Differential development of autoreceptor subsensitivity and enhanced dopamine release during amphetamine sensitization

Various changes in the function of dopamine neurons have been proposed to underly the development of behavioral sensitization to the locomotor stimulant effects of d-amphetamine. The present study examined the relative importance of two such mechanisms after both short (3-4 days off) and longer (10-14 days off) withdrawals from repeated amphetamine or saline injection (1 mg/kg/day, days 1-5 and 8-12). First, single-unit recording was used to examine the sensitivity of impulse-regulating somatodendritic autoreceptors located on mesoaccumbens dopamine neurons in the rat ventral tegmental area. Second, in vivo microdialysis was used to examine the ability of amphetamine challenge to increase extracellular dopamine levels in the rat nucleus accumbens. Amphetamine-treated rats exhibited robust behavioral sensitization at both time points as compared to saline-treated rats. At 3 to 4 days off, autoreceptor subsensitivity was observed in the ventral tegmental area of amphetamine-treated rats, but there was no significant change in the ability of amphetamine to increase extracellular dopamine levels in nucleus accumbens. However, after 10 to 14 days off, autoreceptor subsensitivity was no longer observed, but amphetamine challenge resulted in a significantly greater increase in extracellular dopamine levels in amphetamine-treated as compared to saline-treated rats. These findings suggest that autoreceptor subsensitivity is a transient effect which may be related to the development of sensitization, whereas enhancement of amphetamine-stimulated dopamine release does not accompany early stages of behavioral sensitization, but may be involved in the persistance of the phenomenon after longer withdrawal periods.