Chapter Five - Effects of adolescent substance use disorders on central cholinergic function

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Abstract

Adolescence is a transitional period between childhood and adulthood, in which the individual undergoes significant cognitive, behavioral, physical, emotional, and social developmental changes. During this period, adolescents engage in experimentation and risky behaviors such as licit and illicit drug use. Adolescents' high vulnerability to abuse drugs and natural reinforcers leads to greater risk for developing substance use disorders (SUDs) during adulthood. Accumulating evidence indicates that the use and abuse of licit and illicit drugs during adolescence and emerging adulthood can disrupt the cholinergic system and its processes. This review will focus on the effects of peri-adolescent nicotine and/or alcohol use, or exposure, on the cholinergic system during adulthood from preclinical and clinical studies. This review further explores potential cholinergic agents and pharmacological manipulations to counteract peri-adolescent nicotine and/or alcohol abuse.

Section snippets

General introduction

Adolescence is a transitional period between childhood and adulthood (Table 1), in which the individual undergoes significant cognitive, behavioral, physical, emotional, and social developmental changes. It is also a period when humans begin experimentation and engage in risky behaviors that include use/abuse of age-restricted licit (i.e., alcohol, tobacco), illicit (i.e., marijuana, cocaine), and prescription (i.e., oxycodone, hydrocodone, amphetamines) drugs. It has been postulated that

Epidemiological findings on adolescent nicotine use

Although tobacco use is on the decline, it is still considered to be the most preventable cause of disease and death in the U.S. (World Health Organization, 2017). Approximately 58.1 million Americans aged 12 or older reported current tobacco use in the past month, however this number does not include use of electronic nicotine delivery devices (Substance Abuse and Mental Health Services Administration, 2020). It has been estimated that smoking causes more than 480,000 deaths and costs the

The cholinergic system

Cholinergic neurons are widely distributed in the brain and acetylcholine (ACh) binds to both central and peripheral cholinergic receptors. In this review we will primarily focus on cholinergic activity in the central nervous system (CNS). ACh is released from neurons projecting to a broad range of cortical and subcortical structures and influences cellular physiology as well as neuronal function throughout the brain (Ferreira-Vieira, Guimaraes, Silva, & Ribeiro, 2016; Mesulam, 2013; Newman,

The cholinergic system and adolescence

The adolescent brain undergoes significant neurobiological changes which manifest in altered internal and external behavior and this appears to be relatively conserved across mammalian species (Adriani et al., 2003; Slotkin, 2002; Spear, 2016, 2018; Spear & Brake, 1983). The maturation of cortical and limbic regions during adolescence is marked by excess production of neuronal networks followed by extensive pruning with a significant reduction of synaptic connections (c.f., Brenhouse &

Observations from preclinical studies on the effects of adolescent nicotine exposure

Preclinical research uses several techniques to investigate the effects of adolescent nicotine exposure on nicotine-related neuroadaptations and reward behaviors in adulthood, such as intraperitoneal (i.p.) and subcutaneous (s.c.) injections, osmotic pumps, intravenous (i.v.) self-administrations, and vapor inhalation. Systemic adolescent (PND 34–44) nicotine (0.4 mg/kg; i.p.) exposure enhanced i.v. nicotine (0.04 mg/kg/infusion) self-administration under a fixed-ratio (FR) schedule for nicotine

Adolescent nicotine effects on nicotinic acetylcholine receptors

Radioligand binding is an important tool that has been used to quantify and qualitatively characterize the effects of adolescent nicotine exposure on nAChR levels. For example, a 3HCytisine-binding (higher affinity for α4β2 than α3β4 subtype) study found that adolescent (PND 30–47) nicotine exposure resulted in equivalent upregulation of nAChR receptors in the midbrain (i.e., reward, movement, pain), cerebral cortex (i.e., higher order cognitive functions) and hippocampus (i.e., learning and

Adolescent nicotine effects on choline acetyltransferase

As previously mentioned, ChAT is responsible for the biosynthesis of ACh and it is the most used cholinergic marker to indicate the functional state of cholinergic neurons. Adolescent (PND 30–47.5) nicotine exposure via osmotic pump reduced ChAT in the midbrain at PND 45, PND 50 (2.5 days after discontinuation), PND 65 (~ 2 weeks after discontinuation), and PND 75 (~ 1-month after discontinuation)  (Abreu-Villaça et al., 2003, Trauth et al., 2000). These findings demonstrated that adolescent

