A considerable research effort has been made to characterize the central effects of daily administration of drugs of abuse. It has been shown that the motor stimulant effect of amphetamine, cocaine and opioids is progressively enhanced after daily administration. With the exception of amphetamine, relatively little experimentation has been conducted to characterize behavioral """"""""sensitization"""""""" to cocaine or opioids in terms of alterations in dopaminergic function. Evidence is presented to suggest that a change in the dopamine (DA) neurons in the A10 region may underlie some aspects of behavioral sensitization. Therefore, neurochemical studies will focus on this brain region, as well as the nucleus accumbens, prefrontal cortex, striatum and A9 DA region. This proposed research will characterize the effects of daily administration of cocaine, ip, morphine, ip, enkephalin analogues, intra-A10, and stress on central DA systems. Rats will receive daily administration of these drugs or stress, and at various times afterward in vitro and postmortem studies will be performed, including measurement of basal and induced DA released from tissue slices, and measurement of DA metabolism, dopa accumulation and DA depletion after tyrosine hydroxylase inhibition. In addition, in vivo measurement of DA release will be assessed using voltammetery and intracranial dialysis. Once changes in dopaminergic function produce by daily exposure to drugs of abuse and stress have been defined, the capacity of daily treatment with one drug to alter the behavioral and neurochemical effects of another drug or stress (i.e. cross-sensitization) will be examined. These studies are designed to determine if a common dopaminergic mechanism may be mediating behavioral sensitization to the daily treatment of cocaine, opioids and stress. Cocaine abuse has markedly increased in recent years, and simultaneous opioid and cocaine abuse appears to be on the rise. Thus, the proposed studies will contribute not only to our understanding of the neurochemical consequence of cocaine and opioid abuse, but how parallel abuse of the drugs may synergize. While a role by stress in promoting drug abuse remains ill- defined, an interaction with DA systems in common with that of drugs of abuse would support such a role.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Pharmacology I Research Subcommittee (DABR)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington State University
Schools of Veterinary Medicine
United States
Zip Code
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
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
Kupchik, Yonatan M; Kalivas, Peter W (2017) The Direct and Indirect Pathways of the Nucleus Accumbens are not What You Think. Neuropsychopharmacology 42:369-370
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756
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

Showing the most recent 10 out of 241 publications