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Background and Purpose: Both types of cannabinoid receptors-CB 1 and CB 2 -regulate brain functions relating to addictive drug-induced reward and relapse. CB 1 receptor antagonists and CB 2 receptor agonists have anti-addiction efficacy, in animal models, against a broad range of addictive drugs. Δ 9 -Tetrahydrocannabivarin (Δ 9 -THCV)-a cannabis constituent-acts as a CB 1 antagonist and a CB 2 agonist. Δ 8 -Tetrahydrocannabivarin (Δ 8 -THCV) is a Δ 9 -THCV analogue with similar combined CB 1 antagonist/CB 2 agonist properties., Experimental Approach: We tested Δ 8 -THCV in seven different rodent models relevant to nicotine dependence-nicotine self-administration, cue-triggered nicotine-seeking behaviour following forced abstinence, nicotine-triggered reinstatement of nicotine-seeking behaviour, acquisition of nicotine-induced conditioned place preference, anxiety-like behaviour induced by nicotine withdrawal, somatic withdrawal signs induced by nicotine withdrawal, and hyperalgesia induced by nicotine withdrawal., Key Results: Δ 8 -THCV significantly attenuated intravenous nicotine self-administration and both cue-induced and nicotine-induced relapse to nicotine-seeking behaviour in rats. Δ 8 -THCV also significantly attenuated nicotine-induced conditioned place preference and nicotine withdrawal in mice., Conclusions and Implications: We conclude that Δ 8 -THCV may have therapeutic potential for the treatment of nicotine dependence. We also suggest that tetrahydrocannabivarins should be tested for possible anti-addiction efficacy in a broader range of preclinical animal models, against other addictive drugs, and eventually in humans., (© 2019 The British Pharmacological Society.)

Background and Purpose: GAT107 ((3aR,4S,9bS)-4-(4-bromo-phenyl)-3a,4,5,9b-tetrahydro-3H-cyclopenta-[c]quinoline-8-sulfonamide) is a positive allosteric modulator (PAM) and agonist of α7 nicotinic acetylcholine receptors (nAChRs)that can cause a prolonged period of primed potentiation of acetylcholine responses after drug washout. NS6740 is a silent agonist of α7 nAChRs that has little or no efficacy for activating the ion channel but induces stable desensitization states, some of which can be converted into channel-active states by PAMs. Although GAT107 and NS6740 appear to stably induce different non-conducting states, both agents are effective treatment for inflammation and inflammatory pain models. We sought to better understand how both of these drugs that have opposite effects on channel activation could regulate signal transduction., Experimental Approach: Voltage-clamp experiments were conducted with α7 nAChRs expressed in Xenopus oocytes., Key Results: Long-lived sensitivity to a PAM or to an agonist was produced by NS6740 or GAT107 respectively. With sequential applications, these two drugs induced varying levels of persistent activation, which is a unique condition for a receptor that is known for rapid desensitization. The non-conducting states induced by NS6740 or GAT107 differ in their sensitivity to an α7 nAChR-selective antagonist and in how effectively they promote current., Conclusions & Implications: Our data suggest that the persistent currents represent a dynamic interconversion between different stable desensitized states and the PAM-inducible conducting states. However, the similarity of NS6740 and GAT107 effects on inflammation and pain suggests that the different stable non-conducting states have common activity on signal transduction., Linked Articles: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc., (© 2017 The British Pharmacological Society.)