Effects of chronic delta9-tetrahydrocannabinol on rat midbrain dopamine neurons: an electrophysiological assessment.

Delta-9-tetrahydrocannabinol (delta9-THC), the principal psychoactive ingredient in marijuana elicits a variety of physiological effects in animals and humans, and with repeated exposure tolerance develops to most of its effects. However, studies in humans found that tolerance did not occur to the pleasurable marijuana "high". Since ventral tegmental dopamine neurons play a pivotal role in drug reinforcement and reward, and possibly in the euphorigenic quality of marijuana, the present study sought to determine whether tolerance develops to the neurophysiological response elicited in these neurons by delta9-THC. Using single-unit extracellular recordings the activity of midbrain ventral tegmental (VTA) and substantia nigra pars compacta (SNpc) dopamine neurons was measured in animals that had received twice-daily injections of 5 mg/kg delta9-THC for 14 days. Cannabinoid-induced changes in body temperature, locomotion, and catalepsy were also assessed in the same animals. After 2 weeks tolerance had developed to delta9-THC-induced hypothermia, catalepsy and reduction in locomotor activity. In naive animals and in animals that had received twice-daily vehicle injections for 14 days, delta9-THC increased VTA neuronal firing by 52% and 46%, respectively, while SNpc neurons showed increases of 23% and 30%, respectively. Following chronic cannabinoid treatment, however, SNpc neurons were significantly less responsive to delta9-THC with a maximum increase in rate of only 3%, while VTA neurons continued to show a robust increase in firing rate (+45%) when challenged with THC. These results suggest that VTA and SNpc dopamine neurons develop a differential response to delta9-THC following long-term cannabinoid exposure. This finding may be relevant to the observation that in humans tolerance occurs to many of marijuana's physiological effects but not to its euphorigenic actions.