Drug use by the inhalation route continues to rise as an increasing number of individuals discover that inhalation is a highly efficient, cost effective means of drug delivery that obviates the possible transmission of communicable diseases associated with i.v. administration. Our goal is to develop animal models of drug inhalation in order to identify drug toxicities that are unique to this route of administration. Several classes of abused drugs will be examined because they represent distinctly different problems that arise from inhalation. Cocaine will be examined because it was found to produce cardiotoxicity in rats allowed to inhale cocaine vapor but not following i.v. administration. Our goal is to identify the mechanism by which cocaine produces bradyarrthymias and determine whether tolerance or sensitization develops to this cardiotoxicity following repetitive cocaine exposures. Experiments will also be carried out to determine whether cocaine metabolites and drugs that are frequently co-abused with cocaine exert any influence on cocaine cardiovascular effects. The popularity of drug inhalation has increased dramatically for both heroin and methamphetamine. While the effects of acute inhalation of methamphetamine, heroin and phencyclidine are similar to an i.v. administration, the consequences of chronic inhalation is unknown, especially with regard to the development of tolerance and dependence. Although most drugs are inhaled in vaporized form, marijuana represents the major illicit drug that is primarily smoked. Despite extensive research on delta-9 THC, the major psychoactive constituent in marijuana, there are numerous unanswered questions regarding marijuana itself. The development of cannabinoid behavioral models, inhalation procedures for exposing mice and rats to marijuana smoke, a specific cannabinoid antagonist and a delta-9 THC dependence model allow us to address some of the questions that were heretofore not possible. The objectives of the grant are to address questions as to whether other constituents in marijuana contribute to delta-9 THC s effects and whether all marijuana effects can be blocked by the specific cannabinoid antagonist. Studies will be carried out to determine whether other drugs, such as ethanol, potentiate the effects of marijuana. It will be important to determine whether mice and rats repetitively exposed to marijuana smoke develop tolerance and dependence comparable to that produced by delta-9 THC. Finally, efforts will be made to develop a volatilized form of delta-9 THC which would be preferable to oral administration of dronabinol for therapeutic uses.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA002396-18
Application #
2897677
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Rapaka, Rao
Project Start
1980-09-01
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Virginia Commonwealth University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Richmond
State
VA
Country
United States
Zip Code
23298
Poklis, Justin L; Amira, Dorra; Wise, Laura E et al. (2012) Determination of naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) in mouse blood and tissue after inhalation exposure to 'buzz' smoke by HPLC/MS/MS. Biomed Chromatogr 26:1393-8
Poklis, Justin L; Amira, Dorra; Wise, Laura E et al. (2012) Detection and disposition of JWH-018 and JWH-073 in mice after exposure to ""Magic Gold"" smoke. Forensic Sci Int 220:91-6
Gamage, Thomas F; Lichtman, Aron H (2012) The endocannabinoid system: role in energy regulation. Pediatr Blood Cancer 58:144-8
Wise, Laura E; Varvel, Stephen A; Selley, Dana E et al. (2011) delta(9)-Tetrahydrocannabinol-dependent mice undergoing withdrawal display impaired spatial memory. Psychopharmacology (Berl) 217:485-94
DeLong, Gerald T; Wolf, Carl E; Poklis, Alphonse et al. (2010) Pharmacological evaluation of the natural constituent of Cannabis sativa, cannabichromene and its modulation by ?(9)-tetrahydrocannabinol. Drug Alcohol Depend 112:126-33
Falenski, Katherine W; Thorpe, Andrew J; Schlosburg, Joel E et al. (2010) FAAH-/- mice display differential tolerance, dependence, and cannabinoid receptor adaptation after delta 9-tetrahydrocannabinol and anandamide administration. Neuropsychopharmacology 35:1775-87
Poklis, Justin L; Thompson, Candace C; Long, Kelly A et al. (2010) Disposition of cannabichromene, cannabidiol, and ??-tetrahydrocannabinol and its metabolites in mouse brain following marijuana inhalation determined by high-performance liquid chromatography-tandem mass spectrometry. J Anal Toxicol 34:516-20
Booker, Lamont; Naidu, Pattipati S; Razdan, Raj K et al. (2009) Evaluation of prevalent phytocannabinoids in the acetic acid model of visceral nociception. Drug Alcohol Depend 105:42-7
Schlosburg, Joel E; Carlson, Brittany L A; Ramesh, Divya et al. (2009) Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. AAPS J 11:342-52
Oltmanns, Matt H; Samudre, Sandeep S; Castillo, Ivan G et al. (2008) Topical WIN55212-2 alleviates intraocular hypertension in rats through a CB1 receptor mediated mechanism of action. J Ocul Pharmacol Ther 24:104-15

Showing the most recent 10 out of 42 publications