18-Methoxycoronaridine blocks context-induced reinstatement following cocaine self-administration in rats

Abstract

Numerous studies utilizing drug self-administration have shown the importance of conditioned cues in maintaining and reinstating addictive behaviors. However, most used simple cues that fail to replicate the complexity of cues present in human craving and addiction. We have recently shown that music can induce behavioral and neurochemical changes in rats following classical conditioning with psychostimulants. However, such effects have yet to be characterized utilizing operant self-administration procedures, particularly with regard to craving and relapse. The goal of the present study was to validate the effectiveness of music as a contextual conditioned stimulus using cocaine in an operant reinstatement model of relapse. Rats were trained to lever press for cocaine with a musical cue, and were subsequently tested during reinstatement sessions to determine how musical conditioning affected drug seeking behavior. Additionally, in vivo microdialysis was used to determine basolateral amygdala involvement during reinstatement. Lastly, tests were conducted to determine whether the putative anti-addictive agent 18-methoxycoronaridine (18-MC) could attenuate cue-induced drug seeking behavior. Our results show that music-conditioned animals exhibited increased drug seeking behaviors when compared to controls during reinstatement test sessions. Furthermore, music-conditioned subjects exhibited increased extracellular dopamine in the basolateral amygdala during reinstatement sessions. Perhaps most importantly, 18-MC blocked musical cue-induced reinstatement. Thus, music can be a powerful contextual conditioned cue in rats, capable of inducing changes in both brain neurochemistry and drug seeking behavior during abstinence. The fact that 18-MC blocked cue-induced reinstatement suggests that α3β4 nicotinic receptors may be involved in the mechanism of craving, and that 18-MC may help prevent relapse to drug addiction in humans.

Ibogaine and addiction in the animal model, a systematic review and meta-analysis

“…Yet, studies with 18-Methoxycoronaridine (a synthetic analogue of ibogaine) and noribogaine (a metabolite of ibogaine) did also show reduced SA for amphetamine and nicotine. 65 , 72 , 73 , 74 , 75 , 76 …”

What We Have Gained from Ibogaine: α3β4 Nicotinic Acetylcholine Receptor Inhibitors as Treatments for Substance Use Disorders

“…decreased cocaine self-administration in rats, with the highest dose depressing intake up to 3 weeks . The same doses also attenuated cocaine craving in rats, as determined through a cue-induced reinstatement model …”

“…16 The same doses also attenuated cocaine craving in rats, as determined through a cue-induced reinstatement model. 61 Several self-administration studies delivering 18-MC to specific brain regions have provided strong evidence that the observed efficacy in these animal models of SUDs stems from α3β4 antagonism. Administering 18-MC directly into either the MHb or the IPN, areas containing high densities of α3β4 nAChRs, decreased morphine and methamphetamine selfadministration in rats.…”

DARK Classics in Chemical Neuroscience: Ibogaine

“…Ibogaine, and to some extent its chief metabolite noribogaine, may exhibit properties that mitigate the physical dependence on opiates and other drugs of abuse, but for many self-experimenters, there is a heavy price to pay in the form of cardiovascular damage, neurotoxicity, and even death. The search for analogs that retain the positive aspects of ibogaine and lack its adverse effects led to the discovery of 18-methoxycoronaridine (18-MC), a compound that inhibits morphine, cocaine, methamphetamine, ethanol, and nicotine self-administration and drug-seeking behavior in rodents 95,96 without displaying ibogaine-like tremors or cerebellar toxicity at therapeutic doses. 38 Ibogaine, noribogaine, 18-MC, and other analogs bind to multiple receptor and transporter proteins, but recent findings suggest that nicotinic acetylcholine receptor subtypes could be the target in blocking the craving for drugs of abuse.…”