Effects of nicotine and LY379268 on functional coupling of mGlu2/3 receptors to G-proteins. Stimulation of [35S]GTPγS binding by the mGlu2/3 receptor agonist LY354740 was significantly decreased in rats self-administering nicotine compared with animals responding for food, suggesting mGlu2/3 receptor downregulation in all assessed brain areas (LY354740 × reward interactions; #p < 0.05, ###p < 0.001; *p < 0.05, **p < 0.01, ***p < 0.001, different from food). Repeated LY379268 administration also decreased [35S]GTPγS binding in the prefrontal cortex and increased [35S]GTPγS binding in the nucleus accumbens and amygdala (LY354740 × LY379268 interactions, †p < 0.05, †††p < 0.001; +p < 0.05, ++p < 0.01, +++p < 0.001, different from food). Data represent mean ± SEM; n = 6.