Alterations in cerebral glutamic acid decarboxylase and 3H-flunitrazepam binding during continuous treatment of rats for up to 1 year with haloperidol, sulpiride or clozapine.
Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and 3H-flunitrazepam binding. Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration. The number of specific 3H-flunitrazepam binding sites (Bmax) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, Bmax for 3H-flunitrazepam binding to cerebellar membrane preparations was decreased by 12 months administration of all drug treatments. The dissociation constant (Kd) for 3H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25-100 microM) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific 3H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003024:Clozapine / Q000494:pharmacology; D005445:Flunitrazepam / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013469:Sulpiride / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism* / Q000502:physiology
D011619:Psychotropic Drugs; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D013469:Sulpiride; D005968:Glutamate Decarboxylase; D003024:Clozapine; D006220:Haloperidol