Acetylcholinesterase inhibitors and nicotine addiction: research studies on potential effects of acetylcholinesterase inhibitors in animal models of nicotine dependence.

Tobacco use though cigarette smoking is the leading preventable cause of death in the developed world. The pharmacological effect of nicotine plays a crucial role in tobacco addiction. Nicotine dependence has a huge impact on global health and although several medications are available, including a wide range of nicotine-replacement therapies (NRTs), bupropion, and recently approved nicotinic receptor partial agonist varenicline, at best only about a fifth of smokers are able to maintain long-term (12 months) abstinence with any of these approaches. Thus, there is a need to identify more effective pharmacotherapy to aid smokers in maintaining long-term abstinence. Converging evidence from animal and human cognitive neurosciences studies indicate that cognitive functions, particularly inhibitory cognitive control, are linked closely to addictive behaviours. Drug addiction has been described as a disease of the brain reward system wherein drugs activate the neuronal circuitry involved in reward and memory. Because of the effect of cholinergic systems on reward and drug self-administration, the prevalence of acetylcholine (ACh) within the striatum, and the involvement of ACh in higher cognitive processes, ACh may play an important role in the addictive processes underlying nicotine dependence. These diverse functions are mediated by nicotinic (nAChRs) and muscarinic (mAChRs) receptors. Cholinergic neurons are either projecting neurons, terminating diffusely in the brain, or interneurons, which are located mainly in striatum and nucleus accumbens (NA). While cholinergic projection neurons are critical in cognitive function, cholinergic interneurons integrate cortical and subcortical information related to reward. The cholinergic system interacts with the dopaminergic reward system at three levels: ventral tegmental area (VTA), NA and prefrontal cortex (PFC). In the VTA, both nAChRs and mAChRs stimulate the dopaminergic system. In the NA, cholinergic interneurons inhibit the dopaminergic system and integrate the cortical and subcortical information related to reward. In the PFC, the cholinergic system contributes to the cognitive control of addictive processes, although the neurobiological mechanism remains to be elucidate. Acetylcholinesterase inhibitors (AChE-Is) have been developed and introduced into clinical practice for the treatment of cognitive deficits in neurological and psychiatric disorders. Their therapeutic action is mediated through increase extracellular acetylcholine (ACh) levels as a result of the inhibition of acetylcholinesterase (AChE), the enzyme that cleaves ACh into choline and an acetyl-moiety. The two AChE-Is galantamine and physostigmine exhibit allosteric potentiation ligand properties (APL) on nAChRs. Tacrine, the first AChE-I introduced into clinical practice, does not act as an APL at nAChRs. The aim of this research is to investigate the role of ACh in nicotine dependence and how ACh modulates the mesocorticolimbic dopamine pathway. To address this question AChE-Is have been used as pharmacological tools to elevate the ACh level in the brain and the experimental paradigms applied in this research for investigating the addictive properties of nicotine were the drug discrimination (DD), self-administration (S/A) and reinstatement models. All these paradigms are operant conditioning models that mimic different phenomena of addictive behaviour. In particular, S/A directly measures the reinforcing and rewarding effects of drugs; drug discrimination provides information regarding the interoceptive stimulus effect that a drug can exert and the reinstatement model corresponds to the human behaviour of relapse. Galantamine, physostigmine and tacrine were initially tested in the drug discrimination model in rats trained to discriminate nicotine from saline. Galantamine and physostigmine partially generalized for nicotine discriminative stimulus; tacrine did not generalize to nicotine except for the highest tested dose. Physostigmine and tacrine were then selected to be tested in the nicotine self-administration model. Physostigmine and tacrine pre-treatment did not induce any significant changes on the number of nicotine infusions. Finally, tacrine was chosen as a test compound to be investigated in the extinction and relapse model. Tacrine administered chronically did not exert any effect either on extinction of nicotine self-administration behaviour, or on drug cues or nicotine priming reinstatement. The present results from animal studies show a lack of effect of AChE-Is on different aspects of nicotine addiction behaviour, but a number of limitations need to be taken into account. These findings also need to be integrated with clinical data available on this pharmacological class of compounds in order to create a more comprehensive picture for the potential use of AChE-Is as treatment for nicotine addiction.