Brain hijack by opiates : focus on the corticotropin-releasing factor system

Topic description

Opiate use disorders (OUD) are chronic, relapsing, diseases with a major health and socio-economic impact worldwide. To date, they are treated mainly by substitutive opioid receptor agonists, such as methadone and buprenorphine. However, the latter is often ineffective, increasingly misused and induces dependence, posing health and regulatory challenges difficult to solve. Novel treatments are thus urgently needed but their development heavily relies on the elucidation of the neural substrates underlying OUD.

Likewise other substances of abuse, opiate drugs dramatically narrow behavior towards substance-oriented activities, to the detriment of naturally rewarding activities, such as social interaction or eating. Closely related brain systems might mediate the rewarding and the motivational properties of substances of abuse, food and social behavior. Thus, substances of abuse might hijack brain systems underlying activities essential to species survival, to deviate behavior towards addictive-like substance seeking and intake.

The corticotropin-releasing factor (CRF) system might mediate substance use disorders. Notably, we previously reported crucial, but often opposite, roles for the two known CRF receptor types (CRF1 and CRF2) in brain and behavioral alterations associated with chronic opiate or cocaine administration and withdrawal (Morisot et al. Neuropsychopharmacology, ; Morisot & Contarino, Neuropharmacology, ; Morisot et al. Br J Pharmacol, ; Piccin & Contarino, J Neurosci Res, ). Thus, elucidation of the specific role for each of the two known CRF receptor types might be crucial to develop effective therapy for substance use disorders. However, to date the role of the CRF system in opiate-driven motivational states and loss of interest for naturally rewarding activities remains largely unknown.

Objectives

By a multidisciplinary integrated strategy, including advanced behavioral, genetic and pharmacological studies in mice, our project aims at identifying the specific role for the CRF1 and the CRF2 receptor in opiate-induced brain reward, social behavior deficits and loss of motivation to eat. Thus, the student could acquire a relatively good knowledge in controlled experimental studies carried out in laboratory animals (e.g., behavioral studies including brain injection of CRF1 or CRF2 receptor-targeting lentivirus and molecular biology techniques, such as the in situ hybridization assay). Moreover, he could learn to correctly analyze and report behavioral and molecular studies. Hence, our research project might shed light on the brain mechanisms underlying behavioral disorders induced by opiate substances. Moreover, since it focuses on cell membrane receptors, our results might foster knowledge that could be easily translated into pharmacological research.

Methods

We will use CRF1 and CRF2 receptor-deficient genetic mouse models (CRF1- / - and CRF2- / -) and clinically-oriented behavioral paradigms assessing brain reward (i.e., conditioned place preference task), social behavior deficits (i.e., 3-chamber sociability task) and loss of motivation to eat (i.e., operant behavior task) induced by the opiate substance morphine. Moreover, molecular biology (i.e., brain in situ hybridization) and pharmacological studies will be carried out to identify the brain mechanisms underlying the morphine-induced behavioral alterations and test the therapeutic potential of CRF1 or CRF2 receptor-targeting compounds.

Funding category

Other public funding

Funding further details