George F. Koob

Neurocircuitry of addiction.

Drug addiction is a chronically relapsing disorder that has been characterized by (1) compulsion to seek and take the drug, (2) loss of control in limiting intake, and (3) emergence of a negative emotional state (eg, dysphoria, anxiety, irritability) reflecting a motivational withdrawal syndrome when access to the drug is prevented. Drug addiction has been conceptualized as a disorder that involves elements of both impulsivity and compulsivity that yield a composite addiction cycle composed of three stages: ‘binge/intoxication’, ‘withdrawal/negative affect’, and ‘preoccupation/anticipation’ (craving). Animal and human imaging studies have revealed discrete circuits that mediate the three stages of the addiction cycle with key elements of the ventral tegmental area and ventral striatum as a focal point for the binge/intoxication stage, a key role for the extended amygdala in the withdrawal/negative affect stage, and a key role in the preoccupation/anticipation stage for a widely distributed network involving the orbitofrontal cortex–dorsal striatum, prefrontal cortex, basolateral amygdala, hippocampus, and insula involved in craving and the cingulate gyrus, dorsolateral prefrontal, and inferior frontal cortices in disrupted inhibitory control. The transition to addiction involves neuroplasticity in all of these structures that may begin with changes in the mesolimbic dopamine system and a cascade of neuroadaptations from the ventral striatum to dorsal striatum and orbitofrontal cortex and eventually dysregulation of the prefrontal cortex, cingulate gyrus, and extended amygdala. The delineation of the neurocircuitry of the evolving stages of the addiction syndrome forms a heuristic basis for the search for the molecular, genetic, and neuropharmacological neuroadaptations that are key to vulnerability for developing and maintaining addiction.

Drug Addiction, Dysregulation of Reward, and Allostasis

This paper reviews recent developments in the neurocircuitry and neurobiology of addiction from a perspective of allostasis. A model is proposed for brain changes that occur during the development of addiction that explain the persistent vulnerability to relapse long after drug-taking has ceased. Addiction is presented as a cycle of spiralling dysregulation of brain reward systems that progressively increases, resulting in the compulsive use and loss of control over drug-taking. The development of addiction recruits different sources of reinforcement, different neuroadaptive mechanisms, and different neurochemical changes to dysregulate the brain reward system. Counteradaptive processes such as opponent-process that are part of normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to form an allostatic state. Allostasis from the addiction perspective is defined as the process of maintaining apparent reward function stability by changes in brain reward mechanisms. The allostatic state represents a chronic deviation of reward set point and is fueled not only by dysregulation of reward circuits per se, but also by the activation of brain and hormonal stress responses. The manifestation of this allostatic state as compulsive drug-taking and loss of control over drug-taking is hypothesized to be expressed through activation of brain circuits involved in compulsive behavior such as the cortico-striatal-thalamic loop. The view that addiction is the pathology that results from an allostatic mechanism using the circuits established for natural rewards provides a realistic approach to identifying the neurobiological factors that produce vulnerability to addiction and relapse.

Neuroscience of Addiction

This is publication number 11130-NP from The Scripps Research Institute. Research was supported by National Institutes of Health grants DA04043, DA04398, and DA08467 from the National Institute on Drug Abuse and AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism. The authors would like to thank Mike Arends for his valuable assistance with manuscript preparation.

Corticotropin Releasing Factor Receptor 1–Deficient Mice Display Decreased Anxiety, Impaired Stress Response, and Aberrant Neuroendocrine Development

Corticotropin releasing factor (CRF) is a major integrator of adaptive responses to stress. Two biochemically and pharmacologically distinct CRF receptor subtypes (CRFR1 and CRFR2) have been described. We have generated mice null for the CRFR1 gene to elucidate the specific developmental and physiological roles of CRF receptor mediated pathways. Behavioral analyses revealed that mice lacking CRFR1 displayed markedly reduced anxiety. Mutant mice also failed to exhibit the characteristic hormonal response to stress due to a disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Homozygous mutant mice derived from crossing heterozygotes displayed low plasma corticosterone concentrations resulting from a marked agenesis of the zona fasciculata region of the adrenal gland. The offspring from homozygote crosses died within 48 hr after birth due to a pronounced lung dysplasia. The adrenal agenesis in mutant animals was attributed to insufficient adrenocorticotropic hormone (ACTH) production during the neonatal period and was rescued by ACTH replacement. These results suggest that CRFR1 plays an important role both in the development of a functional HPA axis and in mediating behavioral changes associated with anxiety.

Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress

Corticotropin-releasing hormone (Crh) is a critical coordinator of the hypothalamic-pituitary-adrenal (HPA) axis. In response to stress, Crh released from the paraventricular nucleus (PVN) of the hypothalamus activates Crh receptors on anterior pituitary corticotropes, resulting in release of adrenocorticotropic hormone (Acth) into the bloodstream. Acth in turn activates Acth receptors in the adrenal cortex to increase synthesis and release of glucocorticoids. The receptors for Crh, Crhr1 and Crhr2, are found throughout the central nervous system and periphery. Crh has a higher affinity for Crhr1 than for Crhr2, and urocortin (Ucn), a Crh-related peptide, is thought to be the endogenous ligand for Crhr2 because it binds with almost 40-fold higher affinity than does Crh (ref. 2). Crhr1 and Crhr2 share approximately 71% amino acid sequence similarity and are distinct in their localization within the brain and peripheral tissues. We generated mice deficient for Crhr2 to determine the physiological role of this receptor. Crhr2-mutant mice are hypersensitive to stress and display increased anxiety-like behaviour. Mutant mice have normal basal feeding and weight gain, but decreased food intake following food deprivation. Intravenous Ucn produces no effect on mean arterial pressure in the mutant mice.

Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens

Abstract The effect of 6-OHDA injections into the nucleus accumbens was examined on cocaine self-administration behaviour. Rats were given access to cocaine (0.75 mg/kg/inj.) for three hours/day on a continuous reinforcement schedule. After daily intake of cocaine had stabilized, rats were injected with 6-OHDA (8 μg/2 μl). When tested the day following the 6-OHDA injection most rats failed to self-administer cocaine, however this disruption did not resemble extinction. After several days self-administration recovered in many animals to near preoperative levels, and the rate of this recovery correlated (r = +0.75) with the levels of dopamine remaining in the nucleus accumbens. The animals with the greatest depletion of dopamine did not recover cocaine intake. In a separate experiment, animals were pretreated with desmethylimipramine and/or pargyline to achieve a more extensive and selective lesion. When tested five days after the lesion all animals in these 6-OHDA groups showed a significant decline in cocaine intake compared to vehicle injected control animals. Several 6-OHDA treated animals displayed a pattern of behaviour resembling extinction, where a high rate of lever pressing was followed by cessation of responding. Some animals were aalso tested for apomorphine self-administration and this was found not to be affected by the 6-OHDA treatment. These data support the hypothesis that non-striatal dopamine may subserve cocaine reward.

A Role for Brain Stress Systems in Addiction

Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take drugs and has been linked to dysregulation of brain regions that mediate reward and stress. Activation of brain stress systems is hypothesized to be key to the negative emotional state produced by dependence that drives drug seeking through negative reinforcement mechanisms. This review explores the role of brain stress systems (corticotropin-releasing factor, norepinephrine, orexin [hypocretin], vasopressin, dynorphin) and brain antistress systems (neuropeptide Y, nociceptin [orphanin FQ]) in drug dependence, with emphasis on the neuropharmacological function of extrahypothalamic systems in the extended amygdala. The brain stress and antistress systems may play a key role in the transition to and maintenance of drug dependence once initiated. Understanding the role of brain stress and antistress systems in addiction provides novel targets for treatment and prevention of addiction and insights into the organization and function of basic brain emotional circuitry.

Dopamine, schizophrenia, mania, and depression: Toward a unified hypothesis of cortico-striatopallido-thalamic function

Considerable evidence from preclinical and clinical investigations implicates disturbances of brain dopamine (DA) function in the pathophysiology of several psychiatric and neurologic disorders. We describe a neural model that may help organize theseindependent experimental observations. Cortical regions classically associated with the limbic system interact with infracortical structures, including the nucleus accumbens, ventral pallidum, and dorsomedial nucleus of the thalamus. In our model, overactivity in forebrain DA systems results in the loss of lateral inhibitory interactions in the nucleus accumbens, causing disinhibition of pallidothalamic efferents; this in turn causes rapid changes and a loss of focused corticothalamic activity in cortical regions controlling cognitive and emotional processes. These effects might be manifested clinically by some symptoms of psychoses. Underactivity of forebrain DA results in excess lateral inhibition in the nucleus accumbens, causing tonic inhibition of pallidothalamic efferents; this perpetuates tonic corticothalamic activity and prevents the initiation of new activity in other critical cortical regions. These effects might be manifested clinically by some symptoms of depression. This model parallels existing explanations for the etiology of several movement disorders, and may lead to testable inferences regarding the neural substrates of specific psychopathologies.

Neurobiological Similarities in Depression and Drug Dependence: A Self-Medication Hypothesis

Epidemiological and clinical data indicate high comorbidity between depression and drug dependence that may reflect an attempt to self-medicate with drugs of abuse. The present review examines whether these two psychiatric disorders are related by attempting to identify similarities in the neurobiology of depression and drug dependence. Emphasis is put on the neuromechanisms that may mediate specific core symptoms of both disorders that reflect alterations in reward and motivational processes. First, the epidemiological and clinical data on the comorbidity of the two disorders are reviewed briefly. Then, the neuroadaptations associated with psychomotor stimulant, opiate, ethanol, nicotine, and benzodiazepine dependence in animals are reviewed. Finally, the neurotransmitter systems whose function appears to be altered in depression (i.e., serotonin, norepinephrine, acetylcholine, dopamine, gamma-aminobutyric acid, corticotropin releasing factor, neuropeptide Y, and somatostatin), as revealed primarily by animal studies, are discussed. It is concluded that drug dependence and depression may be associated with alterations in some of the same neurotransmitter systems and, in particular, with alterations of neurotransmitter function in limbic-related brain structures. Thus, these two psychiatric disorders may be linked by some shared neurobiology. Nevertheless, it remains unclear whether drug abuse and depression are different symptomatic expressions of the same preexisting neurobiological abnormalities, or whether repeated drug abuse leads to the abnormalities mediating depression (i.e., drug-induced depressions). The hypothesis of self-medication of non-drug-and drug-induced depressions with drugs of abuse is also discussed as a potentially important explanatory concept in understanding the observed clinical comorbidity of these two psychiatric disorders.

Dramatic decreases in brain reward function during nicotine withdrawal.

Tobacco smoking is a worldwide public health problem. In the United States alone, over 400,000 deaths and