Adolescent alcohol use/abuse

Alcohol is the most commonly abused drug among adolescents in the United States (Johnston, O'Malley, Bachman, & Schulenberg, 2004), with an annual economic cost of $24 billion (Sacks, Gonzales, Bouchery, Tomedi, & Brewer, 2015). Despite a legal drinking age of 21, 11% of all alcohol consumed in the US is by individuals aged 12–20 (Office of Juvenile Justice and Delinquency Prevention, 2005), with 80–90% having consumed alcohol before graduating from high school (Johnston et al., 2004). Binge

Adolescent voluntary alcohol drinking and adult alcohol drinking

Preclinical research has developed several animal models to study the neurobehavioral consequences of adolescent alcohol or binge effects on adulthood. In the voluntary free choice models, the animals usually have access to two-bottles with a choice between ethanol or water. However, in some studies, the animals may have three-bottle choice or two-lever operant access. During adolescence, voluntary ethanol consumption in selectively bred P rats altered alcohol-related behaviors during adulthood

Adolescent voluntary alcohol drinking and the cholinergic system

The DID-MSA procedure can lead to 80–100 mg% BEC within an hour in adolescent P rats (Bell, Rodd, Lumeng, Murphy, & McBride, 2006; Bell et al., 2011; McClintick et al., 2015, McClintick et al., 2016). Exposure to the DID-MSA alcohol binge model altered gene expression of nAChRs and mAChRs in the dorsal raphe nucleus (DRN; the primary source of serotonin) and the periaqueductal gray area of adolescent P rats. Adolescent binge drinking in P rats reduced ChAT, Chrna4, Chrnb3, and Chrm2 in the DRN (

Adolescent intermittent ethanol and adulthood alcohol drinking

The adolescent intermittent ethanol (AIE) exposure model is an experimenter-administered binge model that is used to produce consistent binge BEC levels in rodents that do not readily consume alcohol or achieve binge BEC levels of alcohol. However, AIE has also been used in alcohol-preferring rodents. AIE animals are exposed to ethanol via intragastric (i.g.) (Boutros, Semenova, Liu, Crews, & Markou, 2014; Boutros, Semenova, & Markou, 2016; Coleman, He, Lee, Styner, & Crews, 2011; Coleman, Liu,

Adolescent intermittent ethanol and the cholinergic system

AIE studies in rodents have consistently found that AIE exposure leads to persistent reductions of ChAT in the basal forebrain during adulthood in rats (Boutros et al., 2014; Ehlers et al., 2011; Swartzwelder et al., 2015; Vetreno & Crews, 2018; Vetreno et al., 2014, Vetreno et al., 2018; Fig. 3) and mice (Coleman et al., 2011). For example, Vetreno et al. (2014) demonstrated AIE reduced ChAT in basal forebrain during late adolescence (PND 56), adulthood (PND 80), and this reduction persisted

Adolescent ethanol and the α7 nicotinic receptor in the ventral tegmental area

Despite convergent data sets indicating that ChAT expression is reduced following adolescent alcohol exposure, there has been a general lack of research examining compensatory alterations in nAChRs. Recently, it was reported that AIE treatment in Wistar and P rats reduced the concentration of ethanol necessary (increased sensitivity) to support ethanol self-administration directly into the posterior VTA (pVTA), during adulthood (Hauser et al., 2019). An analysis of ACh-related gene expression

Effects of pharmacological manipulation of the cholinergic system and adolescent ethanol exposure

The substantial evidence that adolescent ethanol exposure can lead to cholinergic dysfunction into adulthood has warranted investigating the effects of cholinergic compounds on these subsequent cholinergic deficits in adulthood. Varenicline (i.e., Chantix), an α4β2 partial agonist, was FDA approved as a smoking cessation aid, and research has tested its effects on reducing ethanol consumption with varying results observed in adult rats. A recent report found that Varenicline reduced ethanol

Conclusion

Accumulating preclinical and clinical evidence indicates that initiation of drug use (i.e., nicotine and alcohol) during adolescence can induce unique and persistent neuroadaptations in the cholinergic system well into adulthood. This can subsequently increase the risk to develop SUDs. Current research has demonstrated that some cholinergic agents can prevent and reverse impairments associated with adolescent drug-induced cholinergic deficits and behavioral changes into adulthood. Nevertheless,

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