McLean Hospital Title:
- Director, Neuroscience and Behavioral Pharmacology Laboratory
Harvard Medical School Title:
- Associate Professor of Psychology, Department of Psychiatry
S. Barak Caine, PhD, began his career as a research technician in the laboratory of Dr. Andrew Winokur at the University of Pennsylvania, before receiving pre-doctoral training in the laboratories of Dr. Mark Geyer at the University of California, and Dr. George Koob at The Scripps Research Institute, with whom Dr. Caine conducted his PhD thesis. Dr. Caine trained as a post-doctoral fellow at Cambridge University, under Drs. Barry Everitt and Trevor Robbins, then at McLean Hospital under Drs. Nancy K. Mello and S. Negus.
Dr. Caine aims to understand brain mechanisms underlying abnormal behaviors and to discover improved medications for psychiatric disorders. Throughout his career, he has pursued two lines of investigation: pharmacological mechanisms underlying stimulant medications and stimulant abuse, and neural mechanisms underlying stimulant-induced psychosis and antipsychotic therapeutics. Dr. Caine has received numerous awards, including one from President William Jefferson Clinton at the White House.
Many psychiatric disorders currently have limited treatment options. Dr. Caine’s Neuroscience and Behavioral Pharmacology Laboratory was founded in 1997 to investigate the effectiveness of potential medications for conditions including schizophrenia, cocaine and amphetamine dependence, and alcohol use disorder.
Dr. Caine and his staff screen new medications in rodents for abuse potential and other effects. For example, drugs that are habit forming in rodents are likely to be addictive in humans. The lab’s findings have showed that the addictive effects of cocaine and amphetamines are related to the dopamine system in the brain. Understanding these physiological mechanisms is critical to developing effective treatments and predicting and minimizing their side effects.
Evidence suggests that acetylcholine, a neurotransmitter, is involved in the abuse-related effects of cocaine and other psychostimulants, and also the symptoms of schizophrenia. This research is suggesting promising treatment targets for cocaine abuse, psychotic disorders, Parkinson’s disease, attention deficit hyperactivity disorder, and disorders leading to cognitive deficits.
The lab’s preclinical behavioral pharmacology studies are designed to identify new targets for medication development and characterize the effects of novel candidate medications for drug abuse and dependence. Brain targets under investigation in the laboratory include the dopamine transporter, muscarinic and nicotinic acethylcholine receptors, and glucagon-like peptide 1 receptors.
In their study of rodent models of drug discrimination and self-administration, the lab evaluates the pharmacological mechanisms underlying the psychomotor stimulant, sensorimotor disruptive, discriminative stimulus, and reinforcing effects of cocaine and related drugs. Molecular targets for the design and synthesis of new medications for drug abuse may be identified by systematic analysis of drug self-administration behavior in genetically engineered mice (knockout, knockin, transgenic). Novel compounds are also investigated in rats that self-administer cocaine to evaluate candidate pharmacotherapies for drug addiction.
The lab’s findings confirmed the principal role for cocaine’s binding to the dopamine transporter in cocaine’s abuse related effects. Studies with dopamine receptor knockout mice suggested a minor, if any, role for the dopamine D3 receptor in cocaine’s direct reinforcing effects, while D1 knockout mice did not self-administer cocaine, and D2 knockout mice showed very high cocaine intake.
Recently, Dr. Caine and his staff have focused on preclinical evaluations of candidate medications for the treatment of nicotine dependence, such as trace alkaloids from the tobacco leaf that are also found in healthful vegetables, and which may serve as all-natural aids for smoking cessation.
The lab is also evaluating the effectiveness of subtype-selective muscarinic receptor ligands for the treatment of cocaine dependence. Evidence is also accumulating to implicate muscarinic receptor dysfunction in the etiology of schizophrenia, and to support the potential of muscarinic receptor agonists as novel antipsychotic and/or cognitive-enhancing treatment options. By combining new, highly selective drugs with genetic engineering (knockout) approaches, they found that muscarinic agonists acting at M1 or M4 receptors can each attenuate the discriminative stimulus and reinforcing effects of cocaine.
- Christopher Adam, Research Assistant
- Camron D. Bryant, PhD, Boston University
- Bill Carlezon, PhD, McLean Hospital
- P. Jeffrey Conn, PhD, Vanderbilt University
- Christopher W. Cowan, PhD, Medical University of South Carolina
- Anders Fink-Jensen, MD, DMSci, Maurice Ptito, PhD, University of Copenhagen, Denmark
- Ann Graybiel, PhD, McGovern Institute, Massachusetts Institute of Technology
- Ryan K. Lanier, PhD, Rock Creek Pharmaceuticals
- Zhicheng (Carl) Lin, PhD, McLean Hospital
- Forrest Payne, PhD, SFC Fluidics, Inc.
- Michael L. Rohan, PhD, McLean Hospital
- Paul A. Rosenberg, MD, PhD, Boston Children’s Hospital, Harvard Medical School
Caine SB, Thomsen M, Gabriel KI, Berkowitz JS, Gold LH, Koob GF, Tonegawa S, Zhang J, Xu M. Lack of self-administration of cocaine in dopamine D1 receptor knockout mice. The Journal of Neuroscience 2007;27:13140-13150.
Thomsen M, Hall FS, Uhl GR, Caine SB. Dramatically decreased cocaine self-administration in dopamine but not serotonin transporter knock-out mice. The Journal of Neuroscience 2009;29:1087-92.
Thomsen M, Han DD, Gu HH, Caine SB. Lack of cocaine self-administration in mice expressing a cocaine-insensitive dopamine transporter. Journal of Pharmacology and Experimental Therapeutics 2009;331:204-11.
Education & Training:
- 1985 BA in Biological Basis of Behavior, University of Pennsylvania
- 1994 PhD in Neurosciences, University of California, San Diego
- 1989-1994 Graduate Research Fellow in Neuroscience, University of California
- 1989-1994 Pre-Doctoral Fellow in Neuropharmacology, The Scripps Research Institute
- 1995-1996 Post-Doctoral Fellow in Neuroscience, Cambridge University, UK
- 1996-1999 Post-Doctoral Fellow in Behavioral Pharmacology, McLean Hospital/Harvard Medical School
Belmont campus - Oaks Building