Modafinil Increases Reward Salience in a Slot Machine Game in Low and High Impulsivity Pathological Gamblers.

Modafinil Increases Reward Salience in a Slot Machine Game in Low and High Impulsivity Pathological Gamblers.

Neuropharmacology. 2013 May 24;
Smart K, Desmond RC, Poulos CX, Zack M

This study examined the effects of modafinil (200 mg) on slot machine betting profiles from a previous sample of low and high impulsivity (LI/HI) pathological gamblers (10/Group; Zack and Poulos, 2009). Hierarchical regression assessed the prospective relationship between Payoff and Bet Size on consecutive trials, along with moderating effects of Group, Cumulative Winnings (low/high) and Phase of game (early/late) under drug and placebo. Y intercepts for the simple regressions of Bet Size on Payoff indexed overall motivation to bet. Under placebo, both groups gauged their bets less closely to the preceding Payoff as trials continued when Winnings were low but not high. Under modafinil, both groups gauged their bets more closely to the preceding Payoff when Winnings were low but gauged their bets less closely to the previous Payoff when Winnings were high. The tendency to gauge bets closely to the previous Payoff coincided with a bias toward low overall Bet Size, and modafinil accentuated this relationship, in LI but not HI subjects. Results suggest that modafinil increases the salience of environmental rewards, leading to more tightly calibrated responses to individual rewards when resources are low, but progressively loosens reward-response calibration when resources are high. Increased relative impact of phasic vs. tonic dopamine signals may account for patterns seen at low vs. high Winnings, respectively, under the drug. Clinically, modafinil may deter pathological gamblers from chasing losses but also encourage them to continue betting rather than quit while they are ahead. Whether low-dose modafinil confers more uniform benefits deserves investigation. HubMed – addiction


Cellular distribution of AMPA receptor subunits and mGlu5 following acute and repeated administration of morphine or methamphetamine.

J Neurochem. 2013 May 27;
Herrold AA, Persons AL, Napier TC

Ionotropic AMPA receptors (AMPAR) and metabotropic glutamate group I subtype 5 receptors (mGlu5) mediate neuronal and behavioral effects of abused drugs. mGlu5 stimulation increases expression of striatal enriched tyrosine phosphatase isoform 61 (STEP61 ) which internalizes AMPARs. We determined the rat brain profile of these proteins using two different classes of abused drugs, opiates and stimulants. STEP61 levels, and cellular distribution/expression of AMPAR subunits (GluA1, GluA2) and mGlu5 were evaluated via a protein cross-linking assay in medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and ventral pallidum (VP) harvested one day after acute, or fourteen days after repeated morphine (8mg/kg) or methamphetamine (1mg/kg) (treatments producing behavioral sensitization). Acute morphine decreased GluA1 and GluA2 surface expression in mPFC and GluA1 in NAc. Fourteen days after repeated morphine or methamphetamine, mGlu5 surface expression increased in VP. In mPFC, mGlu5 were unaltered; however, after methamphetamine, STEP61 levels decreased and GluA2 surface expression increased. Pretreatment with a mGlu5-selective negative allosteric modulator, blocked methamphetamine-induced behavioral sensitization and changes in mPFC GluA2 and STEP61 . These data reveal (1) region-specific distinctions in glutamate receptor trafficking between acute and repeated treatments of morphine and methamphetamine, and (2) that mGlu5 is necessary for methamphetamine-induced alterations in mPFC GluA2 and STEP61 . This article is protected by copyright. All rights reserved. HubMed – addiction


The role of ventral and dorsal striatum mGluR5 in relapse to cocaine-seeking and extinction learning.

Addict Biol. 2013 May 27;
Knackstedt LA, Trantham-Davidson HL, Schwendt M

Cocaine addiction is a chronic, relapsing disease characterized by an inability to regulate drug-seeking behavior. Here we investigated the role of mGluR5 in the ventral and dorsal striatum in regulating cocaine-seeking following both abstinence and extinction. Animals underwent 2 weeks of cocaine self-administration followed by 3 weeks of home-cage abstinence. Animals were then reintroduced to the operant chamber for a context-induced relapse test, followed by 7-10 days of extinction training. Once responding was extinguished, cue-primed reinstatement test was conducted. Both drug-seeking tests were conducted in the presence of either mGluR5 negative allosteric modulator, MTEP or vehicle infused into either the nucleus accumbens (NA) core or dorsolateral striatum (dSTR). We found that MTEP infused in the NA core attenuated both context-induced relapse following abstinence and cue-primed reinstatement following extinction training. Blocking dSTR mGluR5 had no effect on context- or cue-induced cocaine-seeking. However, the intra-dSTR MTEP infusion on the context-induced relapse test day attenuated extinction learning for 4 days after the infusion. Furthermore, mGluR5 surface expression was reduced and LTD was absent in dSTR slices of animals undergoing 3 weeks of abstinence from cocaine but not sucrose self-administration. LTD was restored by bath application of VU-29, a positive allosteric modulator of mGluR5. Bath application of MTEP prevented the induction of LTD in dSTR slices from sucrose animals. Taken together, this data indicates that dSTR mGluR5 plays an essential role in extinction learning but not cocaine relapse, while NA core mGluR5 modulates drug-seeking following both extinction and abstinence from cocaine self-administration. HubMed – addiction