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Accumbens nNOS Interneurons Regulate Cocaine Relapse

Drug addiction is a chronic disorder in which individuals compulsively seek the use of drugs despite adverse effects. Re-lapse is the recurrence of compulsive drug use even after a per-son has reached remission. Relapse can be triggered by drug-related cues in the environment. Part of the brain that plays a role in relapse behavior is the nucleus accumbens (NA), a re-ward-related area. Research has shown that drug-related cues trigger transient synaptic potentiation       (t-SP), which refers to the difference in voltage between the inside and outside of a postsynaptic neuron. A postsynaptic neuron is the neuron that receives a neurotransmitter once it has crossed the synapse. The magnitude of t-SP in the NA is associated with drug-seeking behavior. To activate t-SP and drug-seeking behavior, however, matrix metalloproteinase (MMP), an enzyme that degrades extracellular material, must be activated, but it is unknown how these enzymes are activated. One idea is that glutamate, an ex-citatory neurotransmitter, activates the MMPs and t-SP. Dr. Rachel Smith, a faculty member of the Department of Psychological and Brain Sciences at Texas A&M University, and colleagues at the Medical University of South Carolina, sought to describe the sequence of neural activity that leads to drug relapse in animal models, focusing specifically on the nucleus accumbens’ mechanisms and cocaine. The researchers hypothesized that by activating a glutamate receptor (mGluR2/3), the spillover of gluta-mate would be inhibited, thus decreasing drug seeking. They also hypothesized that activation of mGluR5, another glutamate receptor, stimulates nitric oxide (NO) production and subsequent MMP activation, which drives drug seeking. To test the hypotheses, the researchers ran an experimental study with lab rats and mice where the animals were trained to self-administer cocaine using a lever for 10 days. During self-administration, light and tone cues were paired with the administration of the substance in response to a press on the active lever. An inactive lever in the chamber served as a control and had no light/tone or substance administration. After these sessions, the rats participated in extinction training where lever pressing produced no consequences. This extinction period lasted ten days. After the extinction period, rats were reinstated by either pressing active levers and receiving the light/tone, or remaining in an extinction trial. Relapse was modeled by usage of the active levers providing a light/tone cue without drug administration. The researchers also investigated neural activity via electrochemical detection, microdialysis, and zymography. Microdialysis enables the monitoring of neurotransmitters in the extracellular fluid, while zymography allows researchers to deter-mine if an enzyme is active. The rat brains were analyzed after the experiment so that electrical properties of neurons could be recorded. Dr. Smith and her colleagues discovered that rats which were reinstated and demonstrated relapse behavior had significant extracellular glutamate increases in the NA as a result of the conditioned cues of the light/tone. The researchers found that drug-related cues, in this case the light/tone, trigger the spillover of glutamate into the synapse, which activates mGluR5. The receptor then increases Nitric Oxide (NO) production, inducing MMP activity and t-SP. This sequence of events ultimately results in relapse. Therefore, when mGluR5 was blocked, cue-induced relapse was reduced. The researchers also found that stimulating mGluR2/3 before beginning the reinstatement period prevented cue-induced relapse. This research is important in the advancement of intervention and relapse programs because it points to new pharmaceutical and therapeutic techniques for drug addiction, specifically to cocaine. By identifying the neural pathways and functions of relapse and addiction, scientists can better formulate drug treatment and therapy programs for those suffering from addiction.


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