Time-dependent effects of repeated THC treatment on dopamine D23 receptor-mediated signalling in midbrain and striatum.
This study examined the time-course of alterations in levels and functional sensitivities of dopamine D23 receptors (D23R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D23R levels in striatum, as assessed using (3)H-()-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D23R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein (3)H-()-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D23R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D23R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D23R function and a decreased DA presynaptic signaling, mediated by increased D23R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D23R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence.