Ethanol reduces tolerance, sensitization, and up-regulation of D2-receptors after subchronic haloperidol.
To study the interrelationships between dopamine D2-receptor density and behavioral responses after chronic treatment with neuroleptics female Wistar rats received haloperidol (HP; 14 mg/l), ethanol (ETOH; 5 vol.%), a combination of both, or tap water as drinking fluids for one or two weeks. Mean intake doses ranged between 1.28 and 1.48 mg/kg/day (HP) and between 3.7 and 4.8 g/kg/day (ETOH). HP administered for one or two weeks raised the number of [3H]spiroperidol binding sites in the striatum by 55%. Concomitant administration of ETOH diminished the increase of Bmax to 23%. The up-regulation was even reversed when ETOH was added with a delay of one week, although the drug alone had no effect on dopamine-D2-receptor density. KD values were not substantially affected. During HP treatment the rats established a tolerance to the motor sedation which was measured by circadian motility recordings. Coadministration of ETOH reduced the development of tolerance, the activity remained at a depressed level. Acute applications of HP (0.3, 0.6, and 0.9 mg/kg, or saline, respectively) also revealed tolerance to the drug for various behavioral responses (exploratory locomotion, rearing, rotarod performance, catalepsy). The tolerance was reduced in all those animals which had received combinations of ETOH and HP. The reduction was most pronounced for the cataleptic response. Pretreatment with ETOH alone had no effect. Sensitization to dopamine agonists was studied by apomorphine-induced stereotypies (licking, sniffing, and forepaw scratching). As expected, chronic HP enhanced the responses. The increased number of stereotypies was reduced in rats pretreated with the combination, although ETOH alone did not affect the response. The reduction was most pronounced for licks.(ABSTRACT TRUNCATED AT 250 WORDS)
Wolffgramm
J
J
Department of Neuropsychopharmacology, Free University, Berlin, F.R.G.
Rommelspacher
H
H
Buck
E
E
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology*; D007700:Kinetics; D004856:Postural Balance / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000187:drug effects* / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
D011954:Receptors, Dopamine; D000431:Ethanol; D013134:Spiperone; D006220:Haloperidol; D001058:Apomorphine