Baclofen reverses the reduction in prepulse inhibition of the acoustic startle response induced by dizocilpine,but not by apomorphine

Rationale Since baclofen, the prototypical GABA_B receptor agonist, is known to reduce the activity of dopaminergic mesolimbic neurons, a putative antipsychotic property of this compound has been suggested, but the evidence for this is still controversial.Objectives The aim of the present study was to elucidate the effects of baclofen on the prepulse inhibition (PPI) of the acoustic startle response (ASR), a behavioral paradigm considered to be one of the most powerful tools for the evaluation of sensorimotor gating and for the screening of antipsychotics.Methods We tested the effects of baclofen (1.25, 2.5, 5 and 10 mg/kg IP) in rats, per se and in co-treatment with some of the substances known to induce a robust reduction of PPI, such as apomorphine (0.25 mg/kg SC) and dizocilpine (0.1 mg/kg SC). Finally, in order to ascertain whether the effects of baclofen could be ascribed to its activity on GABA_B receptors, we analyzed whether its action could be prevented by pretreatment with SCH 50911, a selective GABA_B receptor antagonist (20 mg/kg IP). All the experiments were carried out using standard procedures for the assessment of PPI of the ASR.Results Baclofen per se produced no significant change in PPI parameters. Moreover, while no effect on apomorphine-mediated alterations in PPI parameters was observed, baclofen proved able to reverse dizocilpine-induced PPI disruption, and this effect was significantly prevented by SCH 50911. On the other hand, this last compound exhibited no effects per se at the same dose.Conclusions These results indicate that GABA_B receptors are implicated in the neurobiological circuitry accounting for glutamatergic action in sensorimotor gating, and therefore can be proposed as putative new targets in the pharmacological therapy of psychotic disorders. Further studies should be addressed to evaluate more closely the clinical efficacy of baclofen in this respect.