Abstract

There is growing concern that adolescence is associated with greater sensitivity to psychostimulant drugs and increased risk of addiction. Such increased susceptibility to drug self-administration could be due to differences in the way the adolescent brain reacts or adapts to repeated drug exposure compared with the adult brain. The overall goal of this proposal is to understand the neurophysiological and behavioral determinants that contribute to adolescent susceptibility to cocaine self-administration, using rodent models. The dopamine system will be the focus of these studies, as it plays a central role in mediating the rewarding effects of addictive drugs.
The specific aims are: to determine whether adolescence is characterized by heightened excitability of dopamine cells, and whether this is mediated by decreased intrinsic inhibitory properties of these neurons (Aim 1) and/or increased excitatory synaptic input to these cells (Aim 2).
Aim 3 will establish whether changes in dopamine neuron function translate into differences in cocaine self-administration behavior. Throughout these aims, adolescent and adult rats will be compared both before and after repeated cocaine exposure to appraise whether individuals exhibit inherent differences, and/or show differential cocaine- induced neuroadaptations that could facilitate self-administration behavior. Neuronal activity will be assessed using in vivo and in vitro electrophysiology techniques;behavioral tests will consist of a variety of self-administration procedures that allow estimating the rewarding effects of cocaine and motivation to self-administer the drug. Overall, using a multidisciplinary approach this proposal will examine, from the cellular to the behavioral level, potential mechanisms underlying adolescent/adult differences in cocaine self-administration. These studies will use behavioral models that are relevant to the human condition to provide insight into both the causes and effects of adolescent drug use. In the long run, these findings will facilitate the development of new targeted therapeutic strategies for the treatment or prevention of cocaine addiction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA020654-03S1
Application #
7847077
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Volman, Susan
Project Start
2006-09-15
Project End
2009-10-31
Budget Start
2009-06-20
Budget End
2009-10-31
Support Year
3
Fiscal Year
2009
Total Cost
$16,386
Indirect Cost

  Institution

Name
Rosalind Franklin University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
069501252
City
North Chicago
State
IL
Country
United States
Zip Code
60064

  Publications

Wong, Wai Chong; Marinelli, Michela (2016) Adolescent-onset of cocaine use is associated with heightened stress-induced reinstatement of cocaine seeking. Addict Biol 21:634-45
Wong, Wai Chong; Ford, Kerstin A; Pagels, Nicole E et al. (2013) Adolescents are more vulnerable to cocaine addiction: behavioral and electrophysiological evidence. J Neurosci 33:4913-22
McCutcheon, James E; Conrad, Kelly L; Carr, Steven B et al. (2012) Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults. J Neurophysiol 108:1620-30
McCutcheon, James E; Loweth, Jessica A; Ford, Kerstin A et al. (2011) Group I mGluR activation reverses cocaine-induced accumulation of calcium-permeable AMPA receptors in nucleus accumbens synapses via a protein kinase C-dependent mechanism. J Neurosci 31:14536-41
McCutcheon, James E; Wang, Xiaoting; Tseng, Kuei Y et al. (2011) Calcium-permeable AMPA receptors are present in nucleus accumbens synapses after prolonged withdrawal from cocaine self-administration but not experimenter-administered cocaine. J Neurosci 31:5737-43
Conrad, Kelly L; McCutcheon, James E; Cotterly, Lindsay M et al. (2010) Persistent increases in cocaine-seeking behavior after acute exposure to cold swim stress. Biol Psychiatry 68:303-5
Steiner, Heinz; Van Waes, Vincent; Marinelli, Michela (2010) Fluoxetine potentiates methylphenidate-induced gene regulation in addiction-related brain regions: concerns for use of cognitive enhancers? Biol Psychiatry 67:592-4
Zahm, Daniel S; Becker, Mary L; Freiman, Alexander J et al. (2010) Fos after single and repeated self-administration of cocaine and saline in the rat: emphasis on the Basal forebrain and recalibration of expression. Neuropsychopharmacology 35:445-63
Conrad, K L; Ford, K; Marinelli, M et al. (2010) Dopamine receptor expression and distribution dynamically change in the rat nucleus accumbens after withdrawal from cocaine self-administration. Neuroscience 169:182-94
Van Waes, Vincent; Beverley, Joel; Marinelli, Michela et al. (2010) Selective serotonin reuptake inhibitor antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum. Eur J Neurosci 32:435-47

Showing the most recent 10 out of 16 publications