Repeated administration of Sigma ligands alters the population activity of rat midbrain dopaminergic neurons

Acute and repeated administration of antipsychotic drugs produce distinctive profiles of electrophysiological effects on the population activity of midbrain dopaminergic (DA) neurons which correlate with their clinical effects. Sigma receptors have been hypothesized to be involved in psychosis and in the efficacy of antipsychotic drugs, but little is known about the effects of repeated treatment with sigma ligands on the activity of midbrain DA neuronal populations. In the present study, the cells-per-track cell-sampling method was used to evaluate the effects of 3 sigma ligands on the numbers of spontaneously active A9 and A10 DA neurons in chloral hydrate-anesthetized rats. One-hour pretreatment with either (+)-pentazocine (10 mg/kg, i.p.), DTG (2 mg/kg, i.p.), or JO 1784 (1 or 10 mg/kg, s.c.) did not alter the number of spontaneously active DA neurons encountered per electrode track. Repeated treatment (21 daily injections) with (+)-pentazocine (1 or 10 mg/kg) or DTG (0.2 or 2 mg/kg) increased the number of A10 DA cells per track; JO 1784 (10 mg/kg but not 1 mg/kg) moderately decreased the number of active A9 DA cells and increased the firing rate of A10 DA neurons. The effect of JO 1784 on A9 DA neurons was not due to depolarization inactivation. The effects of all 3 sigma ligands differ from those of antipsychotic drugs, all of which inactivate A10 DA neurons after repeated treatment. Clinical studies are necessary to determine if selective sigma ligands will provide a novel alternative to DA antagonists in the treatment of psychosis.