Facilitating mGluR4 activity reverses the long-term deleterious consequences of chronic morphine exposure in male mice

Abstract

doi: bioRxiv preprint Background: Understanding the neurobiological underpinnings of abstinence from drugs of abuse is critical to allow better recovery and ensure relapse prevention in addicted subjects. Methods: By comparing the long-term transcriptional consequences of morphine and cocaine exposure, we identified the metabotropic glutamate receptor subtype 4 (mGluR4) as a promising pharmacological target in morphine abstinence. We evaluated the behavioral and molecular effects of facilitating mGluR4 activity in abstinent mice.Results: Transcriptional regulation of marker genes of medium spiny neurons (MSNs) in the nucleus accumbens (NAc) allowed best discriminating between 4-week morphine and cocaine abstinence. Among these markers, Grm4, encoding mGluR4, displayed down-regulated expression in the caudate putamen and NAc of morphine, but not cocaine, abstinent mice. Remarkably, chronic administration of the mGluR4 positive allosteric modulator (PAM) VU0155041 (2.5 and 5 mg/kg) rescued social abilities, normalized stereotypies and anxiety and blunted locomotor sensitization in morphine abstinent mice. This treatment improved social preference but increased stereotypies in cocaine abstinent mice. Finally, the beneficial behavioral effects of VU0155041 treatment in morphine abstinent animals were correlated with restored expression of key MSN and neural activity marker genes in the NAc. Conclusions:This study is the first report of relieving effects of a pharmacological treatment, chronic administration of the mGluR4 PAM VU0155041, on long-term deleterious consequences of morphine exposure. It illustrates the neurobiological differences between opiate and psychostimulant abstinence and points to pharmacological repression of excessive activity of D2-MSNs in the NAc as a promising therapeutic lever in drug addiction.

Chronic sodium bromide treatment relieves autistic-like behavioral deficits in three mouse models of autism

“…or per os, in a volume of 20 ml/kg – except for combination with VU0155041: 10 mg/kg) or acutely (250 mg/kg, 20 ml/kg), KBr (Sigma-Aldrich, Saint-Quentin Fallavier, France; 145 mg/kg; i.p., 20 ml/kg), bumetanide (R&D systems, Minneapolis, USA, 0.5 and 2 mg/kg; i.p., 20 ml/kg) or VU0155041 (Cayman Chemical, Ann Arbor, USA, once a day, i.p., 1 mg/kg, 10 ml/kg). Doses of bumetanide were chosen based on previous studies in rodent models of ASD ( 40, 74 ); liminal dose of VU0155041 was set based on our previous studies ( 51, 100 ) and a pilot experiment showing no detectable effect in the social interaction test. When treatment was given chronically, behavioral testing started 8 days after beginning of daily administration.…”

“…When assessing effects of chronic administration, experiments were performed successively (timelines in Fig. 1, 4 and 5) ( 51, 100 ). Testing order was chosen to minimize the incidence of anxiety on later assays.…”

“…Statistical significance in behavioral experiments was assessed using one or two-way analysis of variance (drug, stimulus and treatment effects) followed by Newman-Keuls post-hoc test. Significance of quantitative real-time PCR (qRT-PCR) results was assessed after transformation using a two-tailed t-test, as previously described ( 100 ). Unsupervised clustering analysis was performed on transformed qRT-PCR data using complete linkage with correlation distance (Pearson correlation) for genotype and treatment (Cluster 3.0 and Treeview software) ( 51, 100 ).…”

“…Significance of quantitative real-time PCR (qRT-PCR) results was assessed after transformation using a two-tailed t-test, as previously described ( 100 ). Unsupervised clustering analysis was performed on transformed qRT-PCR data using complete linkage with correlation distance (Pearson correlation) for genotype and treatment (Cluster 3.0 and Treeview software) ( 51, 100 ). When used for clustering analysis (Figure 7B), behavioral data were normalized to vehicle-vehicle condition and transformed using the same formula as qRT-PCR data.…”

Regulation and functional consequences of mGlu4 RNA editing

“…Cocaine use in rats increased the expression of both mGlu4 and mGlu7 within the hippocampus and NAc while decreasing expression in the amygdala 419 . Within mice, however, mGlu4 expression was unchanged in both the NAc and CPu following cessation from cocaine administration 420 , again raising questions regarding whether these alteration are species-specific, or model-specific, effects. In rat models of self-administration, systemic administration of the agonist LSP2-9166 or the mGlu4-specific PAM Lu AF21934 decreased sensitization to cocaine 419,421 .…”