guanosine-triphosphate and Schizophrenia

Receptor binding studies with a variety of dopaminergic ligands have confirmed behavioral and biochemical findings that the central nervous system and peripheral nervous system contain several dopamine receptor subtypes. These subtypes can be discriminated on the basis of their agonist-antagonist pharmacological specificities, linkage to adenylate cyclase, cellular location, regulation by guanine neucleotides and ions, and involvement in several human diseases. Although questions remain unanswered, progress is rapidly being made in equating the subgroupings arrived at by these different experimental approaches. Dopamine receptors are regulated by a number of factors. Acutely, guanine nucleotides and some ions regulate agonist but not antagonist binding and are essential for receptor coupling with adenylate cyclase. Chronically, changes in the level of dopaminergic stimulation modulate the number of at least some receptor subtypes, resulting in "up or down regulation." An increase in receptor number appears central to the pathology of Parkinson's disease, tardive dyskinesia, and perhaps schizophrenia. Animal models indicate that it may be possible to exploit inherent capabilities for receptor modulation in clinical therapy. The therapeutic precedents set by the indentification of distinct subtypes of adrenoreceptors. histamine, and cholinergic receptors portends and exciting future for dopamine receptor research.

Topics: Adenylyl Cyclases; Animals; Binding, Competitive; Brain; Butyrophenones; Ganglia, Sympathetic; Guanosine Triphosphate; Humans; Kinetics; Parkinson Disease; Receptors, Dopamine; Schizophrenia; Structure-Activity Relationship

Binding studies with [3H]8-hydroxy-2-(di-n-propylamino)tetralin ([3H]8-OH-DPAT), a specific serotonin1A (5-HT1A) receptor agonist, were done on the autopsied brains from control subjects and from patients with chronic schizophrenia. All the patients and controls were of the Japanese race. In the controls, representative Scatchard plots for the specific [3H]8-OH-DPAT bindings in the prefrontal cortex and hippocampus revealed a single component of high affinity binding site (Kd value = 5.7 and 5.9 nM, Bmax value = 80.1 and 101.0 fmol/mg protein, respectively). The [3H]8-OH-DPAT bindings to the prefrontal cortex and hippocampus were potently inhibited by serotonin (IC50 = 6.3 x 10(-9) M) and 5-HT1A agonists (IC50 = 5.0 x 10(-9) - 2.3 x 10(-7) M), while other neurotransmitters, 5-HT2 and 5-HT3 related compounds did not inhibit the binding (IC50 greater than 10(-5) M). The bindings were decreased in the presence of 0.1mM GTP and 0.1mM GppNHp but not in the presence of 0.1mM GMP. In the prefrontal and temporal cortices of schizophrenics, there was a significant increase in the specific [3H]8-OH-DPAT binding, by 40% and 60%, respectively, with no change in the hippocampus, amygdala, cingulum, motor cortex, parietal or occipital cortex, as compared to findings in the controls. Scatchard analysis showed that this increased binding reflects changes in the number of sites but not in the affinity. The effect of 0.1mM GppNHp on the binding to prefrontal cortex was observed in both controls and schizophrenic patients. The bindings were significantly greater in the schizophrenic patients than in controls, in the presence of 0.1mM GppNHp. Our findings suggest that there are GTP-sensitive 5-HT1A sites in the human brain and that selective increases in GTP-sensitive 5-HT1A sites in the prefrontal and temporal cortices of schizophrenics relate to the pathophysiology of schizophrenia.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Aged; Binding, Competitive; Cell Membrane; Cerebral Cortex; Female; Guanosine Triphosphate; Guanylyl Imidodiphosphate; Hippocampus; Humans; Kinetics; Male; Middle Aged; Receptors, Serotonin; Reference Values; Schizophrenia; Serotonin Antagonists; Temporal Lobe; Tetrahydronaphthalenes

alpha-Adrenergic receptor function was assessed in platelets from drug-free schizophrenic patients and control subjects. The number of alpha-receptors was similar in platelet membranes from schizophrenic patients and control subjects. In intact platelets from schizophrenic male, but not female, patients, prostaglandin E1 (PGE1)-stimulated cyclic adenosine monophosphate (cAMP) level was less than in control subjects. This defect may be due, at least in part, to decreased adenylate cyclase activity. In platelet lysates from schizophrenic patients, but not from normal control subjects, adenylate cyclase activity was diminished and PGE1-stimulated adenylate cyclase activity could be restored partially by the addition of guanosine triphosphate. Treatment with neuroleptic drugs or lithium carbonate did not change alpha-receptor number or cAMP production in platelets from schizophrenic patients, but high doses of propranolol hydrochloride increased cAMP production without affecting the number of alpha-receptors. If the production of cAMP in neurons is similar to that in platelets, diminished cAMP production may be associated with a vulnerability to schizophrenia.

Topics: Adenylyl Cyclases; Adult; Antipsychotic Agents; Blood Platelets; Cell Membrane; Cyclic AMP; Female; Guanosine Triphosphate; Humans; Lithium; Lithium Carbonate; Male; Norepinephrine; Propranolol; Prostaglandins E; Receptors, Adrenergic; Receptors, Adrenergic, alpha; Schizophrenia; Sex Factors

The antipsychotic effects of neuroleptic drugs are mediated by dopamine DA-2 receptors, and dopamine DA-1 receptors, linked to cyclic AMP formation, are not involved. Dopamine receptor binding is enhanced in brain specimens of deceased schizophrenic patients, an increase which may relate to chronic neuroleptic treatment. The binding of 3H-butyrophenones to dopamine receptors can be used for a radioreceptor assay that detects blood levels of all clinically used neuroleptics and their pharmacologically active metabolites and may facilitate routine monitoring of blood levels.

Topics: Adenylyl Cyclases; Antipsychotic Agents; Apomorphine; Brain; Brain Chemistry; Caudate Nucleus; Dopamine; Guanosine Triphosphate; Haloperidol; Humans; Nucleus Accumbens; Radioligand Assay; Receptors, Dopamine; Schizophrenia; Spiperone