TY - JOUR
T1 - Positive allosteric modulation of mGluR5 accelerates extinction learning but not relearning following methamphetamine selfadministration
AU - Kufah, Peter R.
AU - Hood, Lauren E.
AU - Nemirovsky, Natali E.
AU - Barabas, Piroska
AU - Halstengard, Casey
AU - Villa, Angel
AU - Moore, Elisabeth
AU - Watterson, Lucas R.
AU - Olive, Michael
PY - 2012
Y1 - 2012
N2 - Recent studies have implicated glutamate neurotransmission as an important substrate for the extinction of conditioned behaviors, including responding for drug reinforcement. Positive allosteric modulation of the type-5 metabotropic glutamate receptor (mGluR5) in particular has emerged as a treatment strategy for the enhancement of extinction of drugmotivated behaviors. Here, we investigated the effects of the mGluR5 positive allosteric modulator CDPPB, a compound known for its cognitive enhancing effects in rodents, on extinction learning in rats with different histories of methamphetamine (METH) training. Rats were trained to selfadminister METH under two conditions: 16 daily sessions of short access (90 min/day, ShA), or eight daily sessions of short access followed by eight sessions of long access (6 h/day, LgA). Control rats selfadministered sucrose pellets in daily 30 min sessions. Next, rats were administered vehicle or 30 mg/kg CDPPB prior to seven consecutive daily extinction sessions, subjected to additional extinction sessions to reestablish a posttreatment baseline, and then tested for reinstatement of behavior in the presence of METH- or sucrosepaired cues. Rats were then subjected to a second series of extinction sessions, preceded by vehicle or 30 mg/kg CDPPB, and an additional test for cuetriggered reinstatement. CDPPB treatment resulted in a more rapid extinction of responding on the active lever, especially in the early sessions of the first extinction sequence. However, treatment effectswere minimal during subsequent cue reinstatement tests and nonexistent during the second series of extinction sessions. Rats with histories of ShA, LgA, and sucrose training expressed similar behavioral sensitivities to CDPPB, with LgA rats demonstrating a modestly higher treatment effect. Positive allosteric modulation of mGluR5 may therefore have some beneficial effects on efforts to facilitate extinction learning and reduce methamphetamine seeking.
AB - Recent studies have implicated glutamate neurotransmission as an important substrate for the extinction of conditioned behaviors, including responding for drug reinforcement. Positive allosteric modulation of the type-5 metabotropic glutamate receptor (mGluR5) in particular has emerged as a treatment strategy for the enhancement of extinction of drugmotivated behaviors. Here, we investigated the effects of the mGluR5 positive allosteric modulator CDPPB, a compound known for its cognitive enhancing effects in rodents, on extinction learning in rats with different histories of methamphetamine (METH) training. Rats were trained to selfadminister METH under two conditions: 16 daily sessions of short access (90 min/day, ShA), or eight daily sessions of short access followed by eight sessions of long access (6 h/day, LgA). Control rats selfadministered sucrose pellets in daily 30 min sessions. Next, rats were administered vehicle or 30 mg/kg CDPPB prior to seven consecutive daily extinction sessions, subjected to additional extinction sessions to reestablish a posttreatment baseline, and then tested for reinstatement of behavior in the presence of METH- or sucrosepaired cues. Rats were then subjected to a second series of extinction sessions, preceded by vehicle or 30 mg/kg CDPPB, and an additional test for cuetriggered reinstatement. CDPPB treatment resulted in a more rapid extinction of responding on the active lever, especially in the early sessions of the first extinction sequence. However, treatment effectswere minimal during subsequent cue reinstatement tests and nonexistent during the second series of extinction sessions. Rats with histories of ShA, LgA, and sucrose training expressed similar behavioral sensitivities to CDPPB, with LgA rats demonstrating a modestly higher treatment effect. Positive allosteric modulation of mGluR5 may therefore have some beneficial effects on efforts to facilitate extinction learning and reduce methamphetamine seeking.
KW - Cognitive enhancement
KW - Extinction learning
KW - Methamphetamine
KW - Positive allosteric modulator
KW - Reinstatement
KW - mGluR5
UR - http://www.scopus.com/inward/record.url?scp=84870743078&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84870743078&partnerID=8YFLogxK
U2 - 10.3389/fphar.2012.00194
DO - 10.3389/fphar.2012.00194
M3 - Article
C2 - 23189054
AN - SCOPUS:84870743078
SN - 1663-9812
VL - 3 NOV
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - Article 194
ER -