Chronic exposure to THC reduces cannabinoid CB1 receptor sensitivity and/or efficacy at GABAergic, but not glutamatergic terminals in the CA1 region . This reduced sensitivity is accompanied by a down regulation of CB1 receptors, likely contributing to reduced receptor sensitivity . In the hippocampus, eCBs facilitate the induction of LTP through the transient suppression of GABAergic transmission, as mentioned previously . However, after chronic THC exposure, the suppression of GABAergic inhibition onto glutamatergic synapses is lost, possibly resulting in LTP impairments. However, this has not been directly tested. Repeated THC exposure also results in the reduction of dendritic spine density in CA1 hippocampal neurons . These results demonstrate that chronic cannabinoid exposure can induce cellular and synaptic changes that alter plasticity to affect behaviors, such as spatial learning and working memory. Generally, drugs of abuse often impair the induction of LTP and LTD in reward-related drug seeking and taking circuits .
Within the ventral tegmental area , chronic THC or CB1 agonist induces LTD at glutamatergic terminals that is dependent on NMDA and AMPA GluA2 receptor endocytosis and CB1 receptor signaling 4×8 grow table with wheels. The VTA is an integral brain region involved in the reward pathway and sends projections to NAc and mPFC, brain regions involved in regulating the cognitive and motivational aspects of behaviors . Chronic drug use can result in long-term changes in synaptic plasticity that persist long after drug cessation. LTD impairments are observed following the self-administration of THC and CBD and a withdrawal period , as well as after chronic exposure of THC . It is reported that CB1 receptor downregulation can persist for a short period of time following termination of cannabinoid exposure . Some of the neurobiological alterations that occur with prolonged cannabinoid use are reversible. More work is needed to determine which of these changes are reversible or how long this reversal process might take. For example, in human cannabis users, CB1 receptor binding function returns to normal levels after a period of abstinence . There is also a partial recovery of LTP after the cessation of THC exposure in rodents, suggesting that the cognitive and reward-processing deficits are not permanent .
The overall net effects of chronic cannabinoid drug use are the loss of synaptic plasticity that may contribute to tolerance and stabilize drug-oriented behaviors. Only one study to date has examined synaptic plasticity in the brain of humans diagnosed with CUD . In this study, continuous theta burst stimulation delivered via transcranial magnetic stimulation of the motor cortex was used to examine plasticity of motor evoked potentials measured in a contralateral muscle. Decreased MEP persisting for 10s of minutes was induced by cTBS in non-cannabis-users and in cannabis users that did not meet CUD criteria. In contrast this decrease was not observed in individuals with CUD. This finding indicates that high levels of cannabis use can reduce plasticity in the human brain.This reduction is likely to contribute to alternations in functional connectivity and cognitive impairments associated with chronic cannabis use . Interestingly, grow table tray prolonged CBD usage has been implicated in restoring hippocampal volume in a region-specific manner and improving cognitive function in chronic cannabis users. More studies examining THC, CB1 agonist effects, and other cannabis derivatives on plasticity, as well as alterations in plasticity and acute drug effects on plasticity in individuals with CUD would help in assessing the translatability of findings in laboratory animals and in back-translating studies from humans to animal models.
There is limited evidence to date of the effects of acute and chronic cannabis use on markers of synaptic function in human brain, but imaging techniques have provided some intriguing findings. Ligands for positron emission tomography -based imaging of CB1 receptors have been developed over the last 10-15 years . Studies employing these PET ligands in humans have revealed evidence of a small but significant decrease in CB1 receptor availability in several cortical and limbic brain regions . As mentioned above, the receptor levels return to near baseline values following cessation of cannabis use . Many psychoactive drugs, including all drugs that give rise to SUDs, alter brain dopamine levels . In general, acute exposure to these drugs increases DA release in the NAc and other brain regions implicated in reward and behavioral actions of these drug . Cannabis and THC have similar acute DA-increasing actions thought to arise from decreased inhibition of midbrain dopaminergic neurons . Thus, it is important to understand cannabis effects on DA in the human brain. To this end, several recent studies have used brain imaging and spectroscopy approaches to estimate changes in brain DA levels, DA receptor density and other molecules involved in dopaminergic transmission following acute of chronic cannabis use.