Immunohistochemical evidence for the involvement of gonadotropin releasing hormone in neuroleptic and cataleptic effects of haloperidol in mice

•GnRH antagonist attenuates neuroleptic and cataleptic effect of haloperidol in mice.•Haloperidol increased GnRH immunoreactivity (GnRH-ir) in various regions of brain.•GnRH antagonist did not alter haloperidol induced increase in GnRH immunoreactivity.•No GnRH-ir seen in hippocampus or components of basal ganglia, but are known to interact with GnRH-ir positive areas.•GnRH probably contributes neuroleptic and cataleptic effect of haloperidol in mice.

Blockade of dopamine D2 receptor by haloperidol is attributed for neuroleptic and cataleptic effects; and also for the release of gonadotropin releasing hormone (GnRH) from the hypothalamus. GnRH agonist is reported to exhibit similar behavioural effects as that of haloperidol, and pre-treatment with GnRH antagonist is shown to attenuate the effects of haloperidol, suggesting a possibility that GnRH might mediate the effects of haloperidol. To substantiate such possibility, the influence of haloperidol on GnRH immunoreactivity (GnRH-ir) in the brain was studied in vehicle/antide pre-treated mice by peroxidase–antiperoxidase method. Initially, an earlier reported antide–haloperidol interaction in rat was confirmed in mice, wherein haloperidol (250 μg/kg, i.p.) exhibited suppression of conditioned avoidance response (CAR) on two-way shuttle box, and induced catalepsy in bar test; and pre-treatment with antide (50 μg/kg, s.c., GnRH antagonist) attenuated both effects of haloperidol. Immunohistochemical study was carried out to identify GnRH-ir in the brain, isolated 1 h after haloperidol treatment to mice pre-treated with vehicle/antide. The morphometric analysis of microphotographs of brain sections revealed that haloperidol treatment increased integrated density units of GnRH-ir in various regions of the limbic system. Considering basal GnRH-ir in vehicle treated group as 100%, the increase in GnRH-ir after haloperidol treatment was by 100.98% in the medial septum; 54.26% in the bed nucleus of the stria terminalis; 1152.85% in the anteroventral periventricular nucleus; 120.79% in the preoptic area–organum vasculosum of the lamina terminalis and 138.82% in the arcuate nucleus. Antide did not influence basal and haloperidol induced increase in GnRH-ir in any of the regions.As significant increase in GnRH-ir after haloperidol treatment was observed in such regions of the brain which are reported to directly or indirectly communicate with the hippocampus and basal ganglia, the regions respectively responsible for neuroleptic and cataleptic effects; and as GnRH antagonist eliminated the effects of haloperidol without affecting GnRH-ir, it appears that GnRH released by haloperidol mediates its neuroleptic and cataleptic effects.