Behavioural and biochemical alterations following haloperidol treatment and withdrawal: the animal model of tardive dyskinesia reexamined.
Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal gamma-aminobutyric acid content and glutamic acid decarboxylase activity by 17% and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000201:enzymology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000378:metabolism; D006220:Haloperidol / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects; D013239:Stereotyped Behavior / Q000187:drug effects; D013375:Substance Withdrawal Syndrome / Q000201:enzymology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D018377:Neurotransmitter Agents; D011954:Receptors, Dopamine; D014446:Tyrosine 3-Monooxygenase; D005968:Glutamate Decarboxylase; D006220:Haloperidol; D001058:Apomorphine; D004298:Dopamine; D009638:Norepinephrine