Cannabinoids are known to exert mainly excitatory effects on dopaminergic cells of the ventral tegmental area (VTA). We have utilized an in vivo multiple-single unit electrophysiological approach to assess different neuronal contributions that may ultimately lead to excitation in this area. Baseline neuron recordings, using low impedance microwires, showed a variety of waveforms with a wide range of durations (0.8-3.2 ms). In the first experiment systemic injection of the potent cannabinoid agonist HU210 (100 microg/kg, i.p.) led predominantly to an increase in firing rate (approximately 214%, compared to pre-drug) in slowly firing cells with broad action potentials, possibly driven by a majority of presumed dopaminergic neurons (n = 31). However, the firing rate of some units was either unaffected (<25%, n = 9) or even decreased (approximately 67%, n = 9) following cannabinoid injection concomitantly with excitation. Apomorphine (75 microg/kg, i.p.) injected following HU210 produced a marked inhibition of both responses (approximately 76%) in 39 out of 49 cells. The second group of animals was treated with the CB(1) receptor antagonist SR141716A (1 mg/kg, i.p.), which had no effect when injected alone but prevented all HU210-evoked changes in firing rate suggesting that cannabinoid receptors mediated the observed responses (n = 39). Taken together, the present results suggest that the observed actions of cannabinoids may involve complex neurotransmitter interactions leading to differential effects on dopamine release. These heterogeneous neuronal responses are likely to underly the behavioural discrepancies reported in animal models of cannabinoid reinforcement.