MAILMAN RESEARCH CENTER
Neurobiology of Motivated Behavior Laboratory
Our research focuses on molecular and behavioral correlates of depressive-like states that accompany withdrawal from drugs of abuse in rodents.Â Alleviation of aversive withdrawal symptoms is thought to be a primary motivation for continued drug taking and relapse (see Figure 1).Â The mesolimbic dopamine system, which includes the nucleus accumbens, plays an important role in both the rewarding and aversive effects of drugs such as morphine and cocaine.Â We work closely with the Behavioral Genetics Laboratory, directed by Dr. Bill Carlezon and the Molecular Pharmacology Laboratory, directed by Dr. Bruce Cohen, to conduct two primary lines of research.Â First, we are investigating the role of nucleus accumbens AMPA glutamate receptors in mediating morphine withdrawal-associated aversive states.Â We focus on the negative affective signs of withdrawal through the use of behavioral assays sensitive to rewarding and aversive states (place conditioning and intracranial self-stimulation [ICSS]).Â We assay AMPA receptor trafficking through biochemical techniques such as fractionation and membrane cross-linking.Â Second, we are studying how kappa opioid receptor systems and ERK modulate cocaine reward and cocaine withdrawal-induced depressive-like states.Â To accomplish this, we are measuring the effects of kappa opioid receptor ligands on acute cocaine reward and on withdrawal from binge cocaine treatments using ICSS.Â We are also using viral vectors to manipulate ERK function in the nucleus accumbens and measuring the effects on reward function.Â We trace the signal transduction pathways activated by kappa receptors using protein immunoblots and qRT-PCR (see Figure 2).Â Together, these studies may lead to an increased understanding of the mechanisms underlying addiction.Â
A new direction for the lab is the study of sex differences in behavioral responses to kappa opioid receptor activation.Â In a recent study, we demonstrated that female rats are less sensitive than males to the depressive-like effects of kappa opioid receptor activation (Russell et al., in press).Â This has important ramifications for the neural mechanisms underlying mood and affect as well as for the contribution of kappa receptors to addictive behavior in men versus women.Â
Neurobiology of Motivated Behavior Laboratory
- Elena Chartoff, Ph.D.; Assistant Professor of Psychiatry, Harvard Medical School
- Jazmine Mays; Undergraduate, Harvard University
- David Potter, M.S.; Research Lab Manager
- Daniel Puttick; B.S.; Research Assistant
- Shayla Russell; B.S.; Research Assistant
- Angela Sparrow, Ph.D.; Postdoctoral Fellow
- National Institute on Drug Abuse (NIDA)
- National Alliance for Research on Schizophrenia and Affective Disorders (NARSAD)
- Chartoff EH, Marck BT, Matsumoto AM, Dorsa DM, Palmiter RD. Induction of stereotypy in dopamine-deficient mice requires striatal D1 receptor activation. Proc Natl Acad Sci U S A. 2001;98(18):10451-6.
- Chartoff EH, Heusner CL, Palmiter RD. Dopamine is not required for the hyperlocomotor response to NMDA receptor antagonists. Neuropsychopharmacology. 2005;30(7):1324-33.
- Chartoff EH, Pliakas AM, Carlezon WA. Microinjection of the L-Type Calcium Channel Antagonist Diltiazem into the Ventral Nucleus Accumbens Shell Facilitates Cocaine-Induced Conditioned Place Preferences. Biol Psychiatry. 2006;59:1236-1239.
- Goussakov I, Chartoff EH, Tsvetkov E, Gerety LP, Meloni EG, Carlezon WA, Bolshakov VY. LTP in the lateral amygdala during cocaine withdrawal. Eur J Neurosci. 2006;23(1):239-50.
- Chartoff EH, Mague SD, Barhight M, Smith A, Carlezon WA Jr. Behavioral and molecular effects of dopamine D1 receptor stimulation during naloxone-precipitated morphine withdrawal. J Neurosci. 2006;26(24):6450-6457.
- Carlezon WA Jr, Chartoff EH. Intracranial self-stimulation (ICSS) in rodents to study the neurobiology of motivation. Nat Protoc. 2007;2(11):2987-95. PubMed PMID: 18007634.
- Chartoff EH, Potter D, Damez-Werno D, Cohen BM, Carlezon WA. Exposure to the Selective kappa-Opioid Receptor Agonist Salvinorin A Modulates the Behavioral and Molecular Effects of Cocaine in Rats. Neuropsychopharmacology. 2008 (11):2676-87. PubMed PMID: 18185499.
- Kenny PJ, Chartoff E, Roberto M, Carlezon WA, Markou A. NMDA Receptors Regulate Nicotine-Enhanced Brain Reward Function and Intravenous Nicotine Self-Administration: Role of the Ventral Tegmental Area and Central Nucleus of the Amygdala. Neuropsychopharmacology. 2009 Jan;34(2):266-81. PMID: 18418357.
- Tomasiewicz HC, Todtenkopf MS, Chartoff EH, Cohen BM, Carlezon WA, Jr. The kappa-opioid agonist U69,593 blocks cocaine-induced enhancement of brain stimulation reward. Biological Psychiatry. 2008; 64(11):982-8. PubMed PMID: 18639235.
- Chartoff EH, Papadopoulou M, MacDonald ML, Parsegian A, Potter D, Konradi C, Carlezon WA Jr. Desipramine reduces stress-activated dynorphin expression and CREB phosphorylation in NAc tissue. Mol Pharmacol. 2009 Mar;75(3):704-12. PubMed PMID: 19106229.
- Chartoff EH, Barhight MF, Mague SD, Sawyer AM, Carlezon WA Jr. Anatomically dissociable effects of dopamine D1 receptor agonists on reward and relief of withdrawal in morphine-dependent rats. Psychopharmacology. 2009 Jun;204(2):227-39. PubMed PMID: 19148621.
- Ebner SR, Roitman MF, Potter DN, Rachlin AB, Chartoff EH. Depressive-like effects of the kappa opioid receptor agonist salvinorin A are associated with decreased phasic dopamine release in the nucleus accumbens.Â Psychopharmacology. 2010 Jun;210(2):241-52.PMID: 20372879
- Potter DN, Damez-Werno D, Carlezon WA Jr., Cohen BM, Chartoff EH. Repeated exposure to the kappa- opioid receptor agonist salvinorin A modulates extracellular signal regulated kinase and reward sensitivity. Biological Psychiatry. 2011. 70(8):744-753. PMID: 21757186
- Chartoff EH, Sawyer A, Rachlin A, Potter D, Pliakas A, Carlezon WA Jr. Blockade of kappa-opioid receptors attenuates the development of depressive-like behaviors induced by cocaine withdrawal in rats. Neuropharmacology. 2012. 62(1):167-176. PubMed: 21736885.
- Russell SE, Rachlin AB, Smith KL, Muschamp J, Berry L, Zhao Z, Chartoff EH.Â Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats. Biological Psychiatry. 2013. In press.