Neurobiological mechanisms of addiction: focus on corticotropin-releasing factor

Abstract

Drug addiction is a chronically relapsing disorder that is characterized by a compulsion to take drugs and loss of control in limiting intake. Medications that are on the market for the treatment of drug addiction target either the direct reinforcing effects of abuse (eg, naltrexone) or the consequent protracted abstinence syndrome (eg, acamprosate). Both conceptual and neurobiological advances in research have suggested that brain stress systems contribute to the withdrawal/negative affect and preoccupation/anticipation stages of the addiction cycle that promote the compulsivity of drug-taking in addiction. Validated animal models of the stress component of addiction and improved understanding of the neurocircuitry and neuropharmacological mechanisms involved in perturbations of this component suggest that corticotropin-releasing factor systems are a viable target for the development of future medications for drug addiction.

Figure 1. The three stages of the addiction cycle and the criteria for substance dependence

There are three stages in the addiction cycle: binge/intoxication, withdrawal/negative affect and preoccupation/anticipation; these stages are defined from a psychiatric perspective, with different criteria for substance dependence incorporated from the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [92]. (Adapted with permission from The American Association for the Advancement of Science and Koob GF, Le Moal M: Drug abuse: Hedonic homeostatic dysregulation. Science (1997) 278(5335):52-58. © 1997 The American Association for the Advancement of Science)

Figure 2. Neurocircuitry associated with the acute positive reinforcing effects of drugs of abuse and the negative reinforcement of dependence, and changes in the transition from non-dependent to dependent drug-taking

(A) Key elements of the reward circuit include dopamine and opioid peptide neurons that intersect at both the VTA (ventral tegmental area) and the nucleus accumbens that are activated during initial drug use and the early binge/intoxication stage of the addiction cycle. Drugs approved for the treatment of this component of the addiction cycle include naltrexone, buprenorphine, varenicline and disulfiram. (B) Key elements of the stress circuit include CRF (corticotropin-releasing factor) and noradrenergic neurons that converge on GABA interneurons in the central nucleus of the amygdala that are activated during the development of dependence. Drugs approved for the treatment of this component of the addiction cycle include methadone, bupropion, acamprosate, varenicline and buprenorphine. DA dopamine, NE norepinephrine (Adapted with permission from Nature Publishing Group and Nestler EJ: Is there a common molecular pathway for addiction? Nat Neurosci (2005) 8(11):1445-1449. © 2005 Nature Publishing Group)