Transition to Addiction: Patterns of Drug-Taking, Animal Models

Different drugs produce different patterns of neuroadaptations with chronic drug exposures. For example, opioid-addicted subjects meet most of the DSM criteria for addiction, including dramatic tolerance and withdrawal (classic symptoms associated with physical dependence) and most of the symptoms associated with motivational withdrawal. A pattern of intravenous or smoked drug-taking evolves, including intoxication, tolerance, escalation in intake, and profound dysphoria, physical discomfort, and somatic withdrawal signs during abstinence. Intense preoccupation with obtaining opioids (craving) develops that often precedes the somatic signs of withdrawal and is linked not only to stimuli associated with obtaining the drug but also to stimuli associated with withdrawal and the aversive motivational state. A pattern develops in which the drug must be obtained to avoid the severe dysphoria and discomfort of abstinence. Other drugs of abuse follow a similar pattern but may involve more the binge/intoxication stage (psychostimulants) or less binge/intoxication and more withdrawal/negative affect and preoccupation/anticipation stages (nicotine and cannabinoids).

Much of the recent progress in understanding the neurobiology of addiction has derived from the study of animal models of addiction to specific drugs such as stimulants, opioids, alcohol, nicotine, and Δ⁹-tetrahydrocannabinol (Δ⁹-THC). Although no animal model of addiction fully emulates the human condition, animal models do permit investigation of specific elements of the process of drug addiction. Such elements can be defined by models of different stages of the addiction cycle (see above; Table 2).

A progressive increase in the frequency and intensity of drug use is one of the major behavioral phenomena characterizing the development of addiction and has face validity with the DSM criteria: ?The substance is often taken in larger amounts and over a longer period than was intended' (American Psychiatric Association, 1994). Two animal models, one involving experimenter-administered drug, and the other involving self-administered drug, have been used to explore the effects of repeated drug administration on neuroplasticity in the neurocircuits identified above. Behavioral sensitization typically involved repeated administration by the experimenter of a drug, usually a psychostimulant, in a specific environmental context and the dependent measure was usually locomotor activity. Here, animals that received drug showed a much more dramatic increase in locomotor activity to a challenge dose of drug (sensitization) than controls that had received only repeated measures of vehicle injections.

A framework, perhaps with more face validity with which to model the transition from drug use to drug addiction, can be found in animal models of prolonged access to self- administration of drugs. Here, using intravenous drug self-administration, extended access to drugs is associated with an escalation in intake over days (Koob, 2009a). Such increased self-administration also has been observed with alcohol in which rats drink excessively during acute and protracted withdrawal from dependence induction using either chronic liquid diet or chronic vapor exposure (Gilpin and Koob, 2008). Animals made dependent on alcohol reliably obtain blood alcohol levels in the 100?150 mg% range, which are equivalent to the levels abused by moderate to heavy alcohol abusers. Changes in the reinforcing and incentive effects of the drug have been observed following extended access and induction of dependence and include increased progressive-ratio responding (Koob, 2009a), increased drug-induced reinstatement after extinction, decreased latency to goal time in a runway model for drug reward (Deroche-Gamonet et al, 2004), and increased resistance to punishment in which the animal will sustain higher aversive punishment to obtain drug (Vanderschuren and Everitt, 2004). Whether the enhanced drug-taking with extended access reflects a sensitization of reward (or of incentive motivation) or a reward-deficit state, or both, remains under discussion (Vezina, 2004).

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Date: 2016-06-12; view: 236