Long-Lasting Impairment of mGluR₅-Activated Intracellular Pathways in the Striatum After Withdrawal of Cocaine Self-Administration

Abstract

Background:Cocaine addiction continues to be a major heath concern, and despite public health intervention there is a lack of efficient pharmacological treatment options. A newly identified potential target are the group I metabotropic glutamate receptors, with allosteric modulators showing particular promise.Methods:We evaluated the capacity of group I metabotropic glutamate receptors to induce functional responses in ex vivo striatal slices from rats with (1) acute cocaine self-administration, (2) chronic cocaine self-administration, and (3) 60 days cocaine self-administration withdrawal by Western blot and extracellular recordings of synaptic transmission.Results:We found that striatal group I metabotropic glutamate receptors are the principal mediator of the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine-induced cAMP responsive-element binding protein phosphorylation. Both acute and chronic cocaine self-administration blunted group I metabotropic glutamate receptor effects on cAMP responsive-element binding protein phosphorylation in the striatum, which correlated with the capacity to induce long-term depression, an effect that was maintained 60 days after chronic cocaine self-administration withdrawal. In the nucleus accumbens, the principal brain region mediating the rewarding effects of drugs, chronic cocaine self-administration blunted group I metabotropic glutamate receptor stimulation of extracellular signal-regulated protein kinases 1/2 and cAMP responsive-element binding protein. Interestingly, the group I metabotropic glutamate receptor antagonist/inverse-agonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride, led to a specific increase in cAMP responsive-element binding protein phosphorylation after chronic cocaine self-administration, specifically in the nucleus accumbens, but not in the striatum.Conclusions:Prolonged cocaine self-administration, through withdrawal, leads to a blunting of group I metabotropic glutamate receptor responses in the striatum. In addition, specifically in the accumbens, group I metabotropic glutamate receptor signaling to cAMP responsive-element binding protein shifts from an agonist-induced to an antagonist-induced cAMP responsive-element binding protein phosphorylation.

Restoring glutamate homeostasis in the nucleus accumbens via endocannabinoid-mimetic drug prevents relapse to cocaine seeking behavior in rats

“…Activating mGluR5 with DHPG significantly increased frequencies of slow inward currents in the saline group but not the cocaine group, indicating long-term disruption of mGluR5-mediated astrocytic activity in cocaine group. While impaired postsynaptic mGluR5 function in animal models of cocaine self-administration has been reported by previous studies [31,[42][43][44][45][46], our present findings are the first to validate that astrocytic mGluR5 is involved. We hypothesize that this reduction in mGluR5-mediated astrocytic glutamate release potentially contributed to a decrease of extrasynaptic glutamate in the NAcore, and consequently resulted in decreased glutamatergic tone on presynaptic mGluR2/3 [37,47].…”

International Union of Basic and Clinical Pharmacology. CXI. Pharmacology, Signaling, and Physiology of Metabotropic Glutamate Receptors

“…In a preclinical model of Huntington's disease, the balance of mGlu 5 receptor signaling pathways are perturbed, where IP 1 accumulation is reduced, but iCa 2+ mobilization, Akt, and ERK1/2 phosphorylation are increased (Ribeiro et al, 2010). Brain region-specific changes in group I mGlu receptor signaling have also been noted after chronic cocaine administration, such that the mGlu 5 receptor NAM MPEP becomes an agonist for inducing cAMP response element-binding protein phosphorylation in the nucleus accumbens but not striatum (Hoffmann et al, 2017). Changes in the balance of intracellular signaling responses specific to the disease setting could be exploited by the development of biased ligands; however, they also offer another layer of complexity with respect to designing appropriate discovery pipelines for the translation of biased ligands.…”

Shared Behavioral and Neurocircuitry Disruptions in Drug Addiction, Obesity, and Binge Eating Disorder: Focus on Group I mGluRs in the Mesolimbic Dopamine Pathway

“…A single exposure to a drug of abuse can impair NAc mGlu-LTD via the reduction of mGlu 5 and dysfunction of CB 1 , ,,,, thus leading to a remodeling of excitatory synaptic transmission and synaptic plasticity. It has been hypothesized that the abolishment of NAc mGlu-LTD following drug exposure may represent a mechanism to counteract the decrease in Glu neurotransmission; , however, the underlying signaling mechanism remains unclear.…”