(−)Alprenolol potentiates the disrupting effects of dizocilpine on sensorimotor function in the rat

Abstract

The β-adrenoceptor antagonist as well as serotonin 5-HT₁ receptor antagonist, (−)alprenolol, was found to potentiate the disrupting effect of the non-competitive NMDA receptor antagonist, dizocilpine, on prepulse inhibition (PPI) of the acoustic startle response (ASR) in the rat. The facilitating effect of dizocilpine on ASR amplitude was also potentiated by (−)alprenolol. (−)Alprenolol by itself did not affect either of these measures. These effects did not seem to be related to the unselective β-adrenoceptor antagonist property of (−)alprenolol, since combined pretreatment with the β₁- and β₂-adrenoceptor antagonists, metoprolol and ICI 118551, did not alter the effects of dizocilpine on startle behaviour. However, a serotonergic influence was suggested by the fact that a facilitating effect of dizocilpine on ASR amplitude was also obtained by pretreatment with the 5-HT precursor, L-5-HTP, in benserazide-pretreated rats. Furthermore, pretreatment with the 5-HT₂ selective receptor antagonist, MDL 100907, significantly reduced the (−)alprenolol-induced potentiation of the effects of dizocilpine on startle behaviour, while the 5-HT₃ selective receptor antagonist, ondansetron, failed to do that. Finally, the (−)alprenolol-induced potentiation of the effects of dizocilpine was significantly reduced by pretreatment with the atypical antipsychotic, clozapine, and by the potential antipsychotic and selective dopamine D₂ receptor antagonist, raclopride. This study suggests that altered 5-HT activity may influence the effects of psychotomimetic drugs such as dizocilpine on sensorimotor function, and this observation may have implications for the pharmacological treatment of schizophrenia in humans.