Ethanol reduces tolerance, sensitization, and up-regulation of D 2-receptors after subchronic haloperidol

Abstract

To study the interrelationships between dopamine D 2-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 B max 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-D 2-receptor density. K D 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. The influence of coadministration of ETOH on both tolerance to dopamine antagonists and sensitization to agonists after chronic HP matches to its effect on D 2-receptors. For catalepsy and stereotyped licking there was a nearly perfect linear correlation between the maximum number of D 2-receptors in the striatum and the behavioral responses. For the other paradigms the degree of reduction of tolerance and sensitization after chronic HP due to concomitant application of ethanol was less than for B max. It is suggested that the development of tolerance and sensitization is coupled to the number of D 2-receptors and that drugs like ETOH interfere with both neuronal and behavioral adaptation during chronic treatment with neuroleptics.