THE ROLE OF THE FRONTAL-CORTEX IN THE MOUSE IN BEHAVIORAL SENSITIZATION TO AMPHETAMINE

Pharmacological studies have shown that a variety of neuroeffectors ar e involved in behavioral sensitization to amphetamine-induced stereoty py. In the present work, the effect of some of these drugs on sensitiz ation was studied after intracortical administration in order to deter mine the role of the cortex in mediating their systemic effects. The d opamine antagonists sulpiride and spiperone were both ineffective agai nst the acute response to amphetamine: nevertheless, both blocked the induction of sensitization, suggesting that the mesocortical dopamine pathway is not involved in the acute response but is necessary for the induction of sensitization. Both CPP, an NMDA receptor antagonist, an d THIP, a GABA(A) agonist, blocked the acute response and the inductio n of sensitization to amphetamine. On the other hand, mecamylamine, th e nicotinic cholinergic antagonist, failed to affect either the acute response or the induction of sensitization, which suggests that the co rtex is not a locus of its activity. Anisomycin, an inhibitor of prote in synthesis, and diltiazem, a calcium-channel blocker, were both inef fective against the acute response, but both blocked induction. All of the drugs, except CPP and THIP, were ineffective against the expressi on of sensitization; therefore, the ability of the other drugs to bloc k expression must reside within another locus. Bicuculline injected in tracortically in non-convulsant doses produced a stereotypy indistingu ishable from that induced by amphetamine: and the effect was readily a ntagonized by CPP administered either systemically or intracortically. In contrast, sulpiride by either route of administration failed to bl ock the bicuculline-induced stereotypy; we conclude, therefore, that t he stereotypic effect of bicuculline is not mediated by dopamine. Thes e results imply that amphetamine-induced stereotypy is mediated in the cortex by the removal of the inhibitory control of the excitatory sys tem. The data also suggest that cortical dopamine, as well as the NMDA and GABA(A) systems, is important in sensitization to amphetamine. In general the data demonstrate that different neuroeffectors involved i n sensitization exert their effects at different brain loci.