The most commonly used paradigm is a single intraperitoneal drug injection followed some hours later by brain slice preparation and electrophysiological recording . For example, Mato and coworkers observed that LTD was impaired at GABAergic synapses in the CA1 hippocampal subregion 15- 20 hours after a single THC injection . These investigators also found a similar impairment of LTD at glutamatergic synapses in the NAc. Impaired LTD persists for up to three days after the drug injection. In slices from the ventral tegmental area , an increase in synaptic AMPA receptors was observed 24 hours following a single THC injection, perhaps indicative of long-term potentiation at these synapses . Chronic cannabinoid drug use is associated with increased risk of developing CUD, which is accompanied by neurobiological changes in reward-related and cognitive circuit functions. Cognitive changes following chronic cannabinoid use contribute in part to the maintenance of CUD via increased impulsivity and impaired decision making.The most consistent neurobiological consequence of chronic THC exposure is decreased CB1 receptor numbers,mobile grow rack as well as decreased CB1 agonist and eCB-induced presynaptic modulation. Long-term exposure to THC and synthetic cannabinoids results in region-specific decreases in CB1 receptor expression which likely contribute to differences in receptor radioligand binding and reduced drug sensitivity .
Furthermore, chronic exposure to cannabinoids impairs synaptic plasticity, and this impairment is accompanied by the desensitization of CB1 receptors . The desensitization and downregulation of CB1 receptors have been consistently implicated in the development of cannabis tolerance and have been observed in individuals that regularly use cannabis . Chronic cannabinoid exposure produces widespread reversible downregulation and desensitization of CB1 receptors . The magnitude of downregulation is generally 25-50% depending on the measurement type and brain region examined. Greater decreases were reported in the cerebellum and hippocampus compared to somewhat smaller magnitudes in the basal ganglia and midbrain . Given that the magnitude of down regulation is smaller in the midbrain and basal ganglia, it is not surprising that the rate of reversal is faster in the striatum and midbrain than in other brain regions . Together, these mechanisms provide the underlying biological properties by which cannabinoid tolerance can develop . The functional significance of AEA and 2-AG in promoting cannabinoid tolerance and dependence have been explored. Repeated administration of AEA or an AEA analog has yielded inconclusive findings on the reduction of CB1 receptor density and signaling . Furthermore, pharmacological blockade of FAAH does not alter CB1 receptor expression and function .
In mice lacking FAAH, chronic administration of THC produces similar magnitudes of CB1 receptor desensitization and down regulation in the striatum, hippocampus, and cerebellum compared to controls . These findings suggest that AEA signaling doesn’t contribute to the receptor down regulation in response to chronic THC exposure. It is worth mentioning that the deletion of FAAH does not alter CB1 receptor expression in brain . On the other hand, chronically elevated levels of 2-AG achieved by genetic deletion or pharmacological blockade of MAGL results in the reduction of CB1 receptor density and function 4×8 grow table . Thus, increased 2-AG tone can possibly desensitize and down regulate CB1 receptors . The molecular mechanisms involved in CB1 receptor desensitization and down regulation have been explored, but to date there is little evidence about which mechanisms are involved in loss of presynaptic receptor function. The radiolig and binding studies mentioned above, and a few immunochemical studies that indicate decreased receptor numbers are consistent with CB1 receptor internalization or degradation as candidate mechanisms for CB1 receptor desensitization. Indeed, loss of cell surface receptors consistent with these mechanisms has been observed in heterologous cellular expression systems and in primary neuronal cultures .
The most direct evidence of decreased CB1 receptor on the plasma membrane of presynaptic terminals induced by chronic THC exposure in adult animals was obtained with super-resolution microscopy imaging or GABAergic terminals in the hippocampal CA1 region . Recovery of terminal surface CB1 levels was observed several weeks after cessation of THC treatment. However, reduced CB1 levels are not always apparent under conditions where decreased receptor induced signaling and tolerance to agonist effects on transmission are observed . Thus, other mechanisms of desensitization, such as uncoupling of CB1 receptors from G proteins and other intracellular signaling mechanisms, or changes in the intracellular signaling systems themselves have also been explored.