How fast and how often: The pharmacokinetics of drug use are decisive in addiction

Abstract

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.

Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior

“…Although this is the first report of a progressive increase in motivation for cocaine with prolonged IntA experience, Zimmer et al (2012) previously reported that rats with a history of IntA cocaine self-administration had a significantly higher P max than those with LgA experience, despite consuming much less drug (they did not report α values). Collectively, these findings are consistent with the notion that, “an intermittent pattern of use, more than the amount of drug used,” (Allain et al, 2015, p. 175) may be especially important in the development of addiction.…”

“…In addition to dose, the temporal patterns by which drugs reach the brain (pharmacokinetics) can powerfully influence their ability to change brain and behavior (Allain et al , 2015; Robinson and Becker, 1986). We asked, therefore, how prolonged experience with a newly developed intermittent access self-administration procedure (IntA; Zimmer et al, 2012), which produces repeated spikes in brain cocaine concentrations, changes motivation for cocaine, as assessed using behavioral-economic indicators of cocaine demand (Bentzley et al , 2013; Hursh and Silberberg, 2008).…”

“…Another is the effectiveness of different patterns of stimulation to produce LTP (e.g., Larson et al, 1986) or LTD (e.g., Bear and Malenka, 1994), or dopamine-induced synaptic plasticity (e.g., Wieland et al, 2015). Temporal factors are equally important for drug experience-dependent plasticity (Allain et al, 2015 for review). For example, spaced injections are much more effective in producing behavioral and neural sensitization than massed injections, and if blood levels of drug are maintained at elevated levels continuously (as with traditional self-administration procedures), tolerance rather than sensitization may result (Post, 1980; Robinson and Becker, 1986; Vezina, 2004).…”

“…Thus, the greater effectiveness of IntA to increase motivation for drug, relative to either ShA or LgA experience (Zimmer et al , 2012), may be because a ‘spiking’ temporal pattern of consumption is more effective in producing incentive-sensitization and associated neuroadaptations relevant to addiction (Allain et al , 2015). Indeed, it is important to note that IntA and LgA are reported to have opposite effects on dopamine transmission when tests are conducted soon after discontinuing self-administration, the former producing sensitization and the latter tolerance (Calipari et al , 2013, 2014a, 2014b, 2015; c.f., Ferrario et al , 2005).…”

“…Another critical factor concerns the temporal dynamics of drug delivery; i.e., pharmacokinetics (Allain et al , 2015; Hatsukami and Fischman, 1996; Zimmer et al , 2012). In addicts, cocaine use is characterized by intermittency , both between and within bouts of use (Allain et al, 2015 for review). To model this, Zimmer et al (2012) developed an Intermittent Access (IntA) self-administration procedure that produces repeated spikes in brain cocaine concentrations.…”