heroin and 6-methyl-2-(phenylethynyl)pyridine

Glutamatergic neurotransmission in the nucleus accumbens (NAc) is crucial for the relapse to heroin seeking. The aim of this study was to determine whether mGluR5 in the NAc core or shell involved in heroin seeking behavior in rats.. Male SD rats were self-administered heroin under a fixed-ratio 1 (FR1) reinforcement schedule for 14 d, and subsequently withdrawn for 2 weeks. The selective mGluR5 antagonist 2-methyl-6-phenylethynyl-pyridine (MPEP, 5, 15 and 50 nmol per side) was then microinjected into the NAc core or shell 10 min before a heroin-seeking test induced by context, cues or heroin priming.. Microinjection of MPEP into the NAc shell dose-dependently decreased the heroin seeking induced by context, cues or heroin priming. In contrast, microinjection of MPEP into the NAc core did not alter the heroin seeking induced by cues or heroin priming. In addition, microinjection with MPEP (15 nmol per side) in the NAc shell reversed both the percentage of open arms entries (OE%) and the percentage of time spent in open arms (OT%) after heroin withdrawal. Microinjection of MPEP (50 nmol per side) in the striatum as a control location did not affect the heroin seeking behavior. Microinjection of MPEP in the 3 locations did not change the locomotion activities.. Blockade of mGluR5 in NAc shell in rats specifically suppresses the relapse to heroin-seeking and anxiety-like behavior, suggesting that mGluR5 antagonists may be a potential candidate for the therapy of heroin addiction.

Topics: Analgesics, Opioid; Animals; Anxiety; Behavior, Animal; Cues; Dose-Response Relationship, Drug; Drug-Seeking Behavior; Excitatory Amino Acid Antagonists; Heroin; Heroin Dependence; Locomotion; Male; Nucleus Accumbens; Pyridines; Rats, Sprague-Dawley; Receptor, Metabotropic Glutamate 5; Recurrence; Self Administration; Substance Withdrawal Syndrome; Time Factors

The mGlu(5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been shown to reduce intravenous self-administration of ketamine and, to a limited extent, heroin in rats. We investigated whether MPEP affects the rewarding effect of ketamine and heroin as assessed in a conditioned place preference (CPP) paradigm. Sprague Dawley rats were subjected to a standard unbiased CPP protocol. Rats were conditioned with either ketamine or heroin (0.316-31.6 and 0.0125-0.5 mg/kg i.p., respectively), in combination with MPEP (10 mg/kg, i.p.) or its vehicle. The effect of MPEP (10 mg/kg) on the duration of extinction and on reinstatement of ketamine- and heroin-induced CPP was also examined. Ketamine and heroin induced CPP with a minimal effective dose (MED) of 10 mg/kg and 0.25 mg/kg, respectively. MPEP (1-31.6 mg/kg) did not induce CPP by itself; however, co-treatment with MPEP resulted in a 10-fold and 5-fold leftward shift in the MED of ketamine and heroin for inducing CPP, respectively. MPEP slowed extinction of ketamine-induced CPP, but not of heroin-induced CPP, and once extinction was achieved, was able to reinstate CPP in both groups. These findings indicate that a moderate dose of MPEP (10 mg/kg i.p.) potentiates, rather than attenuates, the rewarding effect of ketamine and heroin. Moreover, these data suggest that the attenuating effect of MPEP on ketamine and heroin intravenous self-administration is due to an increase, rather than a decrease, of the rewarding/reinforcing effect of these compounds.

Topics: Animals; Conditioning, Psychological; Dose-Response Relationship, Drug; Extinction, Psychological; Heroin; Ketamine; Male; Pyridines; Rats; Rats, Sprague-Dawley; Reward

We recently reported that the mGlu5 receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) reduces intravenous self-administration of ketamine and, to a lesser extent, heroin in rats. We also found that MPEP potentiates conditioned place preference induced by these drugs, suggesting that the reduction of self-administration results from an MPEP-induced potentiation of the rewarding effect of the self-administered drug. The aim of the present study was to examine whether MPEP has intrinsic positive reinforcing and rewarding effects. In experiment 1, rats were trained to self-administer either ketamine [0.5 mg/kg/infusion, 2 h sessions, fixed-ratio (FR) 3] or heroin (0.05 mg/kg/infusion, 1 h sessions, FR 10), followed by a number of substitution sessions with MPEP (1 mg/kg/infusion) or saline. In experiment 2, drug-naïve rats were allowed to acquire intravenous self-administration of MPEP (1 mg/kg/infusion, 2 h sessions, FR 3) or saline. In experiment 3, rats were subjected to a single-trial unbiased conditioned place preference protocol with MPEP (0.3-10 mg/kg i.v., 20 min conditioning). It was found that (1) substitution with MPEP in rats which had learned to self-administer ketamine or heroin resulted in stable self-administration behavior, whereas substitution with saline resulted in a typical extinction profile, (2) drug-naïve rats learned to self-administer MPEP, but not saline, and self-administration remained stable for at least 7 sessions, and (3) MPEP induced dose-dependent place preference with a minimal effective dose of 3 mg/kg. These data clearly demonstrate that MPEP has (weak) positive reinforcing and rewarding effects when administered i.v.

Topics: Animals; Conditioning, Operant; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Heroin; Infusions, Intravenous; Ketamine; Male; Pyridines; Rats; Rats, Long-Evans; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reinforcement Schedule; Reward; Self Administration; Time Factors

The mGluR5 antagonist 2-methyl-6-(phenylethynyl) pyridine (MPEP) may be beneficial for drug abuse treatment, as it has been found to reduce self-administration of ethanol, nicotine and cocaine in preclinical models. This study investigated whether this finding can be extended to dissociative anaesthetics and opioids. Long Evans rats were trained to intravenously self-administer ketamine (0.5 mg/kg/infusion, 2 h sessions, fixed ratio 3) or heroin (0.05 mg/kg/infusion, 1 h sessions, fixed ratio 10). After reaching stable responding, the effect of MPEP pretreatment (1.25-20 mg/kg, intraperitoneal; t=-30 min) on intravenous self-administration (IVSA) of each compound was investigated. Behavioural specificity of MPEP on IVSA was assessed using a food-reinforcement procedure. IVSA of ketamine was dose-dependently reduced by MPEP pretreatment, with a minimal effective dose of 5 mg/kg and a 75% reduction at the highest dose tested. IVSA of heroin was only modestly reduced by the highest dose of MPEP (20% reduction). Food-reinforced behaviour was not altered by MPEP, either given alone or in combination with ketamine or heroin, indicating that the effect in the IVSA paradigm was behaviourally specific. It is suggested that the differential effect of MPEP on IVSA of ketamine and heroin is related to the particular class of the self-administered drug or its relative reinforcing efficacy.

Topics: Animals; Conditioning, Operant; Heroin; Injections, Intravenous; Ketamine; Male; Pyridines; Rats; Rats, Long-Evans; Self Administration