An enduring alteration in the behavioral response to an acute psychostimulant challenge is produced by repeated psychostimulant pretreatment. Termed behavior sensitization, this example of neuronal plasticity can culminate in paranoid psychosis, panic attacks and anxiety disorders. Using a rat animal model, sensitization can be studied in two temporally and spatially distinct components, initiation and expression. The study of initiation attempts to describe the neural and cellular substrates upon which repeated drug administration impinges to establish the long-term behavioral alterations. The study of expression endeavors to identify enduring changes in neural and cellular function that mediate the augmented behavioral response. During the previous funding period it was shown that the initiation of sensitization to cocaine arises from drug action in the ventral tegmental area (VTA) and that the expression of sensitization is partly the result of altered excitatory amino acid (EAA) and dopamine transmission in the nucleus accumbens. In this proposal, rats will be treated with repeated cocaine injections for one week, and models of the synaptic organization in the VTA and nucleus accumbens in the initiation and expression of sensitization to repeated cocaine will be tested. These models provide a basis for evaluating not only dopamine transmission, but other neurotransmitters arising from intrinsic and afferent projections to the VTA and nucleus accumbens, including EAAs, gamma-aminobutyric acid (GABA) and the opioid peptide, enkephalin. Rats will be examined at early and late withdrawal times to characterize the time course of biochemical changes that may parallel the time course of behavioral sensitization. A combination of behavioral pharmacology, microdialysis and biochemical measures of signal transduction will be used to identify alterations in neurotransmission. By identifying the neural substrates of sensitization to cocaine it will be possible to provide rational interventions in treating the sensitization-based psychopathologies present in some cocaine addicts.
| 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 |
| Neuhofer, Daniela; Kalivas, Peter (2018) Metaplasticity at the addicted tetrapartite synapse: A common denominator of drug induced adaptations and potential treatment target for addiction. Neurobiol Learn Mem 154:97-111 |
| Taniguchi, Makoto; Carreira, Maria B; Cooper, Yonatan A et al. (2017) HDAC5 and Its Target Gene, Npas4, Function in the Nucleus Accumbens to Regulate Cocaine-Conditioned Behaviors. Neuron 96:130-144.e6 |
| 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 |
| Heinsbroek, Jasper A; Neuhofer, Daniela N; Griffin 3rd, William C et al. (2017) Loss of Plasticity in the D2-Accumbens Pallidal Pathway Promotes Cocaine Seeking. J Neurosci 37:757-767 |
| Bobadilla, Ana-Clara; Heinsbroek, Jasper A; Gipson, Cassandra D et al. (2017) Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior. Prog Brain Res 235:93-112 |
| Spencer, Sade; Kalivas, Peter W (2017) Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse. Int J Neuropsychopharmacol 20:797-812 |
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