Neuronal Nicotinic Receptors as Brain Targets for Pharmacotherapy of Drug Addiction

Abstract

Nicotine addiction and other forms of drug addiction continue to be significant public health problems in the United States and the rest of the world. Accumulated evidence indicates that brain nicotinic acetylcholine receptors (nAChRs) are a heterogenous family of ion channels expressed in the various parts of the brain. A growing body of preclinical studies suggests that brain nAChRs are critical targets for the development of pharmacotherapies for nicotine and other drug addictions. In this review, we will discuss the nAChR subtypes, their function in response to endogenous brain transmitters, and how their functions are regulated in the presence of nicotine. Furthermore, we will discuss the role of nAChRs in mediating nicotine-induced addictive behavior in animal models. Additionally, we will provide an overview of the effects of nicotine and nicotinic compounds on the mesolimbic dopamine system, part of the reinforcement/reward circuitry of the brain, as an example of the neurochemical basis of nicotine addiction and other drug addictions. An appreciation of the complexity of nicotinic receptors and their regulation will be necessary for the development of nicotinic receptor modulators as potential pharmacotherapy for drug addiction.

Cotinine: A Potential New Therapeutic Agent against Alzheimer's disease

“…Of these nAChRs, the α7 receptors are considered to be ideal therapeutic targets for several neurological conditions, including AD, schizophrenia, and Parkinson's disease (PD) as well as tobacco addiction [6,7]. The α7nAChR is a homomeric pentamer that has a high permeability to calcium (P Ca :P Na ≈ 10), and undergoes rapid and reversible desensitization and pronounced inward rectification [8].…”

“…The degenerative process involves a sequence of pathological events, including early degeneration of the cerebral basal forebrain and subsequent deterioration of the cortical cholinergic system [3,4]. This deterioration commonly includes a reduction in the levels of acetylcholine (ACh) and α3, α4, and α7 nicotinic ACh receptors (nAChRs) as well as a decrease in the activity of choline acetyltranferase in the brain [5].Of these nAChRs, the α7 receptors are considered to be ideal therapeutic targets for several neurological conditions, including AD, schizophrenia, and Parkinson's disease (PD) as well as tobacco addiction [6,7]. The α7nAChR is a homomeric pentamer that has a high permeability to calcium (P Ca :P Na ≈ 10), and undergoes rapid and reversible desensitization and pronounced inward rectification [8].…”

Cholinergic Receptor System as a Target for Treating Alcohol Abuse and Dependence

“…Brain nicotinic acetylcholine receptors (nAChRs) are a super family of ligand gated ion channels and are widely expressed throughout the central nervous system [14][15][16][17][18]. Evidence suggests that nAChR mediated signaling plays a crucial role in many forms of drug addiction, including alcohol dependence [19][20][21][22][23]. Thus far, twelve neuronal nAChR subunits which are classified as either alpha subunits (2)(3)(4)(5)(6)(7)(8)(9)(10) or beta subunits (2)(3)(4) [14][15][16].…”

Poster Abstracts

“…Although the majority of nAChR-selective compounds are natural molecules, more recently, novel nicotinic synthetic ligands have been developed in an effort to develop more specific agonists, antagonists, or modulators ). Moreover, the modulation of nAchRs is of utmost importance for the pharmacological research mainly due to the implications of these receptors in a number of diseases and syndromes as Alzheimer's disease, Parkinson, schizophrenia, as well as target for the development of analgesics, anxiolytics, neuroprotectors, and smoking cessation molecules (Steinlein and Bertrand 2008;Rahman et al 2008). The role of nAChR in addiction symptoms of several abuse drugs, from tobacco to cocaine, has also been shown (Fagen et al 2007;Williams and Adinoff 2008).…”