Serotonin [1A] receptor agonism in the expression of behavioral dopaminergic supersensitivity in subchronic haloperidol treated rats

ABSTRACT

The idea that serotonin [5-hydroxytryptamine; 5-HT] is contributed in schizophrenia has long been advocated and alterations in 5-HT neurotransmission has been hypothesized to modulate both the therapeutic and extrapyramidal symptoms [EPS] liability of conventional neuroleptics. The 8-hydroxy-2-[di-n-propylamino] tetralin [8-OH-DPAT], a preferential 5-HT1A ligand, has been reported to attenuate EPS functions of haloperidol in animals. In view of a possible role of 5-HT1A receptors in the management of EPS functions of a neuroleptic drug, the present study was designed to investigate behavioral responses of 8-OH-DPAT at a challenge dose of 0.5mg/kg in rats with subchronic haloperidol administration at a dose of 5mg/kg twice daily for 5 days. The intensity of 5-HT syndrome provoked by 8-OH-DPAT was taken as a measure of postsynaptic responses. In the present study administration of haloperidol at a dose of 5mg/kg twice daily for 5 days decreased locomotion significantly [p<0.01] in familiar [home cage] environment. Subchronic administration of haloperidol at the same dose elicited significant [p<0.01] cataleptic responses in rats when compared with saline treated rats. Results revealed that 8-OH-DPAT-induced hyperlocomotion [p<0.05] and forepaw treading [p<0.1] were significantly smaller in rats pre-treated with haloperidol for 5 days than repeatedly saline injected rats. Conversely, the other components of the syndrome i.e. flat body posture [p<0.001], hind limb abduction [p<0.001] and straub tail [p<0.01] were significantly greater in repeated haloperidol treated rats when compared with repeated saline injected rats. These findings help to demonstrate a causal link between the upregulation of DA-D2 receptors and the decrease in the effectiveness of presynaptic 5-HT1A receptors following subchronic haloperidol administration and this may further help to yield an antipsychotic agent with an improved profile of efficacy to EPS, thereby widening its therapeutic window