Neuronal activity was recorded from the ventral tegmental area (VTA) of immobilized, locally anesthetized rats on the day immediately following long-term treatment (twice daily for 6 consecutive days) with saline, 1.0 or 5.0 mg/kg d-amphetamine (d-AMPH). Each rat was challenged intravenously with d-AMPH (beginning with 0.0625 mg/kg) or with 0.005 mg/kg apomorphine. Treatment with d-AMPH significantly reduced the ability of this drug to inhibit VTA activity. In fact, nearly half of the neurons in the high-dose treatment group were excited by d-AMPH, whereas only 20% of control neurons showed this response. Moreover, apomorphine routinely accelerated firing rate in the VTA following treatment with 5.0 mg/kg d-AMPH but this response was never observed in control neurons, not even in those that were excited by d-AMPH. Thus, tolerance appears to develop to the ability of dopamine agonists to inhibit VTA activity and this effect may be mediated, at least in part, by a subsensitivity of inhibitory dopamine autoreceptors.