Neurobiology of George F. Koob, Ph.D. Addiction CONCEPTUAL FRAMEWORK, different stages of the addiction cycle. While much SYNTHESIS CLINICAL DEFINITIONS, AND ANIMAL MODELS focus in animal studies has been on the synaptic sites and transductive mechanisms in the nervous system Drug addiction, also known as substance dependence, on which drugs with dependence potential act initially is a chronically relapsing disorder characterized by (1) to produce their acute positive reinforcing effects compulsion to seek and take the drug, (2) loss of con- (binge/intoxication stage), new animal models of trol in limiting intake, and (3) emergence of a negative chronic drug taking and seeking (withdrawal/negative emotional state (e.g., dysphoria, anxiety, irritability) affect stage) and the craving stage (preoccupation/antic- when access to the drug is prevented (defined here as ipation) have been developed and are beginning to be dependence) (1). Addiction and substance dependence used to explore how the nervous system adapts to drug (as currently defined by the Diagnostic and Statistical use (Table 1). The neurobiological mechanisms of ad- Manual of Mental Disorders, 4th edition) (2) will be diction that are involved in various stages of the addic- used interchangeably throughout this paper to refer to tion cycle have a specific focus on certain brain circuits a final stage of a usage process that moves from drug and the molecular/neurochemical changes associated use to addiction. Clinically, the occasional but limited with those circuits during the transition from drug- use of a drug with the potential for abuse or depen- taking to drug addiction and how those changes per- dence is distinct from escalated drug use and the emer- sist in the vulnerability to relapse (5). gence of a chronic drug-dependent state. An impor- tant goal of current neurobiological research is to NEUROBIOLOGICAL MECHANISMS OF understand the neuropharmacological and neuroad- THE BINGE/INTOXICATION STAGE aptive mechanisms within specific neurocircuits that mediate the transition from occasional, controlled A long-hypothesized key element of drug addic- drug use and the loss of behavioral control over drug- tion is that drugs of abuse activate brain reward seeking and drug-taking that defines chronic addic- systems, and understanding the neurobiological tion. bases for acute drug reward has been a key to how Addiction has been conceptualized as a chronic re- these systems change with the development of ad- lapsing disorder with roots both in impulsivity and diction (1, 6). A principle focus of research on the compulsivity and neurobiological mechanisms that neurobiology of the positive reinforcing effects of change as an individual moves from one domain to drugs with addiction potential has been the origins the other (3). In addiction, drug-taking behavior pro- and terminal areas of the mesocorticolimbic dopa- gresses from impulsivity to compulsivity in a three- mine system, and there is compelling evidence for stage cycle: binge/intoxication, withdrawal/negative af- fect, and preoccupation/anticipation. As individuals move from an impulsive to a compulsive disorder, the Adapted and updated from Koob G: “Neurobiology of Addiction,” in Textbook of Substance drive for the drug-taking behavior shifts from positive Abuse Treatment. Galanter M, Kleber HD (eds). Washington, DC, American Psychiatric Publishing, to negative reinforcement (Figure 1). Impulsivity and 2008, pp 3–16. compulsivity can coexist in different stages of the ad- diction cycle. CME Disclosure George F. Koob, Ph.D., Committee on the Neurobiology of Addictive Disorders, The Scripps Much of the recent progress in understanding the Research Institute, La Jolla, CA neurobiology of addiction has derived from the study of animal models of addiction on specific drugs such Dr. Koob reports the following: Advisory Board: Addex Pharmaceuticals; Consultant: Alkermes, as opiates, psychostimulants, and alcohol (4). While Arkeo Pharmaceuticals, Case Palmera, Embera Neuro Therapeutics, GlaxoSmithKline, Lilly, no animal model of addiction fully emulates the hu- Psychogenics. man condition, animal models do permit investiga- Address correspondence to George F. Koob, Ph.D., Committee on the Neurobiology of Addictive tion of specific elements of the process of drug addic- Disorders, The Scripps Research Institute, 10550 North Torrey Pines Rd., SP30-2400, La Jolla, tion. Such elements can be categorized by models of CA 92037; e-mail: [email protected] focus.psychiatryonline.org FOCUS Winter 2011, Vol. IX, No. 1 55 KOOB Figure 1. (Top left) Diagram showing the stages of impulse control disorder and compulsive disorder cycles related to the sources of reinforcement. In impulse control