment of Schizophrenia was the discovery that dopamine D2-blocking agents can control the hallucinations and delusions of Schizophrenic patients. Initial reports of increased dopamine levels in Schizophrenic brains have not been replicated. One explanation for the increased D2 binding in Schizophrenics is that chronic treatment with neuroleptics can increase the expression of D2 receptors and enhance the binding of the legend. PET and SPECT imaging showed that psychotic symptoms can persist, even after full blockade of D2 receptors and that some patients who had a good clinical response to clozapine showed low occupancy of D2 receptors. Thus, although the D2 receptors may have a role in the therapeutic effects of typical neuroleptics, evidence for D2 receptor alternation as a cause of Schizophrenia is lacking.
Another often-cited weakness of the dopamine hypothesis involves the time course of the clinical effects of antipsychotics. While neuroleptics block D2 receptors shortly after crossing the blood-brain barrier, their antipsychotic effects do not reach a clinically significant level until, on average, one to two weeks later. In addition, antipsychotics neither cure the illness, nor stop the relapse of symptoms completely, and about 30% of patient are refractory to treatment with dopamine blockers. More over our over concern with treating positive symptoms has resulted in neglecting other outcome measures like cognitive deficits and quality of life.
One of the corner-stones in the dopamine hypothesis is the observation that dopaminergic drugs can elicit psychotic symptoms in normal individuals. these symptoms, however, are primarily paranoid ideation and hallucinations, which represent only a small part of the constellation of symptoms seen in Schizophrenia. Hyper-dopaminergia, even if it exists, would not explain the deficit symptoms and the abnormalities in memory and executive functions, which are more enduring than are paranoid ideation and hallucinations. In contrast, there is evidence that deficit symptoms may be related to decreased dopamine release in the prefrontal cortex. In primates prefrontal dopamine is important for the performance on working memory tests that depends on normal frontal lobe function. Furthermore, in Schizophrenics, dopamine agonists enhance the performance on Wisconsin Card Sorting (WCST). a cognitive test that relies also on working memory and prefrontal activity. These observations suggest that at least in terms of certain cognitive functions that are related to prefrontal cortex, if dopamine is a factor, it may be because its activity is too low, not too high.
Alternation of other neuro-transmitters has also been associated with psychosis, including the serotonin, glutamate, acetylcholine and adrenergic systems. These systems interact with each other and with dopamine, and any alteration in one can have significant impact on the others, depending on the region studied and the sub-types of receptors involve.
The number of DA receptor subtypes appears considerably larger than envisaged originally within the D1/D2 schema; current theory encompasses at least six DA receptors sequences which, on the basis of their known pharmachological characteristics, are best grouped into two families: DI-like (DIA/1, DIB/5); and D2-like (D2L/S, D3, D4) receptors.
Earlier emphasis on D2 antagonism has required recasting to substitute D2 with D2-like, given the inability of most conventional antipsychotic to distinguish among cloned D2L/S, D3 and D4 receptors. Dopamine type-2 receptors inhibit adenylate cyclase, whereas stimulate this enzyme.
Given the weight of evidence for some primacy of D2 blocked in the therapeutic action of conventional antipsychotic drugs, investigators were surprised by the activity of the first selective D1 (i.e. DI-like) antagonist Sch 23390 in essentially all conventional models held to predict antipsychotic activity. This profile appeared to have its basis in DI-like D2-like interaction which regulate critically the totality of dopaminergic neurotransmission in the CNS. SCH 23390. unlike conventional antipsychotics, appears active in putative non-human primate models, both of positive and negative symptoms. Thus, the therapeutic potential of selective DI antagonists remains open. It is important to emphasis that the functional effects of drugs may not be reliably predicted solely on the basis of their receptor binding profiles. In particular, clozapine appears to exert much more prominent and preferential attenuation of DI-like mediated behaviour than would be predicted from its binding affinities. Clozapine and Onlazapine have a higher DI/D2 binding ratio than typical agents.
It may be relevant to note that the action of Clozapine, onlazapine and zotepine include DI-like antagonism, which may encompass a dispro-portianate attenuation of DI-like mediated function. Curiously, while the selective D1-like antagonist SCH-39166 appears to have no activity against positive psychotic symptoms, it appears to reduce negative symptoms, as may the D1-like antagonist NNC 01-687. Also a reduce link between D1 and D2 dopamine receptors has been reported in schizophrenia and Huntington diseased brain by some investigators.
Another line of evidence for D1-like over activity in schizophrenia is the occurance of spontaneouse or idiopathic orofacial dyskinesia in schizophrenics. They are apparently indistinguishable from tardive dyskinesia. They have been observed in between 1% and 15% elderly individuals who have never received antipsychotic drugs. Movement disorder, particularly orofacial dyskinesia, appears to be part of the clinical presentation of schizophrenia. More-over D1 receptor agonists have been shown to cause tongue protrusion and chewing movements in animals. There is also evidence that clozapine can have an ameliorating effects on TD-probably through D1 receptor blockade.
Although dopaminergic agonists can mimic positive symptoms such as paranoid and hallucinations reasonably well, they do not produce negative symptoms. Because it seems unlikely that simple hyperdopaminergia can account for both the positive and the negative symptoms of schizophrenia, several investigators have suggested that negative symptoms in schizophrenia may actually be related to hypodopaminergic activity, particularly in the frontal regions.
If positive symptoms are in fact related to hypodopaminergic activity and negative symptoms to hypodopaminergic activity, it seems counter-intuitive to think that positive and negative symptoms could occur simultaneously in a given individual. Various studies have demonstrated that there are complex feedback circuits between the prefrontal cortical and sub cortical dopamine systems. Animal studies have found that a disruption of the dopamine system in the prefrontal cortex blocks feedback  inhibition of the sub cortical dopamine system, resulting in a functional hyperactivity of basal ganglia and limbic dopamine. Thus a putative hypofunction of the prefrontal dopamine system provides a neurobiological basis for negative systems and that increased sub cortical dopamine activity would account for positive symptoms.
It is difficult to review pharmacological and metabolic studies of schizophrenia without concluding that dopamine plays a significant role in mediating both negative and positive symptoms. Nevertheless, the characteristics of dopaminergic involvement remain unclear. Likewise, the role of dopamine receptor subtypes remains ambiguous. One possibility is the interaction and balance between the D1-like and D2-like Dopamine ;receptors. A combination of D1 block in the sub cortical dopamine system may afford the full spectrum of anti-schizophrenic activity.