Novel Therapy for Nicotine Addiction in Alcohol Dependent Rats

Abstract

IntroductionNicotine and alcohol addiction are frequently co-morbid problems [1]. The co-dependence of nicotine and alcohol addiction complicates treatment and is often associated with significant morbidity and mortality. Prevalence of smoking in alcoholics is as high as 90% compared to 30% for the general population [2] and alcohol consumption is associated with high nicotine use [3,4]. Co-morbid cigarette smoking and alcoholism has been associated with higher rates of depression in comparison with non-alcoholic smokers [5] and increased cravings for nicotine in comparison with non alcohol dependent smokers [6]. Additionally, smoker alcoholics are more likely to die from smoking related diseases rather than directly from an alcohol related medical condition [7]. Pharmacotherapeutic options for the treatment of alcohol and tobacco co-dependence are limited. Thus, there is a critical need for the development of novel drugs implementing new therapeutic targets.Neurotensin (NT) is a neuropeptide that is closely associated with, and modulates dopamine (DA) [8], acetylcholine (ACh), glutamate, and γ-aminobutyric acid (GABA) neurotransmission, all of which are involved in addiction and reward pathways. Local administration of NT in the prefrontal cortex (PFC) increases extracellular levels of ACh and GABA [9]. Similar data were obtained with the extracranial injection of the NT agonist NT69L [10], a compound that was developed in our laboratory. NT also enhances GABAergic activity in rat hippocampus [11] and reduces glutamatergic neurotransmission in dorsolateral striatum [12]. However, NT must be administered centrally to have an effect because it is easily degraded by peptidases. Our laboratory has developed many NT agonists that can be administered extracranially and mimic the central effects of NT. The most studied of these agonists is NT69L, which binds with equal affinity to the two well-characterized NT receptors, subtype 1 (NTS1) and subtype 2 (NTS2). Our work with NT69L shows that it blocks nicotine-induced sensitization and nicotine self-administration [13][14][15].In addition to its role in animal models for nicotine addiction, the NT system has been strongly implicated in the neurochemical and behavioral effects of alcohol use [16,17]. Chronic administration of NT69L reduces alcohol preference and consumption in mice through modulation of the NTS1 [18]. Biochemically, NT69L normalizes the nicotine-induced changes in DA [19], the neurotransmitter that promotes the motivational process for both nicotine and alcohol, and the alcohol-induced increase in DA and glutamate in the striatum [20]. Additionally, NT modulates other neurotransmitters implicated in alcohol use disorder (AUD). It causes neurochemical changes similar to acamprosate (the calcium salt of acetylhomotaurine), which is one of three FDA-approved drugs to treat AUD. Administration of acamprosate or NT69L increases extracellular concentration of DA in striatum [10,11] and both acamprosate and NT69L modulate glutamate [21,22].Considering the behav...

Elucidating the Role of Neurotensin in the Pathophysiology and Management of Major Mental Disorders

“…NT, because it is co-localized with dopamine neurons and modulates dopamine transmission, is a candidate for a regulatory role in reward and addiction [87]. This review will focus on NT’s involvement in addiction to psychostimulant drugs, nicotine and alcohol [168,169,170]. …”