Drug Abuse and Addiction

Introduction to Drug Abuse and Addiction

Features of Drug Abuse and Addiction

• High levels of drug use continue in our society despite significant governmental attempts to control such use.
• Although early ideas about addiction emphasized the role of physical dependence, more recent conceptions have focused on the compulsive features of drug seeking and use (despite the potentially harmful consequences) and on the concept of drug addiction as a chronic, relapsing disorder characterized by repeated periods of remission followed by relapses.
• In the DSM-5 problematic patterns of drug use are categorized by a disorder called substance use disorder. In its severe form, substance use disorder has characteristics that correspond closely to those usually associated with addiction.
• The DSM-5 also contains a diagnostic category called gambling disorder. This disorder falls within a group of compulsive non-substance-related behaviors sometimes called behavioral addictions.
• Young people often progress from legal substances like alcohol or tobacco to marijuana, and some even go on to try cocaine, heroin, or illegally obtained prescription drugs. The gateway theory attempts to account for this progression, although other explanations have been offered to explain the same findings.
• A second kind of progression consists of cycles of pathological drug use consisting of three components: preoccupation–anticipation, binge–intoxication, and withdrawal–negative affect. Repeated cycles can cause spiraling distress in the user that eventually leads to addiction. Nevertheless, even addicts may show periods of abstinence interspersed among the intervals of regular drug consumption.
• The Schedule of Controlled Substances classifies potentially abused drugs into five categories, or schedules, on the basis of their degree of abuse potential and medicinal value. Alcohol and tobacco are not listed on the schedule, so they can be purchased for recreational use and without a prescription.
• Debate has arisen about whether the Schedule of Controlled Substances is a reasonable classification system based on current scientific knowledge, or whether it has been driven too much by sociopolitical considerations.

Factors That Influence the Development and Maintenance of Drug Abuse and Addiction

• Several types of factors contribute to the development and maintenance of compulsive drug seeking and drug use.
• Most abused drugs produce positive reinforcing effects in humans and experimental animals, as shown by IV self-administration. The reinforcing efficacy of a drug can be investigated by means of a dose–response function (which typically yields an inverted U-shaped curve) or preferably by means of breaking point determination using a progressive-ratio schedule.
• In animals that have been trained to self-administer a drug by performing an operant response (e.g., a lever press) and then have been extinguished on that response, renewed responding can be provoked by administering a priming dose of the drug, presenting a stimulus cue that was previously paired with drug delivery, or stressing the animal. This procedure is called reinstatement of drug-seeking behavior and is considered to be an experimental model of relapse in an abstinent addict.
• The rewarding effects of drugs are studied using place-conditioning procedures, as well as the effects of drugs on the threshold for electrical self-stimulation of the brain. Acute administration of most abused drugs leads to a reduction in the self-stimulation threshold, whereas withdrawal from drug exposure in dependent animals leads to an increase in the threshold.
• Drugs also sometimes produce aversive effects, although these may not be sufficiently strong to outweigh other factors that promote compulsive drug use.
• Repeated use of some drugs leads to physical dependence. Once this has occurred, attempts at stopping drug use give rise to a highly unpleasant withdrawal, or abstinence, syndrome. Koob and Le Moal proposed that in the development of addiction, drug-taking behavior progresses from an impulsive stage (primary motivation for drug use is the positive reinforcing effect) to a compulsive stage (primary motivation is negative reinforcement from alleviation of these unpleasant withdrawal symptoms). This shift is hypothesized to involve the recruitment of an antireward system in the brain.
• Through conditioning, environmental stimuli previously associated with drug use can elicit withdrawal symptoms such as drug craving in an abstinent individual. This response is accompanied by activation of brain areas that have been implicated in the addictive process.
• Psychoactive drugs, including drugs of abuse, can produce discriminative stimulus effects in animals that are thought to correspond to the subjective effects produced by these same compounds in human users. Experienced users come to expect these subjective effects, and such expectations are thought to contribute to the persistence of drug use.
• Addiction is a heritable disorder, but there is no addiction gene per se. Rather, specific alleles of many different genes are believed to each contribute a small increase in the risk for developing addiction. Different alleles of a gene may vary in just a single nucleotide, thus giving rise to single-nucleotide polymorphisms, or SNPs.
• The common disease–common variant hypothesis and the common disease–rare variant hypothesis are alternative hypotheses to account for the genetic contribution to neuropsychiatric disorders like addiction. These hypotheses differ with respect to whether the risk alleles for a disorder are relatively common or rare within the affected population.
• The genetics of neuropsychiatric disorders are studied using candidate gene analysis, linkage analysis, and genome-wide association studies (GWAS). For reasons yet to be determined, the GWAS approach has identified different addiction vulnerability genes than the other two.
• Psychosocial variables may either increase addiction risk or have a protective effect. One risk factor is suffering from an anxiety, mood, or personality disorder. Some investigators have proposed a self-medication hypothesis that addicts are using drugs to treat the symptoms of a preexisting psychiatric disorder. However, alternate hypotheses such as shared etiology have been put forth to explain the high comorbidity of such disorders with addiction.
• Personality variables such as impulsivity, antisociality, anxiety, high stress reactivity, sensation seeking, and extraversion have been associated with various pathways to drug addiction. The risk of becoming an addict is also affected by familial and sociocultural influences. For example, drugs may promote social facilitation, remove the user from normal social roles and responsibilities, promote solidarity within a particular ethnic group, or lead to association with a specific drug subculture.
• Finally, various protective factors can reduce the likelihood of an individual’s becoming addicted or can help prevent relapse in drug users attempting to maintain stable abstinence. These factors encompass the person’s personality structure, social (including family) life, and environment.
• Many individuals who at one time had a substance use disorder are able to achieve remission over time. This is often achieved through a process of natural recovery, which may be facilitated by transitional life events and/or by the negative consequences of continuing drug use. However, the likelihood of achieving natural recovery is lower for more severely affected substance users. These individuals may require formal treatment or a self-help group like Alcoholics Anonymous to have the best chance of recovery from their addiction.
• Combining the full range of pharmacological, biological, and psychological/sociocultural factors that influence addiction risk can be called a biopsychosocial model of addiction.

