Time-course of the cannabinoid receptor down-regulation in the adult rat brain caused by repeated exposure to Δ9-tetrahydrocannabinol
✍ Scribed by Julián Romero; Fernando Berrendero; Jorge Manzanares; Alberto Pérez; Javier Corchero; J. Angel Fuentes; J. Javier Fernández-Ruiz; J. Antonio Ramos
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 263 KB
- Volume
- 30
- Category
- Article
- ISSN
- 0887-4476
No coin nor oath required. For personal study only.
✦ Synopsis
Recent studies have demonstrated that the pharmacological tolerance observed after prolonged exposure to plant or synthetic cannabinoids in adult individuals seems to have a pharmacodynamic rather than pharmacokinetic basis, because downregulation of cannabinoid receptors was assessed in the brain of cannabinoid-tolerant rats. In the present study, we have examined the time-course of cannabinoid receptor down-regulation by analyzing cannabinoid receptor binding, using autoradiography, and mRNA expression, using in situ hybridization, in several brain structures of male adult rats daily exposed to ⌬ 9 -tetrahydrocannabinol (⌬ 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 progressive decrease in cannabinoid receptor binding. Two facts deserve to be mentioned. First, the pattern of this down-regulation process presented significant regional differences in terms of onset of the decrease and magnitude reached. Second, the loss of cannabinoid receptor binding was usually accompanied by no changes in its mRNA expression. Thus, some structures, such as most of the subfields of the Ammon's horn and the dentate gyrus in the hippocampus, exhibited a rapid (it appeared after 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 ⌬ 9 -THC administration. However, no changes 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 ⌬ 9 -THC administration), and, in particular, in the globus pallidus (more than 3 days). The magnitude of the decrease in binding was also more moderate, with maximal reductions always less than 28%. No changes were seen in the entopeduncular nucleus and only a trend in the medial caudate-putamen. However, the decrease in binding in some basal ganglia was, in this case, accompanied by a decrease in mRNA levels in the lateral caudate-putamen, but this appeared after 7 days of daily ⌬ 9 -THC administration and, hence, after the onset of binding decrease. In the limbic structures, cannabinoid receptor binding decreased in the septum nuclei (it needed at least 3 days of daily ⌬ 9 -THC administration), tended to diminish in the nucleus 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