REGULATION OF [H-3] DOPAMINE RELEASE FROM MESOLIMBIC AND MESOCORTICALAREAS OF GUINEA-PIG BRAIN BY SIGMA-RECEPTORS

The role of sigma (sigma) receptors in brain function is poorly define d. They are located in limbic areas, including nucleus accumbens (NAG) and prefrontal cortex (PFC), both of which are thought to be involved in schizophrenia. Many antipsychotics (APs), including haloperidol, b ind with high affinity to sigma receptors. Dopaminergic hyperactivity in NAC is thought to underlie positive symptoms of schizophrenia, whil e dopaminergic hypoactivity in PFC is thought to underlie negative sym ptoms. Sigma receptors regulate N-methyl-D-ASPARTATE (NMDA)-STIMULATED [H-3]dopamine ([H-3]DA) release in caudate-putamen (CP), the neuroana tomical substrate for extrapyramidal side effects resulting from chron ic AP treatment. In the current study, we investigated whether a recep tors could similarly regulate DA release in mesolimbic and mesocortica l tissue, and the relative participation of different sigma receptor s ubtypes in this process. We found that, in NAC, regulation of DA relea se by the prototypical sigma agonist (+) pentazocine was mediated pred ominantly by the sigma(1) receptor, whereas in the PFC a portion of th e (+)pentazocine effect was likely mediated by the sigma(2) receptor. We also observed, in both the NAC and PFC, that regulation of DA relea se by the sigma agonist BD737 was mediated primarily by the sigma(1) r eceptor. In addition, we determined that (+)pentazocine or BD737 effec ts on DA release were not mediated via opioid receptors, nor the phenc yclidine (PCP) binding site within the NMDA receptor-operated cation c hannel, nor by sigma receptor effects upon [H-3]DA accumulated by nora drenergic terminals in PFC.