mGluR: A SUBSTRATE IN THE NEUROBIOLOGY OF ADDICTION
Metabotropic Glutamate 5 Receptors: Role in Drug Self-Administration and in Regulating the Activity of Brain Reward Systems
Paul J. Kenny, Ph.D.
Emerging evidence suggests that glutamate-mediated transmission, particularly in metabotropic glutamate (mGlu) receptors, plays an important role in regulating the physiological and behavioral actions of drugs of abuse. This study shows that the mGlu5 receptor antagonist MPEP (2-methyl-6-[phenylethynyl]-pyridine hydrochloride) decreased intravenous cocaine and nicotine self-administration in rats. These observations, together with similar findings from other laboratories, provide strong evidence that mGlu5 receptors regulate the reinforcing effects of drugs of abuse. Little is currently known about the mechanisms by which mGlu5 receptors regulate drug reinforcement. Drugs of abuse, such as nicotine and cocaine, increase the sensitivity of brain reward systems, as measured by the drug-induced lowering of intracranial self-stimulation (ICSS) thresholds. Such drug-induced increases in reward sensitivity likely contribute to the reinforcing effects of addictive drugs. This study shows that in contrast to the actions of addictive drugs, the mGlu5 receptor antagonist MPEP decreased the sensitivity of brain reward systems, as measured by MPEP-induced elevations of ICSS thresholds in rats. When MPEP was administered in combination with nicotine or cocaine, the antagonism of mGlu5 receptors resulted in attenuation of the magnitude by which nicotine or cocaine lowered reward thresholds. These observations demonstrate that mGlu5 receptors play an important role in regulating drug consumption. In addition, mGlu5 receptors regulate the baseline sensitivity of brain reward systems. It is likely that the antagonism of mGlu5 receptors decreases the consumption of drugs of abuse by attenuating the stimulatory effects of these drugs on brain reward systems.
mGluR-Homer Interactions: A Cellular Mediator of Alcohol Reward
Karen K. Szumlinski, Ph.D.
[Slides not available]
Dr. Karen Szumlinski discussed a potential therapeutic target for the treatment of alcoholism, Group 1 metabotropic glutamate receptors (mGluRs), which are indirectly inhibited by alcohol via a protein kinase C-dependent mechanism. There is an important role for Group 1 mGluRs in mediating the rewarding and motor-sensitizing effects of opiate and psychomotor-stimulant drugs. Pharmacological blockade of either the mGluR5 or mGluR1 (a subtype of Group 1 mGluRs) reduces both the conditioned and unconditioned aspects of alcohol reward in rodents and abolishes alcohol-induced increases in extracellular dopamine and glutamate within the nucleus accumbens—two neural substrates implicated in addiction-related behaviors. The trafficking, localization, and signaling of Group 1 mGluRs depend on interactions with members of the Homer family of postsynaptic scaffolding proteins. Recently, a series of behavioral and neurochemical studies revealed an active and necessary role for Homer2 expression in the accumbens in alcohol-induced neural plasticity. Similar to the effects of mGluR blockade on alcohol-related behaviors, Homer2 knockout mice exhibit an alcohol-avoiding and -intolerant phenotype that is associated with a lack of alcohol-induced neurochemical sensitization in the accumbens. Intra-accumbens, virus-mediated overexpression of the Homer2b isoform enhances the expression of alcohol reward in alcohol-preferring B6 mice and facilitates alcohol-induced locomotor and neurochemical sensitization. As manipulations of either Group 1 mGluR or Homer function alter sensitivity to the behavioral effects of other drugs of abuse (including cocaine and PCP), these data pose the physical interaction between Group 1 mGluRs and constitutively expressed Homer proteins within the nucleus accumbens as one cellular mediator of addiction to alcohol and perhaps other drugs of abuse.
mGluR Regulation of Endocannabinoid Release From Midbrain Dopamine Neurons
Carl R. Lupica, Ph.D.
Mesolimbic dopamine (DA) neurons are involved in mediating the rewarding effects of virtually every abused drug. The cell bodies of these neurons are found in the ventral tegmental area (VTA), and their afferent axons target a variety of forebrain structures, including the nucleus accumbens and prefrontal cortex. In addition, the DA neurons are targeted by both excitatory and inhibitory axons, which strongly regulate their activity and their involvement with drug abuse and addiction. Recent work in the laboratory of Dr. Lupica indicates that presynaptic metabotropic glutamate autoreceptors (mGluRs), located on the axon terminals of glutamatergic afferents to the VTA DA neurons, can strongly control the strength of excitatory input to these cells and, consequently, the degree of DA neuron activation. This mGluR regulation of the level of DA neuron activity can then modulate the release of endogenous cannabinoid molecules (endocannabinoids) from the DA neurons, which then act on cannabinoid CB1 receptors to limit both inhibitory and excitatory neurotransmitter release onto these cells. Through this mechanism, mGluRs and endocannabinoids can interact to modify the integration of synaptic inputs to the DA neurons, presenting an additional neurobiological mechanism that may be involved with reward and addictive processes.