Dissociable roles of mGlu5 and dopamine receptors in the rewarding and sensitizing properties of morphine and cocaine

Abstract

RationaleDrugs of abuse are initially used because of their rewarding properties. As a result of repeated drug exposure, sensitization to certain behavioral effects of drugs occurs, which may facilitate the development of addiction. Recent studies have implicated the metabotropic glutamate receptor 5 (mGlu5 receptor) in drug reward, but its role in sensitization is unclear. Stimulation of dopamine receptors plays an important role in drug reward, but not in the sensitizing properties of cocaine and morphine.ObjectiveThis study aims to evaluate the role of mGlu5 and dopamine receptors in the development of cocaine- and morphine-induced conditioned place preference (CPP) and psychomotor sensitization.Materials and methodsRats were treated with the mGlu5 receptor antagonist MTEP (0, 1, 3, and 10 mg/kg, i.p.) or the dopamine receptor antagonist α-flupenthixol (0, 0.125, 0.25, and 0.5 mg/kg, i.p.) during place conditioning with either morphine (3 mg/kg, s.c.) or cocaine (15 mg/kg, i.p.). Furthermore, MTEP (1 mg/kg, i.p.) or α-flupenthixol (0.5 mg/kg, i.p.) was co-administered during cocaine (30 mg/kg, i.p.) or morphine (3.0 mg/kg, s.c.) pretreatment and psychomotor sensitization was tested 3 weeks post-treatment.ResultsMTEP attenuated the development of morphine- but not cocaine-induced CPP. In contrast, MTEP suppressed the development of cocaine- but not morphine-induced psychomotor sensitization. α-Flupenthixol blocked the development of both cocaine- and morphine-induced CPP but did not affect the development of sensitization to either drug.ConclusionDopamine receptor stimulation mediates cocaine and morphine reward but not sensitization. In contrast, the role of mGlu5 receptors in reward and sensitization is drug-specific.

Glutamate Mechanisms Underlying Opiate Memories

“…AMPA-R (Layer et al 1993;Tzschentke and Schmidt 1997;Harris et al 2004;ShabatSimon et al 2008) and mGluR5 (Popik and Wrobel 2002;Aoki et al 2004;Herzig and Schmidt 2004;Veeneman et al 2011) antagonists block both the acquisition and expression of morphine CPP, and at least for the mGluR5 antagonist MPEP, effective doses do not alter spatial learning and memory in other tasks (Popik and Wrobel 2002). This pattern of results is strikinglysimilar to those observed with NMDA-R antagonists.…”

Marked global reduction in mGluR5 receptor binding in smokers and ex-smokers determined by [ 11 C]ABP688 positron emission tomography

“…Although dopamine receptor stimulation mediated cocaine and morphine reward but not sensitization, mGluR5 antagonism specifically affected cocaine reward and sensitization (12). A previous study explored whether the mGluR5 antagonist MPEP decreased nicotine and cocaine self-administration, reflecting attenuation of the reinforcing and incentive motivational effects of these drugs (13).…”

Social Play Behavior in Adolescent Rats is Mediated by Functional Activity in Medial Prefrontal Cortex and Striatum

“…To assess whether effects of the drug treatment on social play were secondary to changes in locomotor activity, rats (at 41 days of age) were tested for horizontal locomotor activity as described previously (Trezza et al, 2009;Veeneman et al, 2011). Between the test for social play behavior and locomotor activity, there was at least one day without testing or infusions.…”