All of the reward-related dopamine and opiate receptors are coupled to the cAMP second messenger system, which is up-regulated in the nucleus accumbens (NAc) following chronic drug exposure. Recently, studies from our laboratory have suggested that the NAc-cAMP system modulates drug reinforcement mechanisms. These studies directly tested the role of inhibitory G proteins and cAMP-dependent protein kinase (PKA) in drug reinforcement by infusing agents that modulate these intracellular proteins into the NAc of rats self-administering cocaine or heroin. In addition, our studies also have suggested that PKA in the NAc is involved in drug craving, and relapse of drug-seeking behavior, since NAc infusions of PKA modulators reinstate drug-seeking behavior following extinction from drug self-administration. The present studies will further characterize the intracellular mechanisms of drug reinforcement and addiction. Firstly, the role of excitatory G (Gs) proteins, specific subunits of PKA, and cAMP Response Element Binding (CREB) proteins (a major substrate of PKA), in drug reinforcement and addiction will be studied by infusing agents that modulate these proteins into the NAc of rats during drug self-administration tests. Parallel biochemical experiments will study (and verify) the modulation of intracellular proteins by the NAc infusions. Similarly, intra-accumbens infusions will be used to study the role of PKA in both the positive and the negative motivational aspects of drug addiction and withdrawal by using the conditioned place preference paradigm. Another major focus of this application will study the pharmacological, anatomical, and intracellular substrates of drug craving and relapse by using a drug reinstatement paradigm. With the reinstatement paradigm, we recently found that Dl dopamine receptor agonists will suppress, while D2 receptor agonists will induce, drug-seeking behavior in rats. Thus, Dl and D2 agonists will be used as probes to identify the anatomical loci that mediate these opposing effects on relapse of drug-seeking behavior. The intracellular substrates of drug craving will be studied by infusing PKA modulators into the specific brain sites that mediate the Dl and D2 receptor effects on reinstatement of drug-seeking behavior. Finally, the neural mechanisms through which conditioned cues trigger drug craving will be studied in a cue reinstatement paradigm. The studies in this grant will continue to provide a mechanistic link between the molecular, cellular, and behavioral aspects of drug abuse, and will seek to identify potential targets for pharmacotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
3R29DA010460-04S1
Application #
6148683
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pilotte, Nancy S
Project Start
1996-09-01
Project End
2001-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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
Nugent, Alexandria L; Anderson, Ethan M; Larson, Erin B et al. (2017) Incubation of cue-induced reinstatement of cocaine, but not sucrose, seeking in C57BL/6J mice. Pharmacol Biochem Behav 159:12-17
Larson, Erin B; Wissman, Anne M; Loriaux, Amy L et al. (2015) Optogenetic stimulation of accumbens shell or shell projections to lateral hypothalamus produce differential effects on the motivation for cocaine. J Neurosci 35:3537-43
Hobson, Benjamin D; O'Neill, Casey E; Levis, Sophia C et al. (2013) Adenosine A1 and dopamine d1 receptor regulation of AMPA receptor phosphorylation and cocaine-seeking behavior. Neuropsychopharmacology 38:1974-83
Ozburn, Angela Renee; Larson, Erin Beth; Self, David W et al. (2012) Cocaine self-administration behaviors in Clock?19 mice. Psychopharmacology (Berl) 223:169-77
Larson, Erin B; Graham, Danielle L; Arzaga, Rose R et al. (2011) Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats. J Neurosci 31:16447-57
Edwards, Scott; Bachtell, Ryan K; Guzman, Daniel et al. (2011) Emergence of context-associated GluR(1) and ERK phosphorylation in the nucleus accumbens core during withdrawal from cocaine self-administration. Addict Biol 16:450-7
Larson, Erin B; Akkentli, Fatih; Edwards, Scott et al. (2010) Striatal regulation of ?FosB, FosB, and cFos during cocaine self-administration and withdrawal. J Neurochem 115:112-22
Bachtell, Ryan K; Self, David W (2009) Effects of adenosine A2A receptor stimulation on cocaine-seeking behavior in rats. Psychopharmacology (Berl) 206:469-78
Simmons, Diana; Self, David W (2009) Role of mu- and delta-opioid receptors in the nucleus accumbens in cocaine-seeking behavior. Neuropsychopharmacology 34:1946-57

Showing the most recent 10 out of 11 publications