The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

Paterson, Neil E.; Semenova, Svetlana; Gasparini, F.; Markou, Athina

doi:10.1007/s00213-003-1432-z

Cited by 209 publications

(179 citation statements)

References 57 publications

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“…Although MPEP reduced ethanol-induced locomotor stimulation, animals were not impaired under these conditions when compared to saline-treated control animals. In other studies MPEP at doses of 2.5-10 mg/kg, delivered i.p., had also no effect on exploratory locomotor activity in rats (Tatarczynska et al, 2001;Henry et al, 2002;Paterson et al, 2003). However, another study indicated that much higher doses of MPEP and ethanol resulted in an additive effect of MPEP on ethanol-induced sedation in mice (Sharko and Hodge, 2003).…”

Section: Discussionmentioning

confidence: 99%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

Neuropsychopharmacol

235

178

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The glutamatergic system plays an important role in mediating neurobehavioral effects of ethanol. Metabotropic glutamate receptors subtype 5 (mGluR5) are modulators of glutamatergic neurotransmission and are abundant in brain regions known to be involved in ethanol self-administration. Here, we studied the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a highly potent, noncompetitive mGlu5 receptor antagonist, on voluntary ethanol consumption and relapse behavior. For this purpose, we used two models for the measurement of relapse behavior: (i) reinstatement of ethanol-seeking behavior by drug-associated cues and (ii) the alcohol deprivation effect in long-term ethanol-consuming rats. In the first set of experiments, rats were trained to lever press for ethanol in the presence of a distinct set of cues. After extinction, the animals were exposed to the respective cues that initiated reinstatement of responding. A response-contingent ethanol prime further enhanced responding compared to the conditioned cues alone. Under these conditions, MPEP (0, 1, 3, and 10 mg/kg) attenuated ethanol seeking significantly and in a dose-related manner. However, at the highest dose, MPEP also decreased the number of inactive lever responses. In the second set of experiments, rats with 1 year of ethanol experience and repeated deprivation phases were used. A subchronic treatment with MPEP (twice daily; 0, 3, and 10 mg/kg) resulted in a significant and dose-dependent reduction of the alcohol deprivation effect (ADE). Although the same MPEP treatment regimen decreased baseline drinking, this effect was not as pronounced as on the ADE. These results show in two commonly used models of relapse to ethanol that pharmacological targeting of mGlu5 receptors may be a promising approach for the treatment of alcoholism.

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Section: Discussionmentioning

confidence: 99%

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Bäckström

Bachteler

Koch

et al. 2003

Neuropsychopharmacol

235

178

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“…The EVH1 domain exhibits a high degree of similarity across Homer isoforms and is essential for Homer interactions with a proline-rich sequence (PPSPF) displayed by proteins regulating drug-induced alterations in neuronal morphology, synaptic architecture, and glutamate receptor signaling/intracellular calcium dynamics. Of particular relevance to drug-induced neuroplasticity [e.g., 20,73,74,[78][79][80][81][82][89][90][91][92][93][94][95][96][97][98][99][100][123][124][125][126][127][128][129][130], these proteins include the mGluR1a and mGluR5 subtypes of Group 1 metabotropic glutamate receptors (mGluRs) [34,102,104,107,[131][132][133][134][135][136][137], the NMDA glutamate receptor scaffolding protein Shank [38,132,138,139], the inositol-1,4,5-triphosphate (IP3) receptor, a down-stream mediator of Group1 mGluR signaling [133,[140]…”

Section: Molecular Aspects Of Homer Proteinsmentioning

confidence: 99%

Homers regulate drug-induced neuroplasticity: Implications for addiction

Szumlinski

Ary

Lominac

2008

Biochemical Pharmacology

118

160

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Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state.

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“…Rats were monitored to ensure that all pellets were consumed before each session. Although insertion of a long TO is sometimes used to decrease food reinforcement rate (Paterson et al, 2003), we did not use this procedure because it can impose an artificial ceiling effect which would not be sensitive to potential increases in the rate of responding. Training continued until stable responding was obtained, defined as (1) a minimum of 10 pellets earned per session, (2) less than 20% variability in the number of pellets earned, and (3) a minimum 2 : 1 active : inactive lever response ratio.…”

Section: Sucrose-maintained Respondingmentioning

confidence: 99%

Methylphenidate Enhances the Abuse-Related Behavioral Effects of Nicotine in Rats: Intravenous Self-Administration, Drug Discrimination, and Locomotor Cross-Sensitization

Wooters

Neugebauer

Rush

et al. 2007

Neuropsychopharmacol

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Stimulant drugs, including D-amphetamine, cocaine, and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination, and locomotor cross-sensitization procedures. Adult male Sprague-Dawley rats were trained to respond for intravenous nicotine (0.01 or 0.03 mg/kg/infusion) or sucrose, and the acute effects of methylphenidate (1.25-10 mg/kg) were determined; in addition, separate groups of rats were treated with methylphenidate (2.5 mg/kg) or saline before 12 consecutive nicotine (0.03 mg/kg/infusion) self-administration sessions. Next, the discriminative stimulus effects of nicotine (0.03-0.3 mg/kg) and methylphenidate (1.25-10 mg/kg), alone and in combination with a low nicotine dose (0.056 mg/kg), were tested in nicotine-trained rats. Finally, the locomotor effect of repeated methylphenidate (2.5 mg/kg) was tested in rats previously treated with nicotine (0.2-0.8 mg/kg). Results indicated that acute methylphenidate increased the rate of nicotine self-administration at doses that reduced sucrose-maintained responding; furthermore, tolerance to this effect was not apparent following repeated methylphenidate. Methylphenidate, while not substituting for nicotine alone, dose-dependently enhanced the discriminative stimulus effect of a low nicotine dose. In addition, repeated nicotine exposure promoted the development of locomotor sensitization to methylphenidate. Taken together with recent clinical findings, these results suggest that methylphenidate may enhance the abuse-related behavioral effects of nicotine, perhaps increasing vulnerability to tobacco dependence.

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The mGluR5 antagonist MPEP decreased nicotine self-administration in rats and mice

Cited by 209 publications

References 57 publications

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

mGluR5 Antagonist MPEP Reduces Ethanol-Seeking and Relapse Behavior

Homers regulate drug-induced neuroplasticity: Implications for addiction

Methylphenidate Enhances the Abuse-Related Behavioral Effects of Nicotine in Rats: Intravenous Self-Administration, Drug Discrimination, and Locomotor Cross-Sensitization

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