Joshua A. Lile, Ph.D.

(Wake Forest University School of Medicine, 2002)

110 Medical Behavioral Science Building
Lexington, KY 40536-0086
Phone: (859) 323-6034
e-mail: jalile2@email.uky.edu

Dr. Lile’s research interests focus on the pharmacological and behavioral determinants of, and potential treatments for, drug addiction. To this end, Dr. Lile is conducting several human laboratory research projects in three primary areas, including:

1) The neuropharmacology of the behavioral effects of THC, the primary active constituent of marijuana. An ongoing series of studies will examine the role of central cannabinoid, dopamine, opioid and GABA systems on the discriminative-stimulus and subject-rated effects of oral THC, in addition to its effects on physiology, psychomotor performance, impulsivity and learning/memory. This outcome from these studies will be used to identify neurotransmitter systems that might be targeted for medications development for the treatment of cannabis-related disorders. Supported by K01 DA018772.

2) In collaboration with Drs. Craig Rush and Bill Stoops, Dr. Lile is pursuing medications development for the treatment of stimulant addiction using laboratory models of drug use. Two pharmacological strategies are being tested. The first is an agonist replacement strategy. In this case, an agonist can be considered a drug that has overlapping behavioral and pharmacological effects with the primary drug of abuse and can be administered in a controlled fashion in place of the abused drug. The second strategy is the use of partial agonists, which are receptor ligands with significant receptor affinity, but low intrinsic activity. Theoretically, these drugs may be expected to have the therapeutic advantages of both agonists and antagonists. For example, a partial agonist might function as a replacement medication in abstinent stimulant users, but could also act as an antagonist, blocking the effects of a stimulant if relapse occurs. Supported by R01 DA017711, DA020429 and DA021155.

3) Dr. Lile is involved in a series of studies, in collaboration with Dr. Tom Kelly, to investigate the influence of the gonadal sex hormones estradiol and progesterone on the behavioral effects of drugs in women. Drs. Kelly and Lile, in collaboration with Dr. Jane Joseph from the Department of Anatomy and Neurobiology, have also begun a series of studies using behavioral measures and functional magnetic resonance imaging (fMRI) in the same subjects to examine the manner and anatomical locations in which estradiol and progesterone modulate neurotransmitter function. These studies should provide important information regarding the influence of menstrual cycle phase in drug addiction, and may result in gender-specific treatment strategies. Supported by P20 RR015592.

2008 Accomplishments

During 2008, Dr. Lile continued to engage in research related to the behavioral pharmacology of commonly abused substances in humans in an effort to understand the initiation and maintenance of, and relapse to, drug taking behavior, and to develop effective approaches for treatment. His primary area of interest is on cannabis-use disorders. He is in the fourth year of a five-year K01 award, which is supporting research to identify the neurotransmitter systems involved in the behavioral and physiological effects of the primary active constituent of cannabis, D9-THC, in humans. This year, Dr. Lile published a manuscript from that research in a special issue of Psychopharmacology on the discriminative-stimulus effects of drugs. In addition, an oral presentation of those data was given to the International Cannabinoid Research Society in Aviemore, Scotland. Dr. Lile also received UK pilot funding to test a method to precipitate withdrawal in cannabis-dependent subjects, which could be used in future studies to test putative medications for cannabis-use disorders, and to identify the underlying determinants of cannabis dependence. Dr. Lile submitted two NIH grants this year, using data from the K01-supported studies as preliminary results. One of these is currently under review, and the other was funded after a single submission. In the funded project the ability of various drugs acting at central GABA systems to enhance the behavioral effects of D9-THC when given in combination will be determined. Drugs that enhance D9-THC might function as agonist-like drugs to manage cannabis dependence. Also worth mentioning is that Dr. Lile was invited to serve as a co-editor for a special issue of the International Review of Psychiatry on Cannabis and Cannabinoids. Another area of involvement for Dr. Lile is the study of the influence of the gonadal sex hormones on the behavioral effects of drugs in women, which is supported by a UK Center of Biomedical Research Excellence. That research also incorporates fMRI to examine the manner and anatomical locations in which these hormones modulate neurotransmitter function and drug effects. Related to that research, Dr. Lile coordinated two studies on intranasal d-amphetamine self-administration and presented the results at the annual College on Problems of Drug Dependence (CPDD) conference. A third area of research for Dr. Lile is the development of pharmacotherapies for the treatment of stimulant dependence in collaboration with Drs. Rush and Stoops. Dr. Lile served as a Co-Investigator on four R-01 awards and an R21 to this end. His involvement in this research resulted in a first-author publication describing a study in which the safety and tolerability of cocaine administration during maintenance on the novel antipsychotic aripiprazole was determined. This involvement also included two studies to evaluate the GABAA positive modulator alprazolam, as well as d-amphetamine, for the treatment of methamphetamine dependence, and two additional studies to determine the ability of alternative reinforcers and maintenance on the dopamine reuptake inhibitor bupropion to modify cocaine self-administration. In terms of service, Dr. Lile began a 3-year term as a member of the Committee on Abuse Liability Testing for the CPDD and completed 17 manuscript reviews for 8 different journals.

