Some people are capable of experimenting casually with drugs, like cocaine, while others escalate their drug intake and seek drugs compulsively to the point of addiction. Like addicts, animals self-administering cocaine adjust their intake to maintain optimal brain cocaine and dopamine levels that ultimately determine the pattern of neural activity in circuits that regulate the behavior. Identifying the specific neuronal mechanisms responsible for the plasticity that controls the feedback on drug intake and drug-seeking is fundamental to understanding addiction. The prolonged (6 hr) access animal model of cocaine self- administration reproduces the high levels of drug intake and enhanced cocaine-seeking during periods of drug abstinence often seen in drug addicts. To date, no in vitro studies have measured the neurophysiological adaptations associated with prolonged access volitional cocaine administration, nor have any studies examined the potential for extinction learning to reverse the neurophysiological adaptations. Self and colleagues (2003) have demonstrated that extinction learning is capable of reversing several molecular changes induced by cocaine self- administration and have proposed a role for extinction in addiction therapy. Unfortunately, almost all studies examining synaptic or intrinsic plasticity have used noncontingent, experimenter delivered drug, which does not allow extinction learning to occur. While effective at inducing behavioral plasticity, like sensitization, noncontingent drug delivery lacks the volitional and motivational components as well as the intermittent temporal activation of brain regions in the reward circuitry important for synaptic plasticity. Ideally, a candidate brain region worth investigating for a role in the plasticity associated with escalation or incubation of cocaine craving would have the following criteria;1) Substantial innervation within the brain reward circuitry;2) Neural responses to rewarding stimuli and conditioned stimuli or contexts associated with them;3) Modulation of neuronal activity by dopamine and cocaine;3) A role in the formation or storage of reward-related memory;4) Regulation of dopamine neuronal activity or levels in the reward circuit;5) Bidirectional regulation of reinstatement of extinguished responding (i.e. neuronal activation triggers and inhibition decreases reinstatement). Few brain regions meet all of these criteria, however, the ventral subiculum -- the major hippocampal output structure and interface to the dopamine system -- is one such structure that does. Our past in vitro experiments have shown the ventral subiculum to be susceptible to repeated psychostimulant-induced plasticity. This study proposes to study synaptic and intrinsic excitability and dopamine modulation of ventral hippocampal CA1-subicular excitability that is associated with acquisition, maintenance, and withdrawal/extinction of cocaine self administration. We will use a combination of state-of-the-art 64 channel planar multielectrode array field potential recording and whole-cell patch clamp recording in rats that have been trained for either short access or long access to cocaine self-administration. Two hallmark features of addiction are the loss of controlled drug intake and the associated high relapse risk. Identifying the brain regions and specific neuronal mechanisms that control the feedback on drug intake and drug-seeking is fundamental to understanding addition. Our goal is to use the cocaine self-administration behavioral model of contingent volitional drug intake to allow us to correlate cocaine intake and extinction of drug taking with detailed measures of neurophysiological excitability for the purposes of better understanding the neural plasticity associated with memory linked to addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA024040-02
Application #
7586641
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Pilotte, Nancy S
Project Start
2008-04-01
Project End
2009-03-31
Budget Start
2009-02-01
Budget End
2009-03-31
Support Year
2
Fiscal Year
2009
Total Cost
$31,400
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Psychiatry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Klipec, William D; Burrow, Kristin R; O'Neill, Casey et al. (2016) Loss of the trpc4 gene is associated with a reduction in cocaine self-administration and reduced spontaneous ventral tegmental area dopamine neuronal activity, without deficits in learning for natural rewards. Behav Brain Res 306:117-27
Baratta, Michael V; Pomrenze, Matthew B; Nakamura, Shinya et al. (2015) Control Over Stress Accelerates Extinction of Drug Seeking Via Prefrontal Cortical Activation. Neurobiol Stress 2:20-27
Nakamura, Shinya; Baratta, Michael V; Cooper, Donald C (2013) A method for high fidelity optogenetic control of individual pyramidal neurons in vivo. J Vis Exp :
Varela, Juan A; Wang, Jungang; Christianson, John P et al. (2012) Control over stress, but not stress per se increases prefrontal cortical pyramidal neuron excitability. J Neurosci 32:12848-53
Dobelis, Peter; Staley, Kevin J; Cooper, Donald C (2012) Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons. PLoS One 7:e41108
Cadle, Brian A; Rasmus, Kristin C; Varela, Juan A et al. (2010) Cellular phone-based image acquisition and quantitative ratiometric method for detecting cocaine and benzoylecgonine for biological and forensic applications. Subst Abuse 4:21-33
Park, Jin-Yong; Remy, Stefan; Varela, Juan et al. (2010) A post-burst after depolarization is mediated by group i metabotropic glutamate receptor-dependent upregulation of Ca(v)2.3 R-type calcium channels in CA1 pyramidal neurons. PLoS Biol 8:e1000534
Sidiropoulou, Kyriaki; Lu, Fang-Min; Fowler, Melissa A et al. (2009) Dopamine modulates an mGluR5-mediated depolarization underlying prefrontal persistent activity. Nat Neurosci 12:190-9
Moore, Shannon J; Cooper, Donald C; Spruston, Nelson (2009) Plasticity of burst firing induced by synergistic activation of metabotropic glutamate and acetylcholine receptors. Neuron 61:287-300
Hawasli, Ammar H; Koovakkattu, Della; Hayashi, Kanehiro et al. (2009) Regulation of hippocampal and behavioral excitability by cyclin-dependent kinase 5. PLoS One 4:e5808