The Neurobiology of Drug Addiction

• The development of addiction has been conceptualized as a repeating spiral of three stages: (1) preoccupation/anticipation, (2) binge/intoxication, and (3) withdrawal/negative affect.
• The binge/intoxication stage is motivated by drug reward and incentive salience. The reward circuit mediates the acute rewarding and reinforcing effects of most abused drugs. One of the key components of this circuit is the DA pathway from the VTA to the NAcc. Virtually all drugs of abuse elevate extracellular DA levels in the NAcc, either by enhancing VTA cell firing or by acting locally to release DA from the dopaminergic nerve terminals and/or blocking DA reuptake. Drug-induced elevations in DA mimic the effect of burst firing of the dopaminergic neurons and cause activation of low-affinity D₁ receptors.
• Over repeated drug exposures, rewarding effects often decline because of drug tolerance. However, the incentive properties of the drug and its related cues become sensitized, thus leading to an increasingly important role for incentive salience as a motivator of continued drug use. The concepts of drug reward versus incentive salience are captured in the difference between drug liking and drug wanting.
• In addition to its involvement in reward and incentive salience, DA has also been implicated in the regulation of effortful behavior and as encoding signal for reward-prediction error.
• Repeated exposure to drugs of abuse lead to within-system and between-systems neuroadaptations involving persistent neurobiological changes of various kinds. Progressive down-regulation of the reward system is an important within-system neuroadaptation. At the same time, there occurs a between-systems neuroadaptation consisting of recruitment of an antireward circuit that mediates the withdrawal/negative affect stage of addiction.
• The antireward system is centered around the extended amygdala and is activated during stress and drug withdrawal. Neurochemically, activation of this system results in increased release of NE, CRF, and dynorphin.
• The opposing actions of the reward system and the antireward system have been conceptualized by Koob and Le Moal in an opponent-process model of addiction. According to this model, early drug use is motivated primarily by positively reinforcing effects (reward circuit), whereas later drug use (after addiction has taken place) is motivated primarily by negative reinforcement produced by alleviation of aversive withdrawal symptoms (antireward system). The opponent-process model further hypothesizes the development of an allostatic reduction in baseline hedonic tone (mood) that persists even after long-term abstinence from drugs.
• The preoccupation/anticipation stage is characterized by intrusive thinking, drug craving, and lack of impulse control. Additionally, chronic drug abuse and addiction are associated with impaired executive function. Together, these abnormalities are associated with dysregulation of the PFC and of the descending glutamatergic projections from the PFC and other cortical areas to the striatum and other subcortical structures.
• Cue-induced craving activates several brain regions, notably a deep cortical area known as the insula. Loss of control over drug use is associated with a transition of behavioral control from the ventral striatum (especially the NAcc) to the dorsal striatum, a brain area important for stimulus–response habit learning. Increased impulsivity has been linked to blunted striatal DA transmission, consisting of reduced DA release and lower D₂ receptor binding.
• Drugs of abuse produce both transient and longer-lasting changes in gene and protein expression. These changes represent molecular neuroadaptations to drug use. The transcription factor ΔFosB can be induced in the NAcc for relatively long periods by a variety of abused drugs, and this factor acts through epigenetic mechanisms to regulate other genes that may contribute to the transition from recreational drug use to addiction.
• Beyond ΔFosB, epigenetic regulation of gene expression can influence substance use and the risk for addiction in several different ways. First, chronic exposure to a drug may, through epigenetic mechanisms, either prime a gene to be expressed more strongly upon later drug administration or desensitize the gene so that its later expression is repressed. Second, epigenetic changes resulting from early adverse experiences (e.g., childhood maltreatment) may increase the risk of substance misuse later in life. Third, drug-induced epigenetic modifications in the germ line of the mother or father may be transmitted transgenerationally to the offspring and influence the offspring’s brain development and behavior.
• The most influential model of addiction in our society is the disease, or medical, model, which is based on brain dysfunction brought about by repeated drug exposure. Despite its wide acceptance, the disease model has been subject to a number of criticisms, including some criticisms based on evidence against the notion that addiction is a life-long disorder (in the absence of treatment) and that drug use by addicts is always uncontrollable and pathological. Alternative models of addiction focus on psychosocial factors that led to and now maintain excessive drug use, and they advocate for behavioral interventions that focus the person’s behavior toward healthier kinds of reinforcers.