Though the effects of naturally occurring and synthetic cannabinoids have been well described, their mechanisms of action are just beginning to become known. Recent breakthrough demonstrating differences between the distribution of cannabinoid receptors and the receptor mRNA in the CNS strongly suggest the existence of cannabinoid neuronal pathways. The objectives of the research proposed in this project are to: 1) identify specific brain region which mediate the behavioral effects of the cannabinoids, and 2) characterize cannabinoid neuronal pathways. These proposed studies will focus on the hippocampus and basal ganglia because, in addition containing high concentrations of cannabinoid receptors and cannabinoid receptor mRNA, they mediate many of the behaviors associated with cannabinoid activity. The behavioral indices which will be assessed are the nociception, catalepsy, short-term memory, spontaneous activity, hypothermia, and rotational behavior. Using a pharmacological approach, which will include dose-response and SAR studies, the effects of cannabinoids in specific brain sites will be examined. In a separate series of studies, the neuronal pathways will be characterized by selective lesions of specific brain structures containing high concentrations of cannabinoid receptors or cannabinoid receptors mRNA. The methods of autoradiography and in situ hybridization histochemistry will then be used to assess changes in receptor number and expression of cannabinoid receptor mRNA, respectively. The results of this research will be an important first step in the elucidation of the neural substances of cannabinoid activity.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA008387-05
Application #
2700871
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1994-05-01
Project End
2000-04-30
Budget Start
1998-06-01
Budget End
2000-04-30
Support Year
5
Fiscal Year
1998
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
Lichtman, A H (2000) SR 141716A enhances spatial memory as assessed in a radial-arm maze task in rats. Eur J Pharmacol 404:175-9
Martin, B R; Lichtman, A H (1998) Cannabinoid transmission and pain perception. Neurobiol Dis 5:447-61
Lichtman, A H; Wiley, J L; LaVecchia, K L et al. (1998) Effects of SR 141716A after acute or chronic cannabinoid administration in dogs. Eur J Pharmacol 357:139-48
Lichtman, A H (1998) The up-and-down method substantially reduces the number of animals required to determine antinociceptive ED50 values. J Pharmacol Toxicol Methods 40:81-5
Lichtman, A H; Martin, B R (1997) The selective cannabinoid antagonist SR 141716A blocks cannabinoid-induced antinociception in rats. Pharmacol Biochem Behav 57:7-12
Lichtman, A H; Martin, B R (1996) Delta 9-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. Psychopharmacology (Berl) 126:125-31
Lichtman, A H; Cook, S A; Martin, B R (1996) Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. J Pharmacol Exp Ther 276:585-93
Wiley, J L; Compton, D R; Gordon, P M et al. (1996) Evaluation of agonist-antagonist properties of nitrogen mustard and cyano derivatives of delta 8-tetrahydrocannabinol. Neuropharmacology 35:1793-804
Lichtman, A H; Dimen, K R; Martin, B R (1995) Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. Psychopharmacology (Berl) 119:282-90