THE ROLE OF GLUTAMATE IN DRUG ADDICTION
Excitatory Control of Mesolimbic and Mesocortical Dopamine Neurons
Susan R. Sesack, Ph.D.
Dr. Susan Sesack presented research suggesting that excitatory brain stem afferents provide important sources of glutamate and cholinergic synapses onto mesolimbic DA neurons that are likely to contribute to the rewarding properties of drugs and their addictive liability. Her team’s research has focused on the major sources of excitatory drive to the ventral tegmental area (VTA), namely the prefrontal cortex (PFC) and the brain stem laterodorsal tegmentum (LDT), to identify the specific sources of afferents that innervate different populations of VTA DA neurons with discrete forebrain targets, specifically those projecting to the nucleus accumbens (NAc; mesolimbic) or to the PFC (mesocortical). Dr. Sesack presented electron microscopic evidence that VTA afferents from the PFC selectively target DA neurons that project back to the PFC and not those that innervate the NAc.
Dr. Sesack also suggested that LDT, a major source of cholinergic innervation to DA neurons, is a likely anatomical substrate for the reinforcing properties of nicotine. Researchers at her laboratory observed that both LDT afferents and axons labeled for cholinergic markers preferentially synapse onto DA cells with projections to the NAc. In addition, Dr. Sesack presented preliminary data showing that nicotinic alpha-7 receptor subunits in the VTA are localized to excitatory synapses, consistent with their role in the presynaptic regulation of glutamate release.
Cocaine- and Extinction-Induced Neuroplasticity in AMPA Receptors Regulate Drug-Seeking Behavior
David W. Self, Ph.D.
Dr. David Self presented data suggesting that that behavior-based approaches aimed at modulating neuroplasticity in the mesolimbic dopamine system could be useful in treating cocaine addiction. Using viral-mediated overexpression of GluR1 in vivo to study the role of enhanced AMPA-mediated input to VTA neurons on the motivation for cocaine in self-administration tests, his team found that chronic cocaine self-administration upregulates the phosphorylated form of the GluR1 AMPA receptor subunit in the VTA, an effect that could contribute to enhanced AMPA-mediated excitability of dopamine neurons. Their results suggest that GluR1 upregulation in VTA neurons increases the motivation for cocaine and that protein kinase A-mediated GluR1 phosphorylation may be critical for this effect.
In contrast to the VTA, GluR1 levels in the NAc shell are up-regulated by repeated extinction training experience, an effect that coincides with a reduction in cocaine-seeking behavior. The research team studied viral-mediated overexpression of GluR1 in NAc neurons, which prevents the development of cocaine sensitization and reduces the ability of D2 dopamine receptor stimulation to elicit cocaine-seeking behavior. Although overexpression of a dominant negative GluR1 mutant to weaken AMPA-mediated input to NAc neurons facilitates sensitization of D2 receptor-mediated behavioral responses, their results suggest that extinction-induced increases in GluR1 in the NAc lessen cocaine addiction by reducing dopaminergic stimulation of D2 receptors.
Role of VTA Glutamate in Contextual Cue-Induced Relapse to Heroin-Seeking
Yavin M. Shaham, Ph.D.
In humans, exposure to stimuli associated with drug intake can provoke relapse to drug use after prolonged abstinence. These stimuli are of two general types: discrete drug cues, which are temporally associated with drug reward, and contextual drug cues, which are not temporally associated with the acute rewarding effects of drugs but predict drug availability. Many laboratories explore the neuronal mechanisms underlying discrete cue-induced drug-seeking in rat models. In contrast, little is known about the mechanisms underlying contextual, cue-induced drug-seeking, despite the important role that these cues play in human drug relapse.
To study the role of the drug context in relapse, Dr. Yavin Shaham and colleagues recently adapted a renewal procedure from the fear-conditioning literature. They found that in rats trained to self-administer cocaine or a heroin-cocaine mixture, exposure to the drug self-administration context, after extinction of the drug-reinforced behavior in a different context, reliably reinstated drug-seeking. Dr. Shaham summarized these findings and presented new data on the effect of systemic and intracranial injections of a group II metabotropic glutamate receptor agonist, LY379268, on context-induced reinstatement of heroin-seeking.
