How much, how often and how fast a drug reaches the brain determine the behavioural and neuroplastic changes associated with the addiction process. Despite the critical nature of these variables, the drug addiction field often ignores pharmacokinetic issues, which we argue can lead to false conclusions. First, we review the clinical data demonstrating the importance of the speed of drug onset and of intermittent patterns of drug intake in psychostimulant drug addiction. This is followed by a review of the preclinical literature demonstrating that pharmacokinetic variables play a decisive role in determining behavioural and neurobiological outcomes in animal models of addiction. This literature includes recent data highlighting the importance of intermittent, 'spiking' brain levels of drug in producing an increase in the motivation to take drug over time. Rapid drug onset and intermittent drug exposure both appear to push the addiction process forward most effectively. This has significant implications for refining animal models of addiction and for better understanding the neuroadaptations that are critical for the disorder.
Taking large and escalating quantities of cocaine does not appear necessary to increase incentive motivation for the drug. Taking cocaine in an intermittent pattern-even in small amounts-is more effective in producing this addiction-relevant change. Thus, beyond the amount of drug taken, the temporal kinetics of drug use predict change in drug use over time.
Studies in humans suggest that women progress more rapidly from initial cocaine use to addiction. Similarly, female rats can show more incentive motivation for cocaine than male rats do. Most preclinical studies on this issue have used self‐administration procedures that provide continuous cocaine access during each session (“long‐access” or LgA and “short‐access”). However, intermittent access (IntA) cocaine self‐administration better models the intermittency of human cocaine use. Here, we compared cocaine use in female and male rats that received ten, daily 6‐hour LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. Only IntA rats (both sexes) developed locomotor sensitization to self‐administered cocaine, and sensitization was greatest in females. Five and 25 days after the last self‐administration session, we quantified responding for cocaine (0.083‐0.75 mg/kg/infusion) under a progressive ratio (PR) schedule, a measure of motivation for drug. Across conditions, females earned more cocaine infusions than males under the PR schedule. Across sexes, IntA rats earned more infusions than LgA rats, even though IntA rats had previously taken much less cocaine. Cumulative cocaine intake significantly predicted responding for cocaine under the PR schedule in male LgA rats only. In IntA rats, the extent of locomotor sensitization significantly predicted responding under the PR schedule. Thus, LgA might be appropriate to study sex differences in cocaine intake, whereas IntA might be best suited to study sex differences in sensitization‐related neuroadaptations involved in cocaine addiction. This has implications for modelling distinct features of cocaine addiction in preclinical studies.
A key question in addiction research concerns how, in some individuals, initial recreational or casual patterns of drug use may change brain and psychological function in ways that promote a transition to the problematic patterns of use that define substance use disorders (addiction). In preclinical studies this is modeled using self-administration procedures. However, most cocaine self-administration procedures produce continuously high brain concentrations of drug, whereas in people bouts of use are thought to be more intermittent. Here we ask whether such temporal pharmacokinetic factors matter, by comparing and contrasting the neuropsychological consequences of intermittent vs. long access cocaine self-administration experience. It turns out the temporal pattern of cocaine use has profound effects on a number of outcomes. First, despite much less total drug consumption, intermittent access to cocaine is more effective in producing addiction-like behavior. Second, intermittent and long access cocaine self-administration change the brain in very different ways to influence motivated behavior. We argue that intermittent access self-administration procedures might be better suited than traditional self-administration procedures for isolating drug-induced changes in neuropsychological function that contribute to the transition to cocaine addiction.
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