The group I metabotropic glutamate receptors (mGluR1a and mGluR5) are important modulators of neuronal structure and function. Although these receptors share common signaling pathways, they are capable of having distinct effects on cellular plasticity. We investigated the individual effects of mGluR1a or mGluR5 activation on dendritic spine density in medium spiny neurons in the nucleus accumbens (NAc), which has become relevant with the potential use of group I mGluR based therapeutics in the treatment of drug addiction. We found that systemic administration of mGluR subtype-specific positive allosteric modulators had opposite effects on dendritic spine densities. Specifically, mGluR5 positive modulation decreased dendritic spine densities in the NAc shell and core, but was without effect in the dorsal striatum, whereas increased spine densities in the NAc were observed with mGluR1a positive modulation. Additionally, direct activation of mGluR5 via CHPG administration into the NAc also decreased the density of dendritic spines. These data provide insight on the ability of group I mGluRs to induce structural plasticity in the NAc and demonstrate that the group I mGluRs are capable of producing not just distinct, but opposing, effects on dendritic spine density.

The authors report that rats that were withdrawn from cocaine self-administration had an in vivo deficit in their ability to develop long-term potentiation and depression in the nucleus accumbens core following prefrontal cortex stimulation. N-acetylcysteine, a drug that prevents relapse, restored the ability to induce plasticity. Cocaine addiction is characterized by an impaired ability to develop adaptive behaviors that can compete with cocaine seeking, implying a deficit in the ability to induce plasticity in cortico-accumbens circuitry crucial for regulating motivated behavior. We found that rats withdrawn from cocaine self-administration had a marked in vivo deficit in the ability to develop long-term potentiation (LTP) and long-term depression (LTD) in the nucleus accumbens core subregion after stimulation of the prefrontal cortex. N-acetylcysteine (NAC) treatment prevents relapse in animal models and craving in humans by activating cystine-glutamate exchange and thereby stimulating extrasynaptic metabotropic glutamate receptors (mGluR). NAC treatment of rats restored the ability to induce LTP and LTD by indirectly stimulating mGluR2/3 and mGluR5, respectively. Our findings show that cocaine self-administration induces metaplasticity that inhibits further induction of synaptic plasticity, and this impairment can be reversed by NAC, a drug that also prevents relapse.

Numerous studies have demonstrated that drugs of abuse activate the mesolimbic dopamine reward pathway, and it is widely held that this activation contributes to the motivational and positive reinforcing properties of these substances. However, there is evidence that endogenous opioid systems within this brain reward circuit also play a role in drug reinforcement and drug-seeking behavior. Using microdialysis in freely moving rats, we sought to determine whether various drugs of abuse (i.e., ethanol, cocaine, d-amphetamine, and nicotine) would increase neurotransmission of endogenous opioid peptides (i.e., endorphins) in the nucleus accumbens. Drugs were administered intraperitoneally twice at 3 h intervals, and the endorphin content of microdialysates was analyzed by a solid-phase radioimmunoassay. Acute administration of ethanol, cocaine, and d-amphetamine transiently elevated extracellular levels of endorphins in the nucleus accumbens, whereas nicotine and saline were without effect. We hypothesize that this drug-induced release of endorphins may contribute to the positive reinforcing and motivating properties of ethanol and psychostimulants.