Drug addiction, and cocaine addiction in particular, is considered a chronic relapsing disorder in which subjects episodically administer the drug and ultimately transition from nondependent drug use to the compulsive drug use of addiction. Knowledge of the neurochemical/neurocircuitry changes that provide the motivational basis for vulnerability for increased drug intake with extended access are beginning to provide insights into the neurobiological changes that may lead to vulnerability to escalation in drug intake and relapse. During the previous funding period an animal model of extended access to cocaine self-administration that resembles the compulsivity of addiction has been established and validated. Animals with extended access increase their drug intake (escalation) over time and show increased motivation to obtain the drug (increased progressive- ratio [PR] responding) and show reward deficits during abstinence from the drug (elevation in brain reward thresholds). Work during the previous funding period also has shown that extended access to cocaine decreases basal release in the mesolimbic dopamine system, and inhibitory G-protein function, and increased sensitivity to dopamine antagonists and partial agonists. Chronic cocaine, cocaine withdrawal, and stress- induced reinstatement of cocaine self-administration also were associated with increases in CRF, norepinephrine, and dynorphin function in the extended amygdala. The overall hypothesis under test is that the neuroplastic changes in the extended amygdala lead to a cascade of neurobiological changes that initially involve excessive dopamine release, subsequent loss of dopamine function, and subsequent activation of CRF and dynorphin brain stress systems. A subhypothesis is that the binge-induced loss of dopamine function observed with psychostimulant drugs interacts with the brain stress systems in the basal forebrain to further promote and sustain the increased cocaine intake with extended access. To test this hypothesis, the present proposal will validate a stress-induced increase in cocaine self-administration paradigm and explore the role of CRF and dynorphin in stress-induced escalation (Specific Aims 1 and 2), explore the role of decreases in dopamine function measured by Go in the dopamine system in drug and stress-induced escalation (Specific Aim 3) and explore the interaction of Go in the ventral striatum and CRF and dynorphin function in the extended amygdala in stress-induced escalation (Specific Aim 4). These studies will not only provide new data in the role of stress in the compulsivity that is associated with cocaine dependence, but may also provide key markers for the development of dependence and ultimately key targets for understanding vulnerability and developing novel treatments.

Public Health Relevance

Cocaine addiction is considered a chronic relapsing disorder with compulsive use that that interacts with stress to cause serious pathology and cost to society. Knowledge of the neurochemical/neurocircuitry changes of the brain motivational and stress systems that provide the motivational basis for vulnerability for increased drug intake with extended access are beginning to provide insights into the neurobiological changes that may lead to vulnerability to the compulsivity and relapse associated with addiction. The present proposal has developed an animal model and brain neurotransmitter and molecular targets in the brain stress and motivational neuronal circuits that will provide insights not only into the role of stress in the compulsivity that is associated with cocaine dependence, but may also provide key markers for the development of dependence and ultimately key targets for understanding vulnerability and developing novel treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA004398-27
Application #
8634085
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Lynch, Minda
Project Start
1987-04-25
Project End
2015-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
27
Fiscal Year
2014
Total Cost
$368,406
Indirect Cost
$174,406
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Schmeichel, Brooke E; Barbier, Estelle; Misra, Kaushik K et al. (2015) Hypocretin receptor 2 antagonism dose-dependently reduces escalated heroin self-administration in rats. Neuropsychopharmacology 40:1123-9
Cohen, Ami; Soleiman, Matthew T; Talia, Reneta et al. (2015) Extended access nicotine self-administration with periodic deprivation increases immature neurons in the hippocampus. Psychopharmacology (Berl) 232:453-63
Buck, Cara L; Vendruscolo, Leandro F; Koob, George F et al. (2014) Dopamine D1 and *-opioid receptor antagonism blocks anticipatory 50ýýkHz ultrasonic vocalizations induced by palatable food cues in Wistar rats. Psychopharmacology (Berl) 231:929-37
Cohen, Ami; Whitfield, Timothy W; Kreifeldt, Max et al. (2014) Virus-mediated shRNA knockdown of prodynorphin in the rat nucleus accumbens attenuates depression-like behavior and cocaine locomotor sensitization. PLoS One 9:e97216
Koob, George F; Buck, Cara L; Cohen, Ami et al. (2014) Addiction as a stress surfeit disorder. Neuropharmacology 76 Pt B:370-82
Repunte-Canonigo, Vez; Lefebvre, Celine; George, Olivier et al. (2014) Gene expression changes consistent with neuroAIDS and impaired working memory in HIV-1 transgenic rats. Mol Neurodegener 9:26
Edwards, Scott; Koob, George F (2013) Escalation of drug self-administration as a hallmark of persistent addiction liability. Behav Pharmacol 24:356-62
Edwards, Scott; Vendruscolo, Leandro F; Schlosburg, Joel E et al. (2012) Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRFýýý receptor antagonism. Neuropharmacology 62:1142-51
Zorrilla, Eric P; Wee, Sunmee; Zhao, Yu et al. (2012) Extended access cocaine self-administration differentially activates dorsal raphe and amygdala corticotropin-releasing factor systems in rats. Addict Biol 17:300-8
Wee, Sunmee; Hicks, Martin J; De, Bishnu P et al. (2012) Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects. Neuropsychopharmacology 37:1083-91

Showing the most recent 10 out of 128 publications