Activation of metabotropic glutamate receptor 5 is associated with effect of amphetamine on brain neurons.

The role of metabotropic glutamate receptor 5 (mGluR5) was explored in mechanisms underlying the action of amphetamine (AMPH). The activity of mGluR5 was monitored by measuring the level of [3H]inositol monophosphates in brain neurons, in response to stimulation of 2-choloro-5-hydroxyphenylglycine (CHPG), a selective agonist of mGluR5. Treatment with 1 microM of AMPH for 1 h or 7 days increased the CHPG (1 mM, 30 min)-evoked phosphoinositide turnover by 46% or 92% and 26% or 84% in cultured cortical and hippocampal neurons, respectively, from that of CHPG-only treated cells. When AMPH was present during CHPG application post-1 h or 7 day AMPH incubation, the rate of phosphoinositide hydrolysis in cortical neurons became 121% or 142% higher than that treated with CHPG only. The postnatal day (P) 21 (juvenile) and P60 (adult) rats received three intraperitoneal injections of 5 mg/kg of AMPH or saline daily for 6 days. They were challenged on the eighth day with one dosage and sacrificed 3 h later. Reversible 3H-glutamate binding detected increases of 22-89% in the binding levels of cortex and hippocampus of both ages following the AMPH injections. Increases of 13-18% in the levels of mGluR5 mRNA were seen in the juvenile pyramidal neurons of hippocampal CA1-4, granular cells of dentate gyrus, and ventral thalamic nuclei, as shown by in situ hybridization. The AMPH-induced altered activity of mGluR5 is probably associated with changes in the expression of the glutamate receptors, including mGluR5. AMPH may modify the sensitivity of mGluR5 or interact with the receptor itself.