Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving
Cue-induced cocaine craving is a major cause of relapse in abstinent addicts. In rats, cue-induced craving progressively intensifies (incubates) during withdrawal from extended-access cocaine self-administration. After ~1 month of withdrawal, incubated craving is mediated by Ca(2+)-permeable AMPA receptors (CP-AMPARs) that accumulate in the nucleus accumbens (NAc). We found that decreased mGluR1 surface expression in the NAc preceded and enabled CP-AMPAR accumulation. Thus, restoring mGluR1 transmission by administering repeated injections of an mGluR1 positive allosteric modulator (PAM) prevented CP-AMPAR accumulation and incubation, whereas blocking mGluR1 transmission at even earlier withdrawal times accelerated CP-AMPAR accumulation. In studies conducted after prolonged withdrawal, when CP-AMPAR levels and cue-induced craving are high, we found that systemic administration of an mGluR1 PAM attenuated the expression of incubated craving by reducing CP-AMPAR transmission in the NAc to control levels. These results suggest a strategy in which recovering addicts could use a systemically active compound to protect against cue-induced relapse.
Loweth, Jessica; Scheyer, Andrew; Milovanovic, Mike; LaCrosse, Amber; Flores-Barrera, Eden; Werner, Craig; Li, Xuan; Ford, Kerstin; Le, Tuan; Olive, M; Szumlinski, Karen; Tseng, Kuei; and Wolf, Marina, "Synaptic depression via mGluR1 positive allosteric modulation suppresses cue-induced cocaine craving" (2014). School of Osteopathic Medicine Faculty Scholarship. 34.