TIME-COURSE OF THE CANNABINOID RECEPTOR DOWN-REGULATION IN THE ADULT-RAT BRAIN CAUSED BY REPEATED EXPOSURE TO DELTA(9)-TETRAHYDROCANNABINOL

Recent studies have demonstrated that the pharmacological tolerance ob served after prolonged exposure to plant or synthetic cannabinoids in adult individuals seems to have a pharmacodynamic rather than pharmaco kinetic basis, because downregulation of cannabinoid receptors was ass essed in the brain of cannabinoid-tolerant rats. In the present study, we have examined the time-course of cannabinoid receptor down-regulat ion by analyzing cannabinoid receptor binding, using autoradiography, and mRNA expression, using in situ hybridization, in several brain str uctures of male adult rats daily exposed to Delta(9)-tetrahydrocannabi nol (Delta(9)-THC) for 1, 3, 7, or 14 days. With only the exception of a few number of areas, most of the brain regions exhibited a progress ive decrease in cannabinoid receptor binding. Two facts deserve to be mentioned. First, the pattern of this down-regulation process presente d significant regional differences in terms of onset of the decrease a nd magnitude reached. Second, the loss of cannabinoid receptor binding was usually accompanied by no changes in its mRNA expression. Thus, s ome structures, such as most of the subfields of the Ammon's horn and the dentate gyrus in the hippocampus, exhibited a rapid (it appeared a fter the first injection) and marked (it reached approximately 30% of decrease after 14 days) reduction of cannabinoid receptor binding as a consequence of the daily Delta(9)-THC administration. However, no cha nges occurred in mRNA levels. Decreased binding was also found in most of the basal ganglia, but the onset of this reduction was slow in the lateral caudate-putamen and the substantia nigra (it needed at least three days of daily Delta(9)-THC administration), and, in particular, in the globus pallidus (more than 3 days). The magnitude of the decrea se in binding was also more moderate, with maximal reductions always l ess than 28%. No changes were seen in the entopeduncular nucleus and o nly a trend in the medial caudate-putamen. However, the decrease in bi nding in some basal ganglia was, in this case, accompanied by a decrea se in mRNA levels in the lateral caudate-putamen, but this appeared af ter 7 days of daily Delta(9)-THC administration and, hence, after the onset of binding decrease. In the limbic structures, cannabinoid recep tor binding decreased in the septum nuclei (it needed at least 3 days of daily Delta(9)-THC administration), tended to diminish in the nucle us accumbens and was unaltered in the basolateral amygdaloid nucleus, with no changes in mRNA levels in these last two regions. Binding also decreased in the superficial and deep layers of the cerebral cortex, but only accompanied by trends in mRNA expression. The decrease in bin ding was initiated promptly in the deep layer (after the first injecti on) and it reached more than 30% of reduction after 14 days of daily D elta(9)-THC administration, whereas, in the superficial layer, it need ed more than 3 days of daily Delta(9)-THC administration and reached l ess than 30% of reduction. Finally, no changes in binding and mRNA lev els were found in the ventromedial hypothalamic nucleus. In summary, t he daily administration of Delta(9)-THC resulted in a progressive decr ease in cannabinoid receptor binding in most of the brain areas studie d, and it was a fact that always occurred before the changes in mRNA e xpression in those areas where these existed. The onset of the decreas e in binding exhibited regional differences with areas, such as most o f the hippocampal structures and the deep layer of the cerebral cortex , where the decrease occurred after the first administration. Other st ructures, however, needed at least 3 days or more to initiate receptor binding decrease. Two structures, the entopeduncular nucleus and the ventromedial hypothalamic nucleus, were unresponsive to chronic Delta( 9)-THC administration, whereas others, the medial caudate-putamen and the basolateral amygdaloid nucleus, only exhibited trends. Synapse 30: 298-308, 1998. (C) 1998 Wiley-Liss, Inc.