Review
Neurobiological mechanisms in the transition from drug use to drug dependence

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Abstract

Drug addiction is a chronic relapsing disorder characterized by compulsive drug intake, loss of control over intake, and impairment in social and occupational function. Animal models have been developed for various stages of the addiction cycle with a focus in our work on the motivational effects of drug dependence. A conceptual framework focused on allostatic changes in reward function that lead to excessive drug intake provides a heuristic framework with which to identify the neurobiologic mechanisms involved in the development of drug addiction. Neuropharmacologic studies in animal models have provided evidence for the dysregulation of specific neurochemical mechanisms in specific brain reward and stress circuits that provide the negative motivational state that drives addiction. The allostatic model integrates molecular, cellular and circuitry neuroadaptations in brain motivational systems produced by chronic drug ingestion with genetic vulnerability, and provides a new opportunity to translate advances in animal studies to the human condition.

Section snippets

Addiction

Substance dependence [8] or addiction, is a chronically relapsing disorder that is characterized by a compulsion to seek and take a drug (loss of control in limiting intake), and impairment in social and occupational function. Both clinically and in experimental animals, the occasional or limited use of an abusable drug is distinct from repeated drug use and the development of addiction. From a psychiatric perspective, drug addiction has aspects of both impulse control disorders and compulsive

Dysregulated reward associated with drug withdrawal

Cocaine is a powerfully reinforcing psychostimulant with high addiction potential. In humans, chronic use of cocaine often is associated with a binge-like, uncontrollable pattern of use (in the sense that the binge is not easily stopped) with tolerance and acute withdrawal. This cocaine withdrawal in outpatients is characterized by severe depressive symptoms combined with irritability, anxiety, and anhedonia, lasting several hours to several days (i.e. the ‘crash’), and may be one of the major

Prolonged access to cocaine as a model of the transition to addiction

Animal procedures of cocaine self-administration provide a framework with which to model the transition from drug use to drug addiction. Animal models of escalation of cocaine intake have been established and are beginning to provide insight into the neurobiological changes that may lead to vulnerability to escalation in drug intake and relapse.

Historically, animal models of cocaine self-administration involved the establishment of stable behavior from day to day to allow the reliable

Prolonged access to heroin as a model of the transition to addiction

The transition from stable to escalated levels of cocaine self-administration has been shown to depend upon duration of drug availability. The generality of this phenomenon was assessed by studying the effects of duration of availability on heroin self-administration. Two groups of rats were trained on a 1-h continuous access schedule of self-administration, after which access to heroin (40 μg/injection) was increased to 11 h in one group (LgA group), or kept to 1 h in the other group (ShA

Neuropharmacological and molecular mechanisms involved in escalated cocaine intake with extended access

Cocaine increases the availability of monoamines at the synaptic level in the brain, and much is known about the neuropharmacological bases of the reinforcing effects of acute administration of cocaine. Early work suggested a primary role for the mesolimbic dopamine system that projects to the basal forebrain [21]. More recent evidence suggests that both dopaminergic and serotonergic terminals within a basal forebrain macrostructure termed the extended amygdala (central nucleus of the amygdala,

Neuroanatomical substrates for escalated drug intake

The term ‘extended amygdala’ has been formulated to represent a neuroanatomical macrostructure in the basal forebrain that shares similarities in morphology, neurochemistry and connectivity. It is composed of several basal forebrain structures: the BNST, the central and medial amygdala, and a transition zone in the posterior medial part of the nucleus accumbens (e.g. shell) [17]. This system receives afferents from limbic and olfactory cortices and projects heavily to the hypothalamus and

An allostatic physiological framework for the transition from drug use to drug addiction

Using the arousal/stress continuum as their physiological framework, Sterling and Eyer [47] argued that homeostasis was not adequate to explain the physiological basis for changes in patterns of human morbidity and mortality associated with modern life. Allostasis, simply defined as the process of achieving stability through change, originally was formulated as a hypothesis to explain such mind-body interactions [47].

The concept of allostasis has several unique characteristics that give it more

Acknowledgements

This is publication number 15830-NP from The Scripps Research Institute. Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043 (GFK), DA04398 (GFK), DA11004 (LHP), DA11946 (AM) and DA13821 (PPS) from the National Institute on Drug Abuse, and DK26741 from the National Institute on Diabetes and Digestive and Kidney Diseases. PJK was supported by a fellowship from the Peter F. McManus Charitable

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