Clozapine does not require 5-HT1A receptors to block the locomotor hyperactivity induced by MK-801: Clz and MK-801 in KO1A mice

5-HT1A receptors mediate some effects of atypical antipsychotic drugs, such as the increase in cortical dopaminergic function, an effect likely related to the superior efficacy of these drugs on negative symptoms and cognitive deficits of schizophrenia. To examine whether 5-HT1A receptors are involved in the therapeutic action of clozapine (Clz) on positive symptoms, here we examined the ability of Clz to antagonize the behavioural syndrome induced by the non-competitive N-methyl-d-aspartate receptor antagonist, MK-801 in wild-type (WT) and 5-HT1A-receptor knockout (KO1A) mice. MK-801 administration induced hyperlocomotion, ataxia, stereotypies and an alteration of the locomotor pattern in both genotypes. However, some symptoms of the behavioural syndrome induced by MK-801 were less intense in KO1A mice compared with wild-type mice. Clz antagonized the majority of MK-801-induced effects in both strains of mice. No differences between genotypes were noted for the ability of Clz to antagonize the hyperlocomotion, yet Clz was more effective in preventing the increased activation time, short movements, circling behaviour and hind-limb abduction in KO1A mice. The present results indicate that 5-HT1A receptors do not play a critical role in Clz-induced antagonism of the main hyperactivity signs evoked by MK-801, suggesting that 5-HT1A receptors are not involved in the therapeutic action of Clz on positive symptoms of schizophrenia.

study was supported by Fondo Clemente Estable (Grant 10.029) and Ministerio de Ciencia e Innovación (SAF2007-62378). AB is recipient of a Ramón y Cajal contract from MICINN-IDIBAPS. AC is recipient of a Postdoctoral fellowship from FIS-ISCIII.