Hypersensitivity of nucleus accumbens neurons to methamphetamine and dopamine following repeated administrations of methamphetamine.

Abstract

Methamphetamine (MAP) abuse is known to induce reverse tolerance in humans. Electrophysiological studies were performed to elucidate time-related changes in dopamine (DA) receptor sensitivities to DA and MAP after withdrawal following repeated MAP administrations. MAP (5 mg/kg) or physiological saline (1 ml/kg) was injected i.p. to rats once daily for 5 days. Single neuronal activities of nucleus accumbens (Acc) of 5-day MAP-administrated rats were extracellularly recorded with a glass microelectrode attached along a seven-barreled micropipette under chloral hydrate anesthesia. Each barrel was respectively filled with DA, MAP, haloperidol, glutamate and NaCl. Drugs were microiontophoretically applied to the immediate vicinity of Acc neurons receiving inputs from the parafascicular nucleus (Pf) of thalamus. Spikes elicited by Pf stimulation- and glutamate-induced firing were inhibited by iontophoretic application of either DA or MAP at doses of 20-40 nA in the saline-treated rats: EC50 for DA and MAP were 23.8 and 23.2 nA, respectively. At 24-30 hr after the final MAP administration, however, the inhibitory effects of both DA and MAP on Pf stimulation- and glutamate-induced firing of Acc neurons were less pronounced than those in the saline-treated animals. Furthermore, spontaneous firing was enhanced during haloperidol application. On day 5 postadministration, the inhibition of Acc neurons by DA or MAP was significantly more marked than that of saline-treated animals. On day 10 postadministration, the inhibition of Acc neurons by DA or MAP was comparable to that in controls. These results indicate that repeated administrations with MAP induce hyposensitivity and hypersensitivity of Acc neurons to DA and MAP at 24-30 hr and on day 5 postadministration, respectively.