Synaptic Neurotransmission Depression in Ventral Tegmental Dopamine Neurons and Cannabinoid-Associated Addictive Learning

Abstract

Drug addiction is an association of compulsive drug use with long-term associative learning/memory. Multiple forms of learning/memory are primarily subserved by activity- or experience-dependent synaptic long-term potentiation (LTP) and long-term depression (LTD). Recent studies suggest LTP expression in locally activated glutamate synapses onto dopamine neurons (local Glu-DA synapses) of the midbrain ventral tegmental area (VTA) following a single or chronic exposure to many drugs of abuse, whereas a single exposure to cannabinoid did not significantly affect synaptic plasticity at these synapses. It is unknown whether chronic exposure of cannabis (marijuana or cannabinoids), the most commonly used illicit drug worldwide, induce LTP or LTD at these synapses. More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed. Here we show in rats that chronic cannabinoid exposure activates VTA cannabinoid CB1 receptors to induce transient neurotransmission depression at VTA local Glu-DA synapses through activation of NMDA receptors and subsequent endocytosis of AMPA receptor GluR2 subunits. A GluR2-derived peptide blocks cannabinoid-induced VTA synaptic depression and conditioned place preference, i.e., learning to associate drug exposure with environmental cues. These data not only provide the first evidence, to our knowledge, that NMDA receptor-dependent synaptic depression at VTA dopamine circuitry requires GluR2 endocytosis, but also suggest an essential contribution of such synaptic depression to cannabinoid-associated addictive learning, in addition to pointing to novel pharmacological strategies for the treatment of cannabis addiction.

Cannabinoid Regulation of Brain Reward Processing with an Emphasis on the Role of CB1 Receptors: A Step Back into the Future

“…According to Castané and colleagues, WIN55,212-2 produced CPP in mice pre-exposed to a priming injection of the drug (118). Similar results have also been reported with HU-210 (100 μg/kg) in Sprague-Dawley rats pre-exposed to a priming phase consisting of four daily home injections of the drug (131, 134). Notably, CPP with WIN55,212-2 has also been reported in OF1 mice without utilizing a pre-exposure protocol (129).…”

Cannabinoid modulation of memory consolidation within the cerebellum

“…Cannabinoid receptor activation has also been reported to cause AMPA receptor endocytosis within the ventral tegmental area (VTA) which resulted in increased LTD expression (Liu et al, 2010). Thus, CB1R activation during the consolidation phase, 1–3 hr after training, could increase AMPA receptor endocytosis in Purkinje cells, which in turn, would increase LTD formation.…”

Cannabinoid modulation of drug reward and the implications of marijuana legalization

“…However, subsequent work shows that animals treated with the CB 1 agonist WIN 55,212-2 (WIN) for 3 days develop robust tolerance to WIN-induced increases in VTA dopamine cell firing (Pistis et al, 2004). One of the few studies to associate the rewarding effects of cannabinoids with cannabinoid-induced VTA plasticity found that development of a Δ 9 -THC CPP was associated with CB 1 -dependent LTD of glutamatergic synapses onto VTA dopamine neurons (Liu et al, 2010). As discussed above, in vivo exposure to virtually all other addictive drug classes promotes LTP at these synapses.…”