Memantine Prevents the WIN 55,212-2 Evoked Cross-Priming of Ethanol-Induced Conditioned Place Preference (CPP)

Abstract

The activation of the endocannabinoid system controls the release of many neurotransmitters involved in the brain reward pathways, including glutamate. Both endocannabinoid and glutamate systems are crucial for alcohol relapse. In the present study, we hypothesize that N-methyl-D-aspartate (NMDA) glutamate receptors regulate the ability of a priming dose of WIN 55,212-2 to cross-reinstate ethanol-induced conditioned place preference (CPP). To test this hypothesis, ethanol-induced (1.0 g/kg, 10% w/v, i.p.) CPP (unbiased method) was established using male adult Wistar rats. After CPP extinction, one group of animals received WIN 55,212-2 (1.0 and 2.0 mg/kg, i.p.), the cannabinoid receptor 1 (CB1) agonist, or ethanol, and the other group received memantine (3.0 or 10 mg/kg, i.p.), the NMDA antagonist and WIN 55,212-2 on the reinstatement day. Our results showed that a priming injection of WIN 55,212-2 (2.0 mg/kg, i.p.) reinstated (cross-reinstated) ethanol-induced CPP with similar efficacy to ethanol. Memantine (3.0 or 10 mg/kg, i.p.) pretreatment blocked this WIN 55,212-2 effect. Furthermore, our experiments indicated that ethanol withdrawal (7 days withdrawal after 10 days ethanol administration) down-regulated the CNR1 (encoding CB1), GRIN1/2A (encoding GluN1 and GluN2A subunit of the NMDA receptor) genes expression in the prefrontal cortex and dorsal striatum, but up-regulated these in the hippocampus, confirming the involvement of these receptors in ethanol rewarding effects. Thus, our results show that the endocannabinoid system is involved in the motivational properties of ethanol, and glutamate may control cannabinoid induced relapse into ethanol seeking behavior.

A morphine reward generalization mouse model based on conditioned place preference and aversion

“…SUD memory is evaluated by the degree of preference of the animal for the condition context in the CPP model (Suzuki, 1999). That is, although direct exposure and drug induction occurred in the original conditioning chamber, the mice were able to retrieve the associative memory between the drug and the context (Marszalek‐Grabska et al., 2021; McKendrick & Graziane, 2020; Napier et al., 2013; Scherma et al., 2021), and our experiments are consistent with these results. However, studies on drug generalization in mice have not been reported, and studies have shown that fear generalization in mice depends on the similarity of cued information, such as shape (Yu et al., 2021; Zhou et al., 2017), sound (Pollack et al., 2018) and floor (Yu et al., 2021).…”

Glutamate as a Target Therapy for Alcohol Dependence Disorder

“…Moreover, the physiological and psychoactive effects of ethanol are because of several receptor systems activation. Including: N-Methyl-D-aspartate (NMDA), the action of ethanol consumption on activity of NMDA receptor are occurred by internalization and phosphorylation of receptor subunits which permit Ca2 + influx inside the cell, in turn promote long-term potentiation (LTP) induction, a key element of memory and learning, causing by example; to habit formation (24). Many studies have been shown that withdrawal effects of alcohol in brain regions is associated with elevation in transmission of excitatory amino acid and dopamine signaling alterations, resulting in executive functions deficits.…”