Reversal of neuroleptic-induced catalepsy by novel aryl-piperazine anxiolytic drugs

Abstract

The novel anxiolytic drug, buspirone, reverses catalepsy induced by haloperidol. A series of aryl-piperazine analogues of buspirone and other 5-hydroxytryptaminergic agonists were tested for their ability to reverse haloperidol induced catalepsy. Those drugs with strong affinity for 5-hydroxytryptamine1a receptors were able to reverse catalepsy. Drugs with affinity for other 5-HT receptors or weak affinity were ineffective. However, inhibition of postsynaptic 5-HT receptors neither inhibited nor potentiated reversal of catalepsy and leaves open the question as to the site or mechanism for this effect.

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

“…Second, numerous laboratories have demonstrated anticataleptic properties of 5-HT 1A agonists in rodents, indicating that activation of 5-HT 1A receptors should reduce EPS induced by D 2 receptor blockade (Invernizzi et al 1988;McMillen et al 1988;Wadenberg et al 1999). The extent to which 5-HT 1A agonists are able to reverse neurolepticinduced catalepsy is dependent on the level of efficacy of the ligand: relatively high efficacy activation, for example by the prototypical agonist, 8-OH-DPAT, is necessary to completely abolish neuroleptic-induced catalepsy (Kleven et al , 2005Prinssen et al 2002Prinssen et al , 1996.…”

Bifeprunox: A Novel Antipsychotic Agent with Partial Agonist Properties at Dopamine D2 and Serotonin 5-HT 1A Receptors

“…Experimentally, 5-HT 1A receptor stimulation produces a preferential increase in prefrontal cortex DA release [23], an effect that is expected to be beneficial against negative and cognitive symptoms in schizophrenia. It is also possible that 5-HT 1A receptor agonism may contribute both to a general antipsychotic effect as well as a reduced EPS liability [24][25][26]. Indeed, 5-HT 1A receptors have been reported by some to be upregulated in frontal cortex of schizophrenic individuals as determined postmortem [27].…”

Aripiprazole (OPC-14597) fully substitutes for the 5-HT 1A receptor agonist LY293284 in the drug discrimination assay in rats

“…A growing number of studies show that stimulation of 5-HT 1A receptors attenuates the extrapyramidal side effects of antipsychotics. For example, 5-HT 1A receptor activation attenuates antipsychotic-induced side effects in humans (Yoshida et al 1998), non-human primates (Christoffersen and Meltzer 1998), antipsychotic-induced catalepsy in rats (Broekkamp et al 1988;Invernizzi et al 1988;McMillen et al 1988;Wadenberg and Ahlenius 1991;Neal-Beliveau et al 1993;Andersen and Kilpatrick 1996;Wadenberg 1996;Prinssen et al 1999Prinssen et al , 2002, and appeared to inhibit expression of D 2 receptor-mediated stereotypic behaviors (Piercey et al 1994).…”