High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice

Abstract

Cholinergic signaling via the nicotinic acetylcholine receptors (nAChRs) in the mesolimbic circuitry is involved in the rewarding effects of abused drugs such as cocaine and opioids. In mouse studies, nonselective nAChR antagonist mecamylamine blocks cocaine-induced conditioned place preference (CPP) and behavioral sensitization. Among subtype-selective nAChR antagonists, the β2-selective antagonist dihydrobetaerythroidine and α7 nAChR antagonist methyllycaconitine (MLA), but not MLA alone prevent behavioral sensitization to cocaine. Since the role of the α3β4 nAChR subtype in the rewarding and behavioral effects of cocaine is unknown, the present study investigated the effect of two potent and selective α3β4 nAChR ligands, AT-1001 and AT-1012, on the acquisition of cocaine-induced CPP and behavioral sensitization in mice. At 5–30 mg/kg, cocaine produced robust CPP, whereas behavioral sensitization of locomotor activity was only observed at the higher doses (20–30 mg/kg). Pretreatment with AT-1001 (1–10 mg/kg) or AT-1012 (3–10 mg/kg) blocked CPP induced by 5 mg/kg cocaine, but not by 30 mg/kg cocaine. Lower doses of AT-1001 (0.3–3 mg/kg) and AT-1012 (1–3 mg/kg) did not affect the increase in locomotor activity induced by 5 or 30 mg/kg cocaine. But AT-1001, at these doses, blocked locomotor sensitization induced by 30 mg/kg cocaine. These results indicate that the α3β4 nAChR play a role in the rewarding and behavioral effects of cocaine, and that selective α3β4 nAChR ligands can attenuate cocaine-induced behavioral phenomena. Since the selective α3β4 nAChR functional antagonist AT-1001 has also been shown to block nicotine self-administration in rats, the present results suggest that α3β4 nAChRs may be a target for the treatment of cocaine addiction as well as for cocaine-nicotine comorbid addiction.

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

“…Work from Fowler and Kenny demonstrated that α5-KO (α5-expressing nAChRs are enriched in the vMHb-IPN pathway) mice show escalations of nicotine self-administration through a blunting of the aversive properties of nicotine and not an increase in the rewarding aspects of the drug (Fowler & Lu Qun 2011;Tuesta et al 2011). Conversely, pharmacological antagonism of β4-expressing nAChR (also enriched in the vMHb-IPN pathway) inhibits the self-administration of morphine and cocaine and blocks the formation of cocaine CPP (Glick et al 2006;McCallum & Glick 2009;Khroyan et al 2015). It is likely that a balance between α5 and β4 subunits is more influential in regulating drug response than a single subunit (Frahm et al 2011; ChAT-Cre DIO-mCherry-infused mice acquire cocaine-induced CPP (2-way ANOVA, main effect of conditioning, F 1,9 = 30.56, p = 0.0004), with no differences between CNO-primed (n = 6) and Veh-primed (n = 5) animals (no effect main effect of CNO-priming (F 1,9 = 0.4273, p = 0.5297).…”

The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats

“…We have previously shown that AT-1001 does not exhibit reinforcing properties per se and does not induce reinstatement of nicotine seeking in extinguished rats [32, 36]. We have also shown that AT-1001 does not induce a conditioned place preference or aversion in mice [51]. …”

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

“…In this latter study, the involvement of α6β2-containing nAChRs was confirmed pharmacologically by the blockade of cocaine reward with the intracerebral administration of the selective nAChR antagonist α-conotoxin MII. Other nAChR-regulated brain circuits may also be involved in cocaine reward, since the high affinity α3β4 nAChR functional antagonists, AT-1001 and AT-1012, can also attenuate cocaine place preference (183). A less selective α3β4 nAChR antagonist, 18-methoxycoronaridine, has also been shown to inhibit the self-administration of both cocaine and methamphetamine (184,185).…”