The neurobiology and genetics of impulse control disorders: Relationships to drug addictions
Introduction
Formal impulse control disorders (ICDs) for which there are diagnostic criteria in the Diagnostic and Statistical Manual (DSM-IV-TR) include pathological gambling (PG), kleptomania, pyromania, intermittent explosive disorder, trichotillomania and ICD not otherwise specified [1]. Criteria for other ICDs (compulsive shopping, problematic internet use, compulsive sexual behavior, and compulsive skin picking) have been proposed and are currently under consideration [2], [3]. Basic characteristics of ICDs include repetitive or compulsive engagement in a specific behavior (e.g., gambling, hair-pulling) despite adverse consequences, diminished control over the problematic behavior, and tension or an appetitive urge state prior to engagement in the behavior [2].
Section snippets
ICDs and addiction
ICDs have been hypothesized to lie along an impulsive–compulsive spectrum [4], representing obsessive–compulsive (OC) spectrum disorders [5], [6]. Although individuals with ICDs engage in repetitive behaviors, often with strong associated urges, behaviors are often related as pleasurable or egosyntonic, whereas repetitive behaviors or rituals in OC disorder (OCD) are generally egodystonic [7], [8]. Individuals with ICDs typically score high on measures of impulsivity and related constructs like
Addiction: an overview
Extensive research has been performed into the neurobiological underpinnings of the development and maintenance of addictions (reviewed in [17], [18], [19]). Emerging views of addiction involve a drug or behavior-acquiring saliency via reinforcement, with subsequent transitions through reward-based learning processes into habitual/compulsive levels of engagement [19].
Appetitive conditioning is an important consideration in the early stages of the addiction process. Appetitive conditioning,
Population genetics of addiction and ICDs
Genes in essence provide the first contribution to the addiction process, as they determine foundational vulnerabilities for normal behavioral processes to go awry. Genetic studies of ICDs suggest similarities to other addictions [31]. Family and twin epidemiologic studies have estimated that genetic contributions account for up to 60% of the variance in the risk for substance addictions [32], [33]. Similarly robust genetic contributions have been found for PG. Using data from the Vietnam Era
Impulsivity
Impulsivity has relevance for many psychiatric disorders, including ICDs and substance addictions [38]. Within the addiction process, impulsivity contributes to early stages such as drug experimentation. Trait impulsivity has multiple components; e.g., one study identified four components (urgency, lack of premeditation, lack of perseverance, and sensation seeking [39]) whereas other structured measures of impulsiveness factor into three elements (the Barratt Impulsivity Scale fractionates into
Dopamine, impulsivity and ICDs
As outlined above, dopamine is relevant early in the addiction process as well as in later aspects. Dopaminergic systems have been implicated in impulsivity and ICDs. Psychostimulants such as amphetamine influence dopamine and other biologic systems and are effective therapies for attention deficit hyperactivity disorder (ADHD), a disorder that has impulsivity as a central feature. Dysregulation of the NAcc DA system has been implicated in ADHD [44]. Dopaminergic systems also contribute to
Dopaminergic regulation and ICDs: roles for γ-aminobutyric acid (GABA) and glutamate
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. It is synthesized in nerve terminals from glutamate by the enzyme glutamate decarboxylase. There is evidence of anatomic and functional connectivity between GABA and dopaminergic systems as well as increasing support for effects of modulation of GABAergic systems on substance use disorders [71]. For example, tiagabine, a GABA reuptake inhibitor used primarily to treat seizures, has shown preliminary efficacy in
Serotonin, impulsivity and ICDs
Like DA, GABA and glutamate, a role for serotonin (5-HT) is supported in impulsivity, ICDs and drug addictions. Serotonergic neurons project form the dorsal raphe nucleus throughout the brain to regions including the hippocampus, frontal cortex and amygdala. In animal models, forebrain 5-HT depletion has been shown to lead to impulsive choice, while the indirect 5-HT agonist fenfluramine decreases such behavior [79], [80]. Additionally, lesion of the rat raphe results in transient preference
Risk–reward assessment, decision-making, and ventral prefrontal cortex (PFC)
Once a behavior has moved beyond the initial stages of associative learning, executive control over its execution becomes increasingly important. Regions of the PFC contribute to decision-making in disorders of impulse control and addiction. The OFC codes the relative value of reward stimuli [124], [125], a process in part mediated by the 5-HT system. The OFC facilitates cognitive flexibility by promoting updating of associative encoding in downstream brain areas such as the amygdala [126].
Decision-making, impulsivity, and the amygdala
Amygdala function contributes significantly to decision-making and impulsivity. The amygdala receives serotonergic and dopaminergic input from the raphe and VTA respectively, and its activation is regulated by a balance between glutamate-induced excitation and GABA-mediated inhibition [143], [144]. The amygdala participates in the processing and memory of emotional reactions. According to the somatic marker hypothesis (which states that decision making relies on neural substrates that regulate
Habit formation
As a behavior shifts from active learning to habitual response, control shifts from an associative cortico-basal ganglia network involving the PFC and ventral striatum to dorsomedial striatum/caudate and then to a more sensorimotor cortico-basal ganglia network involving the dorsolateral striatum/putamen (see Fig. 1b) [29]. Overtraining of behaviors shifts activation from dorsolateral PFC and caudate to putamen and motor cortices [149], [150]. In addiction, repeated cocaine self-administration
Stress responsiveness and ICDs
Stressful events and psychological distress frequently contribute to relapse to drug use among individuals with opiate and cocaine dependence [160], [161]. Preclinical evidence indicates that acute stress leads to increases in self-administration of drugs such as amphetamines [162], cocaine [163], [164], and alcohol [165], [166]. Mechanisms related to stress are critical in the establishment of addictions and their propagation as chronic disorders [167]. Stress exposure produces an increased
Opioids, stress and ICDs
Opioids modulate mesolimbic DA pathways in the VTA by activating μ opioid receptors on secondary interneurons causing hyperpolarization and inhibition of GABA release on primary neurons (the dopaminergic output neurons) with consequent increased DA release [183]. However, activation of κ opioid receptors on primary neurons causes their direct inhibition [184]. Recently it has been shown that opioid receptor activation (κ versus μ) differentially inhibits mesolimbic neurons depending on their
Conclusions and future directions
Emerging data on the neurobiology of impulsivity and ICDs suggest parallels with drug addictions. Although many fewer studies have investigated ICDs than have drug addictions (and most existing studies have investigated PG), genetic, behavioral and treatment data implicate multiple neurotransmitter systems and neuronal circuits in the establishment and maintenance of behavioral addictions. Despite these advances, controversy remains regarding the nosology and underlying pathophysiology of
Acknowledgments
We would like to thank Dr. Christopher Pittenger for his thorough review of and helpful comments regarding this manuscript. Support for this research was provided by NIH grant T32-MH19961 Clinical Neuroscience Research Training in Psychiatry (J.A.B.), a Mind and Life Institute Research Varela Grant (J.A.B.), the National Institute on Drug Abuse grants R01-DA019039 (M.N.P.) and R01-DA020908 (M.N.P.), Women's Health Research at Yale (M.N.P.), and the VA VISN1 MIRECC (M.N.P.) and REAP (M.N.P.).
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