Research Focus

A major challenge for the successful treatment of drug addiction is the long-lasting susceptibility to relapse during abstinence. The goal of our studies is to advance the understanding of the implication of the orexin (Orx/Hcrt) system in cocaine and alcohol seeking. In addition to the Orx/Hcrt system, which includes the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA), the paraventricular nucleus of the thalamus (PVT), which receives projections from the LH and projects to regions integrated in the circuitry of addiction (i.e., nucleus accumbens shell, ventral pallidum, ventral tegmental area, central nucleus of the amygdala, and bed nucleus of the stria terminalis), has been recently identified as a structure involved in the modulation of reward function in general and drug-directed behavior in particular. Importantly, we recently characterized a correlation between cocaine-seeking behavior and activation of the PVT, but not in the case of natural reward (food)-seeking behavior. This suggests that cocaine dysregulates neurotransmission within the PVT. Capitalizing on these findings, our working hypothesis is that following repeated drug use, the Orx/Hcrt system acquires a preferential role in mediating the seeking of drugs of abuse vs. natural rewards (such as food). Therefore, the main effort of my laboratory is to study the neurobiological basis of chronic vulnerability to relapse by focusing on Orx/Hcrt transmission in the PVT as a novel neural substrate that may be responsible for the distinctly compulsive nature of drug (cocaine or alcohol) seeking as opposed to behavior motivated by natural rewards. Specifically, we are (i) behaviorally characterizing the specific implication of the PVT in drug seeking, (ii) investigating drug-induced neuroplastic changes within Orx/Hcrt transmission, and (iii) investigating the effects of dysregulated Orx/Hcrt-PVT transmission on the mesolimbic system. Overall, this work will provide novel insights into the specific involvement of Orx/Hcrt-PVT transmission in drug-seeking behavior compared with natural reward-seeking behavior and will likely highlight a previously unrecognized neurotransmission system in the etiology of compulsive drug seeking during abstinence.

Education

B.S., Cellular Biology and Physiology, Université Montpellier II, France, 1989
M.S., Physiology and Pharmacology, Université Montpellier II, France, 1990
Diploma, Diplôme d’Etudes Approfondies, Reproduction & Development, Université Montpellier I, France, 1991
Ph.D., Biochemistry & Molecular Biology, Université Montpellier II, France, 1996

Professional Experience

1997 Postdoctoral Fellow, Institut de Recherche Jouveinal, Fresnes, France
1997-02 Research Associate, The Scripps Research Institute, La Jolla, CA
2002-04 Senior Research Associate, The Scripps Research Institute, La Jolla, CA
2004-12 Staff Scientist, The Scripps Research Institute, La Jolla, CA
2012-Present Assistant Professor of Neuroscience, The Scripps Research Institute, La Jolla, CA

Awards & Professional Activities

1995-Present French Society for Neurosciences, Member
1995-Present Federation of European Neuroscience Societies (FENS), Member
1998-Present Society for Neuroscience (SFN), Member
1998-Present International Brain Research Organization (IBRO), Member
2005-Present Research Society on Alcoholism (RSA), Member
2009-Present American Society for Pharmacology and Experimental Therapeutics (ASPET), Member
2009-Present College on Problems of Drug Dependence (CPDD), Member

Selected References

Boutrel B, Kenny PJ, Specio SE, Martin-Fardon R, Markou A, Koob GF, de Lecea L (2005): A novel role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci USA 102:19168-19173.

Martin-Fardon R, Maurice T, Aujla H, Bowen WD, Weiss F (2007): Differential effects of s1 receptor blockade on self-administration and conditioned reinstatement motivated by cocaine vs. natural reward. Neuropsychopharmacology 32:1967-1973.

Dayas CV, McGranahan TM, Martin-Fardon R, Weiss F. (2008): Stimuli linked to ethanol availability activate hypothalamic cart and orexin neurons in a reinstatement model of relapse. Biol Psychiatry. 63: 152-157.

Martin-Fardon R, Baptista MA, Dayas CV, Weiss F. (2009): Dissociation of the effects of MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine] on conditioned reinstatement and reinforcement: Comparison between cocaine and a conventional reinforcer. J Pharmacol Exp Ther. 329: 1084-1090.

Martin-Fardon R, Zorrilla EP, Ciccocioppo R, Weiss F (2010): Role of innate and drug-induced dysregulation of brain stress and arousal systems in addiction: Focus on corticotropin-releasing factor, nociceptin/orphanin fq, and orexin/hypocretin. Brain Res. 1314:145-161.

Sidhpura N, Weiss F, Martin-Fardon R (2010): Effects of the mGlu2/3 agonist LY379268 and the mGlu5 antagonist MTEP on ethanol-seeking and reinforcement are differentially altered in rats with a history of ethanol dependence. Biol Psychiatry. 67:804-811.

Martin-Fardon R, Weiss F (2012): (–)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine (MTEP) similarly attenuate stress-induced reinstatement of cocaine seeking. Addiction Biology (2012) 17: 557-564.

Martin-Fardon R, Weiss F (2012): N-(2-methyl-6-benzoxazolyl)-N'-1,5-naphthyridin-4-yl urea (SB334867), a hypocretin receptor-1 antagonist, preferentially prevents ethanol seeking: comparison with natural reward seeking. Addict Biol. 2012 Jul 26. doi: 10.1111/j.1369-1600.2012.00480.x. [Epub ahead of print]

Martin-Fardon R, Weiss F (2012): (–)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]piperidine (MTEP) similarly attenuate stress-induced reinstatement of cocaine seeking. Addiction Biology. 17: 557-564.

Martin-Fardon R, Boutrel B (2012); Orexin/Hypocretin (Orx/Hcrt) transmission and drug-seeking behavior: Is the paraventricular nucleus of the thalamus (PVT) part of the drug seeking circuitry? Front Behav Neurosci. 2012;6:75. doi: 10.3389/fnbeh.2012.00075. Epub 2012 Nov 9.