disor- ders, an increasing tension and arousal occurs before the impulsive act, with pleasure, gratification, or relief during the act. Following the act, there may or may not be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts (obsessions) that cause marked anxiety and stress followed by repetitive behaviors (compulsions) that are aimed at preventing or reducing distress (2). Positive reinforcement (pleasure/gratification) is more closely associated with impulse control disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closely associated with compulsive disorders. (Top right) Collapsing the cycles of impulsivity and compulsivity results in the addiction cycle, conceptualized as three major components: preoccupation/anticipation, binge/intoxication, and with- drawal/negative affect. [Taken with permission from Koob GF, Everitt BJ, Robbins TW: Reward, motivation, and addiction, in Fundamental Neuroscience, 3rd ed. Edited by Squire LG, Berg D, Bloom FE, Du Lac S, Ghosh A, Spitzer N. Amsterdam, Academic Press, 2008, pp 987-1016.] (Bottom) Change in the relative contribu- tion of positive and negative reinforcement constructs during the development of substance dependence on alcohol. the importance of this system in drug reward. the medial shell region of the nucleus accumbens, Much work suggests that activation of the mesocor- the role of dopamine becomes less critical as one ticolimbic dopamine system has multiple func- moves to opioid drugs, alcohol, and ⌬9-tetrahydro- tional attributes, including giving incentive salience cannabinol (⌬9-THC). Here, other neurotransmit- to stimuli in the environment (7) to drive perfor- ter systems such as opioid peptides, GABA, and mance of goal-directed behavior (8) or activation in endocannabinoids may play key roles either in se- general (9). However, the specific circuitry associ- ries or independent of activation of the mesolimbic ated with drug reward in general has been broad- dopamine system. Other components of the basal ened to include the many neural inputs and outputs forebrain that have been identified with drug re- that interact with the basal forebrain, specifically ward have also focused on the amygdala (5, 10). For the nucleus accumbens (Figure 2). As the neural example, a particularly sensitive site for blockade of circuits for the reinforcing effects of drugs with de- the acute reinforcing effects of alcohol with opioid pendence potential have evolved, the role of neu- and GABA-ergic antagonists appears to be the cen- rotransmitters/neuromodulators also has evolved, tral nucleus of the amygdala (11). Opioid peptide and four of those systems have been identified to antagonists also block the reinforcing effects of ⌬9- have a role in the acute reinforcing effects of drugs: THC, a key active ingredient in marijuana. Canna- ␥ dopamine, opioid peptides, -aminobutyric acid binoid CB1 antagonists block opioid, alcohol, and (GABA), and endocannabinoids (Table 2). cannabinoid reward (12, 13). In summary, all The mesolimbic dopamine system is well estab- drugs of abuse activate the mesolimbic dopamine lished as having a critical role in the activating and system, but much evidence suggests that dopamine- reinforcing effects of indirect sympathomimetics independent reinforcement occurs at the level of such as cocaine, methamphetamine, and nicotine. the nucleus accumbens, suggesting multiple inputs However, while all drugs of abuse acutely activate to the activation of critical reinforcement circuitry the mesolimbic dopamine system, particularly in in these brain regions (14, 15). Thus, multiple neu- 56 Winter 2011, Vol. IX, No. 1 FOCUS THE JOURNAL OF LIFELONG LEARNING IN PSYCHIATRY KOOB rotransmitters are implicated in the acute reinforc- Table 1. Animal Models of the Three ing effects of drugs of abuse. Key players in the Stages of the Addiction Cycle nucleus accumbens and amygdala are dopamine, opioid peptide, and GABA systems with modula- Stage of Addiction Cycle Animal Models tion via endocannabinoids. Binge/intoxication Drug/alcohol self-administration Other elements of the acute drug reward circuit Conditioned place preference include the ventral pallidum and dorsal striatum. A Brain stimulation reward thresholds major output from the nucleus accumbens is to the Increased motivation for self-administration ventral pallidum/substantia innominata, and ele- in dependent animals ments of the ventral pallidum may not only be crit- Withdrawal/negative affect Anxiety-like responses ical for further processing of the drug reward signal Conditioned place aversion SYNTHESIS CLINICAL but also may be directly modulated by drugs of Withdrawal-induced drug self- abuse (16, 17). The dorsal striatum does not appear administration to play a major role in