Behavioural and pharmacological characterization of a novel cannabimimetic adamantane-derived indole, APICA, in C57BL/6J mice

The novel adamantane derivative APICA (N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide) was recently identified as a cannabimimetic indole of abuse (1, 2). Despite its novel structure, APICA recalls cannabimimetic indoles, such as representative member JWH-018. The emerging abuse problem, together with the paucity of information about the bioactivity of APICA (3) emphasize the need for further evaluation of the in vivo pharmacology of this novel indole-derived compound. In the present study, the effects of APICA (0 - 1 - 3 mg/Kg, i.p.) were tested in C57BL/6J mice, in a battery of tests that are sensitive to the effects of psychoactive cannabinoids, including body temperature; locomotor activity and behavioural reactivity in the open field test; nociception in the tail flick assay; motor coordination in the accelerating Rotarod; recognition memory in the novel object recognition test. Furthermore, the highest dose was also evaluated following the pre-treatment with the CB1 antagonist AM251 (3 mg/Kg, i.p.) or the CB2 antagonist AM630 (3 mg/Kg, i.p.). Our results show that APICA was able to dose-dependently decrease locomotor activity and behavioural reactivity in the open field, whereas only the highest dose was able to induce hypothermia, analgesia, motor ataxia and recognition memory impairment, with respect to vehicle (p<0.01; p<0.001). The pretreatment with the CB1 antagonist AM251 elicited an increase in body temperature, total distance travelled in the open field, descent latency in the Rotarod, and a decrease in tail flick latency (p<0.05; p<0.01). On the other hand, pretreatment with AM630 did not induced significant differences, resulting in hypothermia, antinociception and motor ataxia, with respect to vehicle. This study supports preliminary reports on APICA cannabimimetic properties, extending its detrimental effects on cognitive function. Moreover, these properties can be attributed to the CB1 receptor activity, indicating APICA as a selective CB1 receptor agonist. Selective CB1 receptor ligands may be useful in the pharmacotherapy of several pathological conditions; nevertheless, the increased use as designer drugs of abuse raises significant public health concerns.   (1) Uchiyama, N., Kawamura, M., Kikura-Hanajiri, R., and Goda, Y. (2012) Forensic Toxicol. 30, 114−125. (2) Uchiyama, N., Kawamura, M., Kikura-Hanajiri, R., and Goda, Y. (2013) Forensic Sci. Int. 227, 21−32. (3) Banister SD, Wilkinson SM, Longworth M, Stuart J, Apetz N, English K, Brooker L, Goebel C, Hibbs DE, Glass M, Connor M, McGregor IS, Kassiou M. (2013) ACS Chem NeurosciJul 4(7):1081-92.