in Florence showed some symptomatic improvement with only minor side effects, but this requires confirmation in a controlled trial. Cyclosporin A does not cause bone marrow depression; but reports of the development of lymphoma in patients treated with the drug after transplantation,6 and indeed in patients treated with other immunosuppressive drugs,7 mean that immunosuppression should be used circumspectly. Another approach is based on the finding that suppressor lymphocyte activity is depressed during acute relapses in multiple sclerosis.8 This has raised the possibility of enhancing suppressor cell activity therapeutically, and is yet another potentially promising line of investigation.

https://www.bmj.com/content/bmj/280/6207/66.full.pdf

Molecular pathology of schizophrenia: more than one disease process?

The dopamine hypothesis of schizophrenia proposes that hyperactivity of dopaminergic transmission is associated with this illness, but direct observation of abnormalities of dopamine function in schizophrenia has remained elusive. We used a newly developed single photon emission computerized tomography method to measure amphetamine-induced dopamine release in the striatum of fifteen patients with schizophrenia and fifteen healthy controls. Amphetamine-induced dopamine release was estimated by the amphetamine-induced reduction in dopamine D2 receptor availability, measured as the binding potential of the specific D2 receptor radiotracer [123I] (S)-(-)-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl) methyl]benzamide ([123I]IBZM). The amphetamine-induced decrease in [123I]IBZM binding potential was significantly greater in the schizophrenic group (-19.5 +/- 4.1%) compared with the control group (-7.6 +/- 2.1%). In the schizophrenic group, elevated amphetamine effect on [123I]IBZM binding potential was associated with emergence or worsening of positive psychotic symptoms. This result suggests that psychotic symptoms elicited in this experimental setting in schizophrenic patients are associated with exaggerated stimulation of dopaminergic transmission. Such an observation would be compatible with an abnormal responsiveness of dopaminergic neurons in schizophrenia.

https://www.pnas.org/content/pnas/93/17/9235.full.pdf

Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects

Dopamine receptors are classified into D1 and D2 subtypes on the basis of their pharmacological and biochemical characteristics. The D2 dopamine receptor has been implicated in the pathophysiology and treatment of movement disorders, schizophrenia and drug addiction. The D2 dopamine receptor interacts with guanine nucleotide-binding proteins to induce second messenger systems. Other members of the family of receptors that are coupled to G proteins share a significant similarity in primary amino-acid sequence and exhibit an archetypical topology predicted to consist of seven putative transmembrane domains. We have taken advantage of the expected nucleotide sequence similarities among members of this gene family to isolate genes coding for new receptors. Using the hamster beta 2-adrenergic receptor gene as a hybridization probe we have isolated related genes including a cDNA encoding the rat D2 dopamine receptor. This receptor has been characterized on the basis of three criteria: the deduced amino-acid sequence which reveals that it is a member of the family of G-protein-coupled receptors; the tissue distribution of the mRNA which parallels that of the D2 dopamine receptor; and the pharmacological profile of mouse fibroblast cells transfected with the cDNA.

Cloning and expression of a rat D2 dopamine receptor cDNA.

The treatment of schizophrenia has evolved over the past half century primarily in the context of antipsychotic drug development. Although there has been significant progress resulting in the availability and use of numerous medications, these reflect three basic classes of medications (conventional (typical), atypical and dopamine partial agonist antipsychotics) all of which, despite working by varying mechanisms of actions, act principally on dopamine systems. Many of the second-generation (atypical and dopamine partial agonist) antipsychotics are believed to offer advantages over first-generation agents in the treatment for schizophrenia. However, the pharmacological properties that confer the different therapeutic effects of the new generation of antipsychotic drugs have remained elusive, and certain side effects can still impact patient health and quality of life. Moreover, the efficacy of antipsychotic drugs is limited prompting the clinical use of adjunctive pharmacy to augment the effects of treatment. In addition, the search for novel and nondopaminergic antipsychotic drugs has not been successful to date, though numerous development strategies continue to be pursued, guided by various pathophysiologic hypotheses. This article provides a brief review and critique of the current therapeutic armamentarium for treating schizophrenia and drug development strategies and theories of mechanisms of action of antipsychotics, and focuses on novel targets for therapeutic agents for future drug development.

/pdf/treatments-for-schizophrenia-a-critical-review-of-1r0u7s3s3j.pdf

Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs

In postmortem studies of patients with schizophrenia, D2 dopamine receptors in the basal ganglia have been observed to be more numerous than in patients with no history of neurological or psychiatric disease. Because most patients with schizophrenia are treated with neuroleptic drugs that block D2 dopamine receptors in the caudate nucleus, it has been suggested that this increase in the number of receptors is a result of adaptation to these drugs rather than a biochemical abnormality intrinsic to schizophrenia. With positron emission tomography (PET), the D2 dopamine receptor density in the caudate nucleus of living human beings was measured in normal volunteers and in two groups of patients with schizophrenia--one group that had never been treated with neuroleptics and another group that had been treated with these drugs. D2 dopamine receptor densities in the caudate nucleus were higher in both groups of patients than in the normal volunteers. Thus, schizophrenia itself is associated with an increase in brain D2 dopamine receptor density.

https://science.sciencemag.org/content/sci/234/4783/1558.full.pdf

Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics

IN patients with Parkinson's disease, the concentration of dopamine in the basal ganglia of the brain is markedly reduced in accordance with the degeneration of the nigrostriatal dopamine-containing neurones1,2. This fact provided the basis for the successful clinical introduction of L-dopa (L-3,4-dihydroxyphenylalaline) for Parkinson's disease3,6. It has been suggested that one of the critical factors compensating for the loss of dopamine neurones may be the development of “denervation supersensitivity” in the striatum, as severe cases react more sensitively to L-dopa than milder cases or controls7–9. By measuring dopamine receptors in the putamen and caudate of postmortem brains from Parkinson patients, we report here evidence in support of the theory of dopaminergic supersensitivity in Parkinson's disease.

Receptor basis for dopaminergic supersensitivity in Parkinson's disease

THE neuroleptic or antipsychotic drugs, introduced in 19521, effectively prevent relapse and rehospitalisation of schizophrenic patients. These drugs provide a strategy2 for localising possible abnormalities in the brain in schizophrenia. The hypothesis that schizophrenia might be associated with abnormally sensitive dopamine synapses3–6 evolved from the suggestion that neuroleptics block dopamine receptors and thus accelerate the turnover of dopamine7,8. The hypothesis received additional support from the observations that dopamine-mimetic drugs (for example d-amphetamine, L-dopa) elicit or exacerbate psychotic symptoms9–12, that neuroleptics produce supersensitivity to dopamine13–15, that the neuroleptic and antipsychotic actions are enhanced by drugs which block the synthesis of catecholamines16, that neuroleptics all have conformations that match that of dopamine17, and that dopamine is the most potent neurotransmitter to inhibit the specific binding of 3H-haloperidol to dopamine-rich regions of the brain18–20. Although all this evidence for the dopamine hypothesis of schizophrenia is circumstantial, we have now obtained direct evidence for some abnormalities in brain dopamine receptors in schizophrenia by measuring the specific binding of 3H-apomorphine and 3H-haloperidol or 3H-spiperone to four regions of postmortem brains from schizophrenic patients.

Irene J. Farley

Papers

Receptor basis for dopaminergic supersensitivity in Parkinson's disease

Binding of 3 H-neuroleptics and 3 H-apomorphine in schizophrenic brains