Microcatalepsy and disruption of forelimb usage during operant behavior: differences between dopamine D1 (SCH-23390) and D2 (raclopride) antagonists

Abstract

In an experiment designed to distinguish between the behavioral consequences of treatment with SCH-23390, a D1 dopamine receptor blocker, and raclopride, a D2 antagonist, rats were trained to perform a water-reinforced forelimb operant response. Response rate and the duration of each forelimb contact with the operandum were recorded. In addition, the durations of the rat's visits to the reward well were detected by a photobeam which was blocked by the rat's muzzle as it remained at the reward well. In a between-groups dosing design, separate groups of rats (11-13 rats/group) received SCH-23390 (0, 0.01, 0.02, 0.04, 0.08, 0.12 mg/kg, IP, 30 min) or raclopride (0. 0.05, 0.1, 0.2, 0.4, 0.8 mg/kg, IP, 30 min) for 21 consecutive days. Quantitative analyses indicated that for comparable amounts of operant rate reduction, raclopride had a significantly greater tendency than SCH-23390 to increase the duration of operant responses and to increase the maximum muzzle entry duration (i.e., to induce microcatalepsy). The results support the idea that at relatively low doses D2 antagonism is more likely than D1 antagonism to produce effects identified preclinically with extrapyramidal side effects.

Haloperidol, raclopride, and eticlopride induce microcatalepsy during operant performance in rats, but clozapine and SCH 23390 do not

“…The validity of rodent catalepsy as a model of EPS rests in part on the fact that clozapine, an atypical antipsychotic drug practically devoid of EPS (Meltzer 1992 ), does not induce catalepsy (e.g., Costall andNaylor 1975, Hoffman andDonovan 1995), whereas potent selective D 2 antagonists such as haloperidol induce robust catalepsy in the laboratory rat (e.g., Sanberg et al 1988;Hoffman and Donovan 1995) and have a high probability of producing EPS in the clinic (Baldessarini 1996). Previous work in our laboratory has detected cataleptic-like, arrest of movement phenomena during the course of operant sessions in rats treated acutely with haloperidol (Fowler et al 1991) or subchronically with the selective D 2 antagonist (Ogren et al 1986) raclopride (Fowler and Liou 1994). The immobility was measured by recording the amount of time that the rat's muzzle blocked a photobeam positioned in the dipper well where the rat consumed the reinforcer.…”

Subchronic effects of clozapine and haloperidol on rats' forelimb force and duration during a press-while-licking task

“…The fact that both clozapine and haloperidol had enduring duration-lengthening effects, raises the possibility that the duration lengthening under these circumstances may somehow be related to antipsychotic potential. This possibility may seem to contradict our earlier reported hypothesis that the lengthening of operant response duration by typical neuroleptics (Fowler and Kirkpatrick 1989;Liao and Fowler 1990) or D 2 dopamine receptor blockers (Fowler and Liou 1994) reflects bradykinesia or Parkinsonism. But in these earlier studies the responses were all brief, ballistic forelimb strikes with durations of about 0.2 s or less, and were thus very different, in neuromuscular demands and in stimulus supports, from the several seconds of controlled forelimb force required in the current press-while-licking task.…”

cAMP-dependent protein kinase and reward-related learning: intra-accumbens Rp-cAMPS blocks amphetamine-produced place conditioning in rats

“…D 1 -like agonists impair responding for a number of rewards, whereas D 2 -like agonists often enhance rewarded responses; D 1 -like agonists may mask (occlude) the signal generated in DA neurons by reward, producing the observed impairments (Beninger and Miller 1998). Both D 1 -and D 2 -like antagonists block responding for reward, but detailed analyses have shown a dissociation of reward-blocking from anti-locomotor effects for D 1 -but not D 2 -like antagonists (Fowler and Liou 1994). Thus, the critical role for D 1 -like receptors in reward-related learning provides indirect support for the hypothesis that stimulation of the cAMP-PKA pathway may also play an important role.…”