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Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog.
Psychopharmacology (Berl). 2009 Apr; 203(2):229-39.P

Abstract

OBJECTIVE

To characterize in vivo the high-affinity CB(1) cannabinoid receptor (CB(1)R) selective anandamide analog AM1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination. Substitution tests involved Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of anandamide (AEA), as well as the CB(1)R antagonist/inverse agonist rimonabant; D: -amphetamine and morphine were also examined to assess pharmacological specificity.

MATERIALS AND METHODS

Rats were initially trained to discriminate between i.p.-injected vehicle and 3 mg/kg AM1346 (group 3 mg/kg; t' = 20 min); subsequently, the rats were retrained with 5.6 mg/kg AM1346 (group 5.6 mg/kg; t' = 20 min).

RESULTS

Dose-generalization curves of AM1346, Delta(9)-THC, and mAEA suggested the following order of potency: Delta(9)-THC > AM1346 > mAEA both for rats discriminating between 3 and 5.6 mg/kg AM1346 from vehicle. In group 3 mg/kg, challenge by 1 mg/kg rimonabant resulted in parallel shifts to the right of the dose-generalization curves for Delta(9)-THC and AM1346, suggesting surmountable antagonism. Surmountable antagonism was not demonstrated with rimonabant-mAEA combinations. A long duration of effect was indicated when 3 mg/kg AM1346 was examined after different time intervals following i.p. administration (group 3 mg/kg). The in vivo half-life was close to 5 h. Neither D: -amphetamine nor morphine generalized in either of groups 3 mg/kg and 5.6 mg/kg, suggesting pharmacological specificity.

CONCLUSION

Unlike mAEA, the surmountable antagonism between rimonabant and AM1346 showed that the structural features of AEA can be modified to produce novel ligands that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB(1)R agonists derived from an AEA template.

Authors+Show Affiliations

Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA 19122, USA. t.jarbe@neu.eduNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18521574

Citation

Järbe, Torbjörn U C., et al. "Discriminative Stimulus Functions in Rats of AM1346, a High-affinity CB1R Selective Anandamide Analog." Psychopharmacology, vol. 203, no. 2, 2009, pp. 229-39.
Järbe TU, Li C, Liu Q, et al. Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog. Psychopharmacology (Berl). 2009;203(2):229-39.
Järbe, T. U., Li, C., Liu, Q., & Makriyannis, A. (2009). Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog. Psychopharmacology, 203(2), 229-39. https://doi.org/10.1007/s00213-008-1199-3
Järbe TU, et al. Discriminative Stimulus Functions in Rats of AM1346, a High-affinity CB1R Selective Anandamide Analog. Psychopharmacology (Berl). 2009;203(2):229-39. PubMed PMID: 18521574.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog. AU - Järbe,Torbjörn U C, AU - Li,Chen, AU - Liu,Qian, AU - Makriyannis,Alexandros, Y1 - 2008/06/03/ PY - 2008/04/07/received PY - 2008/05/02/accepted PY - 2008/6/4/pubmed PY - 2009/10/6/medline PY - 2008/6/4/entrez SP - 229 EP - 39 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 203 IS - 2 N2 - OBJECTIVE: To characterize in vivo the high-affinity CB(1) cannabinoid receptor (CB(1)R) selective anandamide analog AM1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination. Substitution tests involved Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and R-(+)-methanandamide (mAEA), a metabolically stable analog of anandamide (AEA), as well as the CB(1)R antagonist/inverse agonist rimonabant; D: -amphetamine and morphine were also examined to assess pharmacological specificity. MATERIALS AND METHODS: Rats were initially trained to discriminate between i.p.-injected vehicle and 3 mg/kg AM1346 (group 3 mg/kg; t' = 20 min); subsequently, the rats were retrained with 5.6 mg/kg AM1346 (group 5.6 mg/kg; t' = 20 min). RESULTS: Dose-generalization curves of AM1346, Delta(9)-THC, and mAEA suggested the following order of potency: Delta(9)-THC > AM1346 > mAEA both for rats discriminating between 3 and 5.6 mg/kg AM1346 from vehicle. In group 3 mg/kg, challenge by 1 mg/kg rimonabant resulted in parallel shifts to the right of the dose-generalization curves for Delta(9)-THC and AM1346, suggesting surmountable antagonism. Surmountable antagonism was not demonstrated with rimonabant-mAEA combinations. A long duration of effect was indicated when 3 mg/kg AM1346 was examined after different time intervals following i.p. administration (group 3 mg/kg). The in vivo half-life was close to 5 h. Neither D: -amphetamine nor morphine generalized in either of groups 3 mg/kg and 5.6 mg/kg, suggesting pharmacological specificity. CONCLUSION: Unlike mAEA, the surmountable antagonism between rimonabant and AM1346 showed that the structural features of AEA can be modified to produce novel ligands that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB(1)R agonists derived from an AEA template. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/18521574/Discriminative_stimulus_functions_in_rats_of_AM1346_a_high_affinity_CB1R_selective_anandamide_analog_ L2 - https://dx.doi.org/10.1007/s00213-008-1199-3 DB - PRIME DP - Unbound Medicine ER -