Repeated nicotine exposure increases the intracellular interaction between ERK‐mGluR5 in the nucleus accumbens more in adult than adolescent rats

Abstract

Intracellular interactions between protein kinases and metabotropic receptors in the striatum regulate behavioral changes in response to drug exposure. We investigated the difference in the degree of interaction between extracellular signal‐regulated kinase (ERK) and metabotropic glutamate receptor subtype 5 (mGluR5) in the nucleus accumbens (NAc) after repeated exposure to nicotine in adult and adolescent rats. The results showed that repeated exposure to nicotine (0.5 mg/kg/day, s.c.) for seven consecutive days increased ERK phosphorylation more in adults than in adolescents. Furthermore, membrane expression of mGluR5 in gamma‐aminobutyric acid (GABA) medium spiny neurons was higher in adults than adolescents as a result of repeated exposure to nicotine. Blockade of mGluR5 with MPEP (0.5 nmol/side) decreased the repeated nicotine‐induced increase in ERK phosphorylation. Either blockade of mGluR5 or inhibition of ERK with SL327 (150 nmol/side) decreased the repeated nicotine‐induced increase in the level of inositol‐1,4,5‐triphosphate (IP3), a key transducer associated with mGluR5‐coupled signaling cascades. Similarly, interference of binding between activated ERK and mGluR5 by the blocking peptide, Tat‐mGluR5‐i (2 nmol/side), decreased the repeated nicotine‐induced increases in IP3 and locomotor activity in adults. These findings suggest that the intracellular interaction between ERK and mGluR5 in the NAc is stronger in adult than in adolescent rats, which enhances the understanding of age‐associated behavioral changes that occur after repeated exposure to nicotine.

The role of the metabotropic glutamate receptor 5 in nicotine addiction

“…In addition, intracellular interactions between protein kinases and metabotropic receptors in the striatum, might regulate behavioural changes in response to drug abuse 30 . Specifically, repeated exposure to nicotine increased ERK phosphorylation in adult rats 31 .…”

“…MPEP's effect on nicotine consumption may be mediated by intracellular protein kinases such as ERK in the brain reward system 31 . Mavoglurant and other medications (e.g.…”

“…30 Specifically, repeated exposure to nicotine increased ERK phosphorylation in adult rats. 31 Interestingly, pharmacological studies have found functional interactions of mGluR5 with DA D1/D2, NMDA, adenosine A2, and GABA receptors. 11,13,15 The mGlu5 receptor was co-localized with DA and adenosine receptors in the striatum, including the NAc, where they are involved in the regulation of dopaminergic neurotransmission.…”

“…37 MPEP's effect on nicotine consumption may be mediated by intracellular protein kinases, such as ERK in the brain reward system. 31 Mavoglurant and other medications (eg, AZD2066, Basimglurant), which target mGluR5, have been examined in human research as an aid for nicotine cessation. However, these medications have the potential to cause some serious side effects in humans, such as hallucinations, skin reactions, and cognitive problems.…”

Group I Metabotropic Glutamate Receptors and Interacting Partners: An Update

“…Of note, T1123/S1126 phosphorylation is not involved in the methamphetamine-induced acute locomotion or locomotor sensitization but is necessary for the reinforcing property of methamphetamine as tested under operant-conditioning procedures [25] and for cocaine sensitization [24]. In addition, repeated nicotine injections increased the interaction of active ERK with mGlu5 in the rat nucleus accumbens (NAc) [26]. An interfering peptide that specifically disrupts the ERK-mGlu5 binding reduced the repeated nicotine-induced increase in locomotor activity, indicating a role of the ERK-mGlu5 interaction in processing the nicotine effect [26].…”