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Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Δ9-THC or (R)-methanandamide (AM-356)

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Abstract

Objective

To characterize in vivo the high-affinity cannabinoid CB1 receptor (CB1R) selective anandamide analog AM-1346 [alkoxyacid amide of N-eicosa-tetraenylamine] using drug discrimination procedures. d-Amphetamine and also morphine in the (R)-methanandamide-trained group (see below) were examined to assess pharmacological specificity.

Methods

Three groups of rats were trained to discriminate between vehicle and (1) 1.8 mg/kg Δ9-tetrahydrocannabinol (Δ9-THC); (2) 5.6 mg/kg Δ9-THC; and (3) 10 mg/kg (R)-methanandamide (AM-356; a metabolically stable analog of anandamide). Δ9-THC was given i.p. 30 min and (R)-methanandamide 15 min before training.

Results

AM-1346 generalized to all three training conditions, both at 15 and 30 min after administration. The rank order potency was: Δ9-THC > AM-1346 > (R)-methanandamide. AM-1346 appeared slightly more potent 30 min compared to 15 min postadministration. In the presence of 0.3 mg/kg of the CB1R antagonist/inverse agonist SR-141716A, the dose generalization curves of Δ9-THC and AM-1346 resulted in parallel shifts to the right in the 1.8 mg/kg Δ9-THC-trained group. A long duration of action for AM-1346 (relative to AM-356) was indicated in tests where AM-1346 was examined in the 5.6 mg/kg Δ9-THC-trained group. Neither d-amphetamine, nor morphine generalized in either of the groups, suggesting pharmacological specificity.

Conclusion

Unlike (R)-methanandamide, the surmountable antagonism between SR-141716A and AM-1346 shows that the structural features of anandamide can be modified in ways that reduce the dissociation between the discriminative stimulus and rate decreasing effects of CB1R agonists derived from an anandamide template.

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Acknowledgements

United States Public Health Service Grants DA 09064, 00253 and 13429 (Philadelphia) and DA 03801, 9158, 7215, and 00152 (Boston) from the National Institute on Drug Abuse (NIDA) supported this work. We thank Michelle Harris for technical assistance. Additionally, three anonymous reviewers made suggestions for improving the manuscript. We also thank NIDA for supplies of (−)-Δ9-THC and morphine SO4. SR-141716A (as the salt) was a generous gift from Sanofi Recherchė, Montpellier, France.

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Authors and Affiliations

  1. Department of Psychology, Temple University, 265-67 Weiss Hall, 1701 North 13th Street, Philadelphia, PA, 19122, USA

    Torbjörn U. C. Järbe

  2. Departments of Psychiatry and Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Richard J. Lamb

  3. Department of Pharmaceutical Sciences, University of Connecticut, U-92, Storrs, CT, 06269, USA

    Qian Liu

  4. Department of Pharmaceutical Sciences, Northeastern University, Center for Drug Discovery (CDD), 116 Mugar, 360 Huntington Ave, Boston, MA, 02115, USA

    Torbjörn U. C. Järbe & Alexandros Makriyannis

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  1. Torbjörn U. C. Järbe
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  4. Alexandros Makriyannis
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Correspondence to Torbjörn U. C. Järbe.

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Järbe, T.U.C., Lamb, R.J., Liu, Q. et al. Discriminative stimulus functions of AM-1346, a CB1R selective anandamide analog in rats trained with Δ9-THC or (R)-methanandamide (AM-356). Psychopharmacology 188, 315–323 (2006). https://doi.org/10.1007/s00213-006-0517-x

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