As yet, there is insufficient evidence as to which of these mechanisms underlie the loss of eCB/CB1-mediated plasticity following chronic THC or agonist exposure. Chronic exposure to THC and CB1 receptor agonists impairs synaptic LTD at glutamatergic synapses in the dorsal and ventral striatum, areas of the brain important for eCB-mediated habitual actions and reward processing, respectively. The NAc/ ventral striatum integrates incoming sensory inputs to modulate cortical activity to influence drug seeking behavior. In fact, drug-induced impairments in LTD have been implicated in compulsive drug seeking and/ or taking behavior . Not surprisingly, operant self-administration of THC and CBD inhibits the induction of LTD at cortical inputs to NAc , again, bolstering the argument that cannabinoid reward-driven signaling, resulting in voluntary drug seeking/taking behavior is mediated by the inhibition of glutamatergic signaling at these synapses. Little is known about the effects of CBD alone on long-term changes in synaptic plasticity. However, CBD is hypothesized to reduce the aversive effects of THC . It is likely that CBD may exert its long-term effects on plasticity at non-CB1/CB2 receptors, given its low affinity for these receptors .

The loss of NAc LTD is accompanied by the desensitization of CB1 receptors following chronic THC and cannabinoid exposure indoor grow table. Differential changes in the signaling strength of these inputs may contribute to the reinforcing properties of cannabinoid drugs and the regulation of behavior. Alterations in dendritic spine density and morphology in NAc medium spiny neurons occur following chronic exposure to THC . Moreover, loss of LTD is observed at synapses originating from the medial prefrontal cortex  and ventral hippocampus. Interestingly, chronic THC exposure during adolescence inhibits LTD induction in the mPFC, which is reversed by enhancing AEA levels . Collectively, these results support the idea that cannabinoids alter CB1 receptor-mediated synaptic modulation to facilitate the reinforcing effects of these drugs and promote tolerance and dependence. Interestingly, chronic THC exposure results in synapse-specific LTD impairments in the NAc, in which LTD at mPFC and vHipp synapses, and not LTD at synapses originating from the basolateral amygdala  are affected . These results suggest that THC-induced synaptic modifications may have very different effects on striatal output, depending on the MSN synapses affected.

However, more research is needed to identify whether the induction of LTD at synapses onto different MSN subtypes, indirect- and direct-projecting, are affected. In addition to these presynaptic changes, there is a postsynaptic strengthening of the BLA and vHipp inputs, and the weakening of inputs from mPFC . These changes in presynaptic and postsynaptic mechanisms of glutamatergic signaling highlight the importance of the synaptic balance among these brain regions to guide behavior. After prolonged exposure to THC, there is a shift from cortical regions involved in cognitive processes to subcortical regions, which are involved in memory and emotional processes to promote drug seeking and dependence . Additionally, it may be this dysregulation in synaptic transmission that contributes to the cannabinoid-induced deficits associated with memory formation. Loss of LTD in dorsolateral striatum  following chronic THC exposure appears to contribute to development of habitual instrumental behavior . The loss of this presynaptic modulation may lead to increased efficacy of inputs from sensorimotor cortical regions that drives DLS and the associated basal ganglia circuitry supporting stimulus/context-driven behavior that overrides goal-direct actions.

Synaptic depression mediated by eCBs and CB1 also plays a role in habitual behavior through suppression of orbitofrontal cortical inputs to dorsomedial striatum . In this case, rolling grow table the eCB-mediated synaptic modulation suppresses cortical input that drives goal-directed behavior, favoring habitual responding. It has yet to be determined how chronic exposure to THC or other CB1 agonists alters this dorsal striatal eCB role. Functional cannabinoid tolerance also occurs at excitatory and inhibitory synapses in the hippocampus.However, these receptors are more abundantly expressed on GABAergic rather than glutamatergic terminals . Modifications at these synapses are likely to contribute to the long-lasting cannabinoid-induced deficits in memory and cognition. Chronic exposure to THC blocks LTP at glutamatergic synapses in the dentate gyrus and CA1 regions of the hippocampus via a CB1 receptor-mediated mechanism . Similar impairments in hippocampal CA1 LTP are observed in vivo with repeated exposure to HU-210, a CB1 receptor full agonist . Moreover, these impairments are associated with deficits in working memory. It is likely that reduction in glutamate receptor expression and function contributes to the impairments in hippocampal synaptic plasticity .