Research Funding

K01 DA018772 (Lile, JA)
National Institutes of Health/National Institute on Drug Abuse
A Pharmacological Analysis of D9-THC in Humans
06/01/2005-05/31/2010
Role: Principal Investigator

P20 RR015592 (Curry, T)
National Institutes of Health/National Center for Research Resources
Center of Biomedical Research Excellence in Women’s Health
09/15/2000-09/30/2010
Role: Junior Investigator (Project 5)

R01 DA017711 (Rush, CR)
National Institutes of Health/National Institute on Drug Abuse
Stimulant Abuse Pharmacotherapy: Novel Antipsychotics
08/01/2005-05/30/2010
Role: Co-Investigator

R01 DA020429 (Rush, CR)
National Institutes of Health/National Institute on Drug Abuse
Cocaine Relapse Prevention: Developing Pharmacotherapies
09/27/2005-07/31/2009
Role: Co-Investigator

R01 DA 021155 (Rush, CR)
National Institutes of Health/National Institute on Drug Abuse
Agonist Replacement Therapy for Cocaine Dependence: Identifying Novel Medications
06/01/2006-03/31/2010
Role: Co-Investigator

Representative Publications

Lile JA, Kendall SL, Babalonis S, Martin CA and Kelly TH (2007). Estradiol enhances the discriminative-stimulus and self-reported effects of d-amphetamine in healthy pre-menopausal women. Pharmacology, Biochemistry and Behavior, 87: 258-266.

Lile JA (2006). Pharmacological determinants of the reinforcing effects of psychostimulants: Relation to agonist replacement treatment. Experimental and Clinical Psychopharmacology 14: 20-33.

Lile JA, Stoops WW, Durell TM, Glaser PEA and Rush CR (2006). Discriminative-stimulus, self-reported, performance and cardiovascular effects of atomoxetine in methylphenidate-trained humans. Experimental and Clinical Psychopharmacology, 142: 136-147.

Lile JA, Stoops WW, Vansickel AR, Glaser PEA, Hays LR and Rush CR (2005) Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of d-amphetamine in humans. Neuropsychopharmacology, 30: 2103-14.

Lile JA, Stoops WW, Hays LR and Rush CR (2004) Acute administration of the GABA reuptake inhibitor tiagabine does not alter the effects of oral cocaine in humans. Drug and Alcohol Dependence 76: 81-91.

Lile JA, Stoops WW, Allen TS, Glaser PEA, Hays LR and Rush CR (2004) Baclofen does not alter the reinforcing, subject-rated or cardiovascular effects of intranasal cocaine in humans. Psychopharmacology 171: 441-449.

Lile JA, Wang Z, Woolverton WL, France JE, Davies HML and Nader MA (2003) The reinforcing efficacy of psychostimulants in rhesus monkeys: the role of pharmacokinetics and pharmacodynamics. Journal of Pharmacology and Experimental Therapeutics 307: 356-366.

Lile JA and Nader MA (2003) The abuse liability and therapeutic potential of drugs evaluated for cocaine addiction as predicted by animal models. Current Neuropsychopharmacology 1: 21-46.

Lile JA, Morgan D, Birmingham AM, Wang Z, Woolverton WL, Davies HML and Nader MA (2002). The reinforcing efficacy of the dopamine reuptake inhibitor PTT as measured by a progressive-ratio schedule and a choice procedure in rhesus monkeys. Journal of Pharmacology and Experimental Therapeutics 303:640-648.