Phenotype-Driven Approaches to Understanding the Neuronal Plasticity Associated With Drugs of Abuse
Marc G. Caron, Ph.D.
Neurotransmitter transporters play a fundamental role in the regulation of neuronal activity by limiting the diffusion and action of neurotransmitters in extracellular space. Genetic inactivation of plasma membrane and vesicular transporters in the mouse has revealed a key role for these proteins in the maintenance of the homeostasis of presynaptic neurochemistry and physiology. Through reverse genetic approaches, Dr. Marc Caron and colleagues used genetic animal models to identify the underlying molecular components associated with neuronal plasticity and relate them to drugs of abuse. These genetic animal models—which recapitulate the pharmacological models of “behavioral sensitization” associated with exposure to psychostimulants (dopamine transporter knockout [DATKO]), tricyclic antidepressants (norepinephrine transporter knockout), and reserpine (vesicular monoamine transporter knockout)—all demonstrated enhanced behavioral responses to direct or indirect DA receptor agonists. Mice lacking PSD-95 (PSD-95-GK) recapitulated the molecular, cellular, and behavioral phenotypes of the original mouse models, suggesting that modulation of PSD-95 might contribute not only to learning and memory but also to drug-related plasticity. Dr. Caron’s team used the ENU mutagenesis of DATKO mice to identify dominant modifier genes of the hyperactivity phenotype. DATKO mice, unlike their heterozygote littermates, display a novelty-dependent hyperactivity phenotype. Several putative mutants were identified that either enhance or attenuate the DATKO phenotype or provoke a hyperactivity phenotype in the DAT heterozygotes. In the DATKO and amphetamine-treated mice, the team demonstrated that neuronal and behavioral responses to either DA or psychostimulants are mediated, at least in part, via a lithium-sensitive signaling cascade involving concomitant inactivation of Akt/PKB and activation of GSK-3. These biochemical changes are not affected by activation of the cAMP pathway but are effectively reversed by the inhibition of DA synthesis, D2 receptor blockade, or lithium. Pharmacological inhibition or genetic inactivation of GSK-3 significantly reduces the DA-dependent locomotor behaviors in mice. These findings support a role for the Akt/GSK-3 signaling pathway as an important mediator of psychostimulant actions in vivo. Pharmacological modulation of this signaling pathway might be relevant to the management of drugs of abuse.
Are New Targets for Addiction Pharmacotherapy Hiding in Excitatory Synapses?
Peter W. Kalivas, Ph.D.
[Slides not available]
Dr. Peter Kalivas discussed recent studies demonstrating that withdrawal from repeated cocaine exposure produces enduring changes in the content and/or function of several proteins in the nucleus accumbens that regulate excitatory synaptic transmission. It was proposed that by reversing these adaptations, it would be possible to block the behavioral plasticity produced by repeated cocaine administration, such as locomotor sensitization and the reinstatement of drug-seeking. Candidate proteins for this process include the catalytic subunit of the cystine/glutamate exchanger (xCT); long-form Homer-1 and Homer-2 gene products; activator of G protein signaling 3 (AGS3); and proteins regulating the disassembly of actin, including Lim kinase (LIMK). These proteins are altered by withdrawal from repeated cocaine exposure, and a variety of strategies were used to restore protein function to normal or to mimic cocaine-induced functional change in drug-naive rats, including systemic drug administration (N-acetylcysteine to restore xCT), adeno-associated viral transfection of Homer cDNA, and Tat-HIV fusion proteins with binding domains of AGS3 or cofilin (LIMK substrate). Dr. Kalivas presented data showing that these proteins offer novel pharmacotherapeutic targets for inhibiting relapse in the reinstatement model of drug-seeking.
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