Abstract
Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.
Highlights
Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain
We hypothesize one such approach involving the combination of a class of nootropics known as AMPA PAMs with behavioral strategies known as cue-exposure therapy or extinction training
The fact that extinction training (ET) recruits “top-down” glutamatergic signaling that mediates and is responsible for the consolidation of extinction behavior has led to an increase in research focusing on these pathways as pharmacotherapeutic targets
Summary
Drug addiction is a chronically relapsing disorder principally characterized by the uncontrollable drive to obtain and failure to limit the use of drugs despite adverse, often severe, consequences. Episodic use motivated primarily by the positive reinforcing and rewarding effects of the drug [19] These hedonic effects, like those of natural reinforcers (i.e., food, water, sex, etc.), are predominantly mediated by increased dopamine (DA) transmission from neurons in the ventral tegmental area (VTA) of the midbrain to the ventral striatum (nucleus accumbens, NAc) [19]. In drug addiction, impaired functioning in these domains, combined with attention biased towards drug-related stimuli, culminates in the inability of the PFC to effectively exert “top-down” inhibitory control over habitual drug-seeking behavior [27,35]. Addiction research has begun to reveal that changes in glutamatergic signaling within corticostriatal and corticolimbic circuits where DA terminals are embedded are essential in mediating drug reward, reinforcement, and the transition to addiction [36,38,39,40], revealing new potential targets for addiction pharmacotherapeutics [17,41,42]
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