Effects of chronic Delta(9)-tetrahydrocannabinol on rat midbrain dopamine neurons: an electrophysiological assessment

Delta-9-tetrahydrocannabinol (Delta(9)-THC), the principal psychoactive ing redient in marijuana elicits a variety of physiological effects in animals and humans, and with repeated exposure tolerance develops to most of its ef fects. However, studies in humans found that tolerance did not occur to the pleasurable marijuana "high". Since ventral tegmental dopamine neurons pla y a pivotal role in drug reinforcement and reward, and possibly in the euph origenic quality of marijuana, the present study sought to determine whethe r tolerance develops to the neurophysiological response elicited in these n eurons by Delta(9)-THC. Using single-unit extracellular recordings the acti vity of midbrain ventral tegmental (VTA) and substantia nigra pars compacta (SNpc) dopamine neurons was measured in animals that had received twice-da ily injections of 5 mg/kg Delta(9)-THC for 14 days. Cannabinoid-induced cha nges in body temperature, locomotion, and catalepsy were also assessed in t he same animals. After 2 weeks tolerance had developed to Delta(9)-THC-indu ced hypothermia, catalepsy and reduction in locomotor activity. In naive an imals and in animals that had received twice-daily vehicle injections for 1 4 days, Delta(9)-THC increased VTA neuronal firing by 52% and 46%, respecti vely, while SNpc neurons showed increases of 23% and 30%, respectively. Fol lowing chronic cannabinoid treatment, however, SNpc neurons were significan tly less responsive to Delta(9)-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 dop amine neurons develop a differential response to Delta(9)-THC following lon g-term cannabinoid exposure. This finding may be relevant to the observatio n that in humans tolerance occurs to many of marijuana's physiological effe cts but not to its euphorigenic actions. (C) 2000 Elsevier Science Ltd. All rights reserved.