The central problem in the treatment of addiction in general and cocaine in particular, is high rates of relapse to drug use after periods of forced or self-imposed abstinence. We suggest testing a new method for reducing addiction, which is based on intervention with memory processing, in a rat model of 'incubation of cocaine craving'. Our preliminary results indicate that an electrical stimulation of the lateral habenula lead to reward devaluation and signals the rat to stop longing for gratifying circumstances. Recent pieces of information may elucidate the molecular mechanisms underlying the effect of electrical stimulation on drug addiction: (i) processes of learning and memory underlie the shift in drug intake to an habitual stage (ii) activation of the DNA binding protein PARP-1 is required for long term memory formation during learning (iii) PARP-1 is activated in response to depolarizing electrical stimulation, and its activation mediates the expression of immediate early genes taking part in memory processing, (iv) and (v) drug addiction is accompanied with PARP activation in brain regions that have been associated with addiction. In view of these findings, we suggest (1) a possible role of PARP activity in cocaine relapse (2) electrical stimulation that teach the animal to devaluate a previous rewarding signal will involve alterations in PARP activity, and (2) a possible effect of memory erasure by PARP inhibitors on mechanisms that underlie cocaine relapse. There is scant preliminary data for this highly novel hypothesis. However, we gained some preliminary but significant data that support our hypothesis. Proving this hypothesis is expected to have a substantial impact on current concepts, and to offer a novel therapeutic approach for cocaine addiction.

Public Health Relevance

No satisfactory treatment for the prevention of both addiction and the relapse of cocaine usage is currently available. As such, the primary significance of this study will be the adaptation of electrical stimulation and the use of PARP inhibitors to prevent relapse of drug usage. Although scant preliminary data exists for the novel hypothesis suggesting that memory processing underlies cocaine relapse, by our elucidating molecular research proving this hypothesis, we expect to make a substantial impact both on current concepts and the delivery of a novel therapeutic approach for preventing cocaine relapse.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZDA1-GXM-A (01))
Program Officer
Volman, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Bar-Ilan University
Ramat Gan
Zip Code
Visochek, Leonid; Cohen-Armon, Malka (2018) PARP1-Erk synergism in proliferating cells. Oncotarget 9:29140-29145
Lax, E; Friedman, A; Massart, R et al. (2017) PARP-1 is required for retrieval of cocaine-associated memory by binding to the promoter of a novel gene encoding a putative transposase inhibitor. Mol Psychiatry 22:570-579
Visochek, L; Grigoryan, G; Kalal, A et al. (2016) A PARP1-ERK2 synergism is required for the induction of LTP. Sci Rep 6:24950
Cohen-Armon, M (2016) A PARP1-Erk2 synergism is required for stimulation-induced expression of immediate early genes. Gene Transl Bioinform 2:
Lax, Elad; Friedman, Alexander; Croitoru, Ofri et al. (2013) Neurodegeneration of lateral habenula efferent fibers after intermittent cocaine administration: implications for deep brain stimulation. Neuropharmacology 75:246-54
Friedman, Alexander; Lax, Elad; Dikshtein, Yahav et al. (2011) Electrical stimulation of the lateral habenula produces an inhibitory effect on sucrose self-administration. Neuropharmacology 60:381-7
Friedman, Alexander; Lax, Elad; Dikshtein, Yahav et al. (2010) Electrical stimulation of the lateral habenula produces enduring inhibitory effect on cocaine seeking behavior. Neuropharmacology 59:452-9