Cognitive effects of Group I metabotropic glutamate receptor ligands in the context of drug addiction

Abstract

Glutamate plays a pivotal role in regulating drug self-administration and drug-seeking behavior, and the past decade has witnessed a substantial surge of interest in the role of Group I metabotropic glutamate receptors (mGlu(1) and mGlu(5) receptors) in mediating these behaviors. As will be reviewed here, Group I mGlu receptors are involved in normal and drug-induced synaptic plasticity, drug reward, reinforcement and relapse-like behaviors, and addiction-related cognitive processes such as maladaptive learning and memory, behavioral inflexibility, and extinction learning. Animal models of addiction have revealed that antagonists of Group I mGlu receptors, particularly the mGlu(5) receptor, reduce self-administration of virtually all drugs of abuse. Since inhibitors of mGlu5 receptor function have now entered clinical trials for other medical conditions and appear to be well-tolerated, a key question that remains unanswered is - what changes in cognition are produced by these compounds that result in reduced drug intake and drug-seeking behavior? Finally, in contrast to mGlu(5) receptor antagonists, recent studies have indicated that positive allosteric modulation of mGlu(5) receptors actually enhances synaptic plasticity and improves various aspects of cognition, including spatial learning, behavioral flexibility, and extinction of drug-seeking behavior. Thus, while inhibition of Group I mGlu receptor function may reduce drug reward, reinforcement, and relapse-related behaviors, positive allosteric modulation of the mGlu5 receptor subtype may actually enhance cognition and potentially reverse some of the cognitive deficits associated with chronic drug use.

Fig. 1

Diagram of a dendritic spine and postsynaptic localization of ionotropic and Group I mGlu receptors. Synaptically released glutamate binds to ionotropic glutamate receptors (NMDA, AMPA, and KA receptors), which allows the influx of Na⁺ and/or Ca²⁺ ions to depolarize the postsynaptic membrane. Group I mGlu receptors are localized to the perisynaptic annulus of the dendritic spine where they are stimulated by high levels of synaptic glutamate release or glutamate released from glia. Group I mGlu are structurally coupled to NMDA receptor via Homer proteins (as well as other scaffolding proteins not shown), and are biochemically coupled to NMDA receptor function via PKC. Activation of Group I mGlu receptors increases the activity of NMDA receptors (denoted by a +), and NMDA receptor activation can positively influence Group I mGlu receptor function as well.

Fig. 2

The mGlu₅ receptor positive allosteric modulator CDPPB reduces extinction responding following intravenous cocaine self-administration. Male Sprague-Dawley rats were trained to self-administer cocaine at a dose of 0.33 mg/kg/infusion under an FR1 schedule of reinforcement in 2 hr daily sessions. Following 12 days of active cocaine self-administration (the average of the last two days is depicted in the graph as SA), animals underwent extinction by eliminating infusions as a consequence of active lever presses, while stimuli that were previously presented during each cocaine infusion (i.e., light/tone stimulus and syringe pump activation) were still presented. Animals were administered vehicle (20% 2-hydroxypropyl-β-cyclodextrin) or CDPPB (30 mg/kg i.p.) 30 min prior to daily 2 hr extinction sessions (E1, E2, or E3). CDPPB significantly (*P<0.05) reduced extinction responding on extinction days E1 and E2, possibly reflecting increased extinction learning, as this dose of CDPPB has no effect on motor activity (Gass and Olive, 2009a).