Addiction to drugs of abuse produces pathological changes in synaptic physiology that impair the capacity of the prefrontal cortex (PFC) to communicate with the basal ganglia and impedes the successful regulation of compulsive drug-seeking. The primary portal of entry by the PFC into the basal ganglia is through the nucleus accumbens, and withdrawal from self-administered cocaine is associated with enduring adaptations at PFC synapses in the accumbens. As part of the current Project 1 (2008-13), we characterized differences in accumbens adaptations depending on whether or not rats were withdrawn with or without extinction training. We recently discovered a rapid, transient synaptic potentiation in the accumbens core (NAcore) but not in the shell (NAshell) that correlated with the intensity of cue-reinstated cocaine seeking. Conversely, a similar synaptic potentiation occurs in the NAshell, not NAcore, when rats are placed into an extinguished context.
Aim 1 will characterize this rapid accumbens synaptic plasticity using different behavioral protocols.
Aim 2 uses optogenetics to test the hypotheses that giutamatergic afferents from the PFC and dopaminergic inputs from the ventral tegmental area (VTA) are necessary forthe rapid, transient synaptic potentiation in excitatory transmission to be characterized in Aim 1. A variety of proteins and signaling mechanisms are purported to account for the cocaine-induced changes in synaptic plasticity at PFC-accumbens synapses. We present preliminary data showing a potential role for matrix metalloproteases (MMPs) in reinstated cocaine seeking and the plasticity being characterized in Aims 1 &2. MMP activity known to be is necessary for shaping the extracellular matrix and for expressing many forms of plasticity, and in Aim 3 we propose to determine: 1) if inhibiting MMP signaling reduces cocaine seeking and extinction responding, and 2) if this is accomplished by preventing the rapid, transient synaptic potentiation being characterized in Aims 1 &2. Project 1 synergizes with other NARC projects and cores by sharing animal and optogenetic use through the Animal Core, and through scientific synergisms based on all projects examining different aspects of PFC and VTA regulation ofthe nucleus accumbens.
Project 1 describes a new form of morphological and physiological synaptic plasticity that is correlated with cocaine seeking. This synaptic plasticity will be evaluated for its importance in cocaine seeking, as well as in the ability to inhibit cocaine seeking. A set of enzymes, the MMPs, are known to regulate synaptic plasticity and have been shown to regulate cocaine seeking. These enzymes will be examined as a possible target for therapeutic intfirvention in animal models of cocaine relapse.
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| Roberts-Wolfe, Douglas; Bobadilla, Ana-Clara; Heinsbroek, Jasper A et al. (2018) Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons. J Neurosci 38:7100-7107 |
| Spencer, Sade; Neuhofer, Daniela; Chioma, Vivian C et al. (2018) A Model of ?9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens. Biol Psychiatry 84:601-610 |
| Parrilla-Carrero, Jeffrey; Buchta, William C; Goswamee, Priyodarshan et al. (2018) Restoration of Kv7 Channel-Mediated Inhibition Reduces Cued-Reinstatement of Cocaine Seeking. J Neurosci 38:4212-4229 |
| Kearney-Ramos, Tonisha E; Lench, Daniel H; Hoffman, Michaela et al. (2018) Gray and white matter integrity influence TMS signal propagation: a multimodal evaluation in cocaine-dependent individuals. Sci Rep 8:3253 |
| Giannotti, Giuseppe; Barry, Sarah M; Siemsen, Ben M et al. (2018) Divergent Prelimbic Cortical Pathways Interact with BDNF to Regulate Cocaine-seeking. J Neurosci 38:8956-8966 |
| Siemsen, Ben M; Lombroso, Paul J; McGinty, Jacqueline F (2018) Intra-prelimbic cortical inhibition of striatal-enriched tyrosine phosphatase suppresses cocaine seeking in rats. Addict Biol 23:219-229 |
| Brown, Robyn Mary; Kupchik, Yonatan Michael; Spencer, Sade et al. (2017) Addiction-like Synaptic Impairments in Diet-Induced Obesity. Biol Psychiatry 81:797-806 |
| Bobadilla, Ana-Clara; Garcia-Keller, Constanza; Heinsbroek, Jasper A et al. (2017) Accumbens Mechanisms for Cued Sucrose Seeking. Neuropsychopharmacology 42:2377-2386 |
| Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624 |
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