Rigorous pharmacological analysis of drugs with affinity for serotonin 2C (5-HT2C) receptors is critical to the characterization of these drugs as hallucinogens, antipsychotics, and antidepressants. In vitro, 5-HT2C receptors exhibit constitutive activity and thereby are capable of initiating signal transduction in the absence of agonists. The ability of a drug to alter the basal constitutive activity, a property referred to as intrinsic efficacy, varies among 5-HT2C ligands; basal activity is increased by full agonists, decreased by inverse agonists (positive and negative efficacy, respectively) and is unaltered if the receptor is occupied by a neutral antagonist (zero efficacy). The role of positive and negative intrinsic efficacy in determining the behavioral and pharmacological outcomes with 5-HT2C agonists, inverse agonists, and neutral antagonists interact will be investigated in this proposal. Two behavioral approaches will be used to study these relationships in mice. In the first procedure, discriminated conditioned taste aversion (CTA), the stimulus effects of 5-HT2C drugs serve as cues for producing CTA. In the second procedure, operant drug discrimination, the stimulus effects of 5 -HT2C drugs act to signal which of two choices will result in reinforcement. Mice will be trained to discriminate a representative 5-HT2C agonist, neutral antagonist, and an inverse agonist in both procedures. Compounds with different receptor selectivities (i.e., 5-HT2A or 5-HT2B) and different pharmacological activity (i.e., agonists versus inverse agonists) will produce different patterns of substitution among the training groups. Additional experiments will examine the role negative intrinsic efficacy plays in the capacity of 5-HT2C neutral antagonist and inverse agonists to block the discriminative stimulus effects of 5-HT2C drugs. Finally, the role of efficacy in the effects of chronic treatment with neutral antagonists and inverse agonists on the discriminative stimulus effects of 5-HT2C drugs will be investigated. It is hypothesized that chronic treatment with inverse agonists will produce greater alteration in dose-response curves of agonists, neutral antagonists, and inverse agonists than chronic treatment with neutral antagonists. Taken together, these experiments will provide a novel pharmacological and/or behavioral profile for 5-HT2C inverse agonists and neutral antagonists while testing hypotheses generated from in vitro data.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA014673-01A1
Application #
6544470
Study Section
Special Emphasis Panel (ZRG1-BBBP-1 (01))
Program Officer
Volman, Susan
Project Start
2002-09-30
Project End
2007-06-30
Budget Start
2002-09-30
Budget End
2003-06-30
Support Year
1
Fiscal Year
2002
Total Cost
$267,750
Indirect Cost
Name
Albert Einstein Medical Center (Philadelphia)
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19141
Farrell, Martilias; Lichtenstein, Maya; Crowley, James J et al. (2018) Developmental Delay, Treatment-Resistant Psychosis, and Early-Onset Dementia in a Man With 22q11 Deletion Syndrome and Huntington's Disease. Am J Psychiatry 175:400-407
Ward, Sara Jane; Raffa, Robert B (2011) Rimonabant redux and strategies to improve the future outlook of CB1 receptor neutral-antagonist/inverse-agonist therapies. Obesity (Silver Spring) 19:1325-34
Farrell, Martilias; Rosenzweig-Lipson, Sharon; Walker, Ellen (2010) Discriminative stimulus effects of serotonin agonists, neutral antagonists, and inverse agonists in pigeons: perspectives on intrinsic efficacy measurements in vivo. Psychopharmacology (Berl) 211:149-59
Walker, Ellen A; Foley, John J (2010) Acquisition session length modulates consolidation effects produced by 5-HT2C ligands in a mouse autoshaping-operant procedure. Behav Pharmacol 21:83-9
Ward, Sara Jane; Walker, Ellen A (2009) Sex and cannabinoid CB1 genotype differentiate palatable food and cocaine self-administration behaviors in mice. Behav Pharmacol 20:605-13
Ward, Sara Jane; Lefever, Timothy W; Rawls, Scott M et al. (2009) Age-dependent effects of the cannabinoid CB1 antagonist SR141716A on food intake, body weight change, and pruritus in rats. Psychopharmacology (Berl) 206:155-65
Ward, Sara Jane; Rosenberg, Marisa; Dykstra, Linda A et al. (2009) The CB1 antagonist rimonabant (SR141716) blocks cue-induced reinstatement of cocaine seeking and other context and extinction phenomena predictive of relapse. Drug Alcohol Depend 105:248-55
Farrell, Martilias S; Gilmore, Kirsti; Raffa, Robert B et al. (2008) Behavioral characterization of serotonergic activation in the flatworm Planaria. Behav Pharmacol 19:177-82
Ward, Sara Jane; Lefever, Timothy W; Jackson, Cavario et al. (2008) Effects of a Cannabinoid1 receptor antagonist and Serotonin2C receptor agonist alone and in combination on motivation for palatable food: a dose-addition analysis study in mice. J Pharmacol Exp Ther 325:567-76
Ward, Sara Jane; Walker, Ellen A; Dykstra, Linda A (2007) Effect of cannabinoid CB1 receptor antagonist SR141716A and CB1 receptor knockout on cue-induced reinstatement of Ensure and corn-oil seeking in mice. Neuropsychopharmacology 32:2592-600

Showing the most recent 10 out of 12 publications