Effects of Chronic Treatment with Δ⁹-Tetrahydrocannabinol on Cannabinoid-Stimulated [³⁵S]GTPγS Autoradiography in Rat Brain

Abstract

Chronic Delta9-tetrahydrocannabinol (Delta9-THC) administration produces tolerance to cannabinoid effects, but alterations in signal transduction that mediate these changes are not yet known. The present study uses in vitro autoradiography of agonist-stimulated [35S]GTPgammaS binding to localize cannabinoid receptor-activated G-proteins after chronic Delta9-THC treatment. Cannabinoid (WIN 55212-2)-stimulated [35S]GTPgammaS binding was performed in brain sections from rats treated chronically with 10 mg/kg Delta9-THC for 21 d. Control animals received saline or an acute injection of Delta9-THC. Acute Delta9-THC treatment had no effect on basal or WIN 55212-2-stimulated [35S]GTPgammaS binding. After chronic Delta9-THC treatment, net WIN 55212-2-stimulated [35S]GTPgammaS binding was reduced significantly (up to 70%) in most brain regions, including the hippocampus, caudate-putamen, perirhinal and entorhinal cortex, globus pallidus, substantia nigra, and cerebellum. In contrast, chronic Delta9-THC treatment had no effect on GABAB-stimulated [35S]GTPgammaS binding. In membranes and brain sections, Delta9-THC was a partial agonist, stimulating [35S]GTPgammaS by only 20% of the level stimulated by WIN 55212-2 and inhibiting WIN 55212-2-stimulated [35S]GTPgammaS at high concentrations. Because the EC50 of WIN 55212-2-stimulated [35S]GTPgammaS binding and the KD of cannabinoid receptor binding were unchanged by chronic Delta9-THC treatment, the partial agonist actions of Delta9-THC did not produce the decrease in cannabinoid-stimulated [35S]GTPgammaS binding. These results suggest that profound desensitization of cannabinoid-activated signal transduction mechanisms occurs after chronic Delta9-THC treatment.

Cannabis Use Disrupts Eyeblink Conditioning: Evidence for Cannabinoid Modulation of Cerebellar-Dependent Learning

“…It has already been established that chronic cannabis users assessed during periods of abstinence demonstrate hypoactive cerebellar activity, which could be interpreted as neuroadaptive endocannabinoid downregulation (Volkow et al, 1996;Block et al, 2000;Chang et al, 2006). Indeed, animal studies have shown that behavioral tolerance to the motor effects of THC is likely mediated by CB1 downregulation throughout the cerebellum (Sim et al, 1996;Romero et al, 1998). More recently, it has been found that chronic cannabis use in humans does in fact lead to significant CB1 downregulation as determined via postmortem [ 3 H]SR141716A binding (Villares, 2007).…”

“…More specifically, Purkinje cells activated by glutamatergic granule cells normally serve to inhibit cerebellar deep nuclei (ie interpositus nucleus) thus modulating the timing of conditioned blink responses (CRs) (Steinmetz, 2000). Chronic cannabis use, which is known to produce behavioral tolerance and may induce long-term endocannabinoid compensatory changes (eg CB1 downregulation; Sim et al, 1996;Romero et al, 1998), could result in increased granule cell glutamate release, and hence overactive inhibitory Purkinje inputs to the interpositus. This position is in agreement with a recent study of CB1 knockout animals, in which mice lacking the CB1 receptor exhibit severely disrupted EBC (Kishimoto and Kano, 2006).…”

Augmented Acquisition of Cocaine Self-Administration and Altered Brain Glucose Metabolism in Adult Female but not Male Rats Exposed to a Cannabinoid Agonist during Adolescence

“…Therefore, a hypoactivation in this area might indicate some deficits in long-term memory storage, at least in the first stages of its initial consolidation. Sim et al (1996) reported decreases in WIN-stimulated GTPg 35 S binding in the entorhinal cortex after a chronic THC treatment. This desensitization of CB1 receptors might account for the hypoactivation observed in this brain region.…”

Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment—a Systematic Review

“…Animal studies lend some credibility to this theory; however, results are not consistently reproducible in human studies. Additionally, many inferential hypotheses were identified that attribute different aspects of CHS to a myriad of dysregulatory issues at CB-1 receptors throughout the body (brain, gastrointestinal tract, and vasculature) [97,98,102,105,133,[135][136][137]. The experimental evidence behind these inferences illustrates the complexity of the pathophysiology of CHS and raises many additional questions.…”