Rapid and Persistent Sensitization to the Reinforcing Effects of Cocaine

Abstract

The development of drug addiction involves a transition from recreational use to compulsive drug seeking and taking, and this progression can occur rapidly with cocaine use. These data highlight the importance of early drug exposure and the development of drug dependence; however, little experimental attention has been paid to this phenomenon in animal models of drug abuse. The present experiments demonstrate a progressive and rapid sensitization to the reinforcing strength of cocaine assessed using a progressive ratio (PR) schedule in rats. The first experiment found that rats show increased breakpoints over a 2-week period following acquisition. Subsequent experiments examined the role of total cocaine intake during the initial exposure period and found that low intakes (20 mg/ kg/day  5 days) resulted in sensitization, whereas relatively higher intake (60 or 100 mg/kg/day  5 days) suppressed the development of sensitization. In contrast, this higher level of intake (60 mg/kg/day  5 days) only transiently suppressed the expression of sensitization. Examination of breakpoints maintained by various doses of cocaine revealed an upward and leftward displacement of the cocaine doseeffect curve, relative to nonsensitized animals. These studies describe a form of sensitization that occurs rapidly to the reinforcing effects of cocaine, and provide a model to study the potential impact of initial experience on the development of drug dependence.

Persistent Alterations in Mesolimbic Gene Expression with Abstinence from Cocaine Self-Administration

“…A 1-day abstinence period was used to provide consistency with our previous reports (Mateo et al, 2005;McCracken et al, 2005;Morgan et al, 2006). No differences in daily intake (Figure 3a) or total intake were observed between groups (Figure 3b).…”

Parsing the addiction phenomenon: Self-administration procedures modeling enhanced motivation for drug and escalation of drug intake

“…Morgan et al [14] showed that final ratios generally increase as long as the quantity animals are permitted to self-administer during training is restricted. Figure 5 shows the expected escalation of final ratios with only a single day of training (filled circles).…”

“…Morgan and colleagues [14] showed that final ratios were more likely to increase at higher unit doses, with 1.5 mg/kg/inj being optimal. Note that the 1.5 mg/kg/inj cocaine dose occurs at the top of the PR dose effect curve, as illustrated in figure 2, [15,16,14] and is selected over lower doses (0.75 mg/kg/inj) in choice experiments [15]. Thus the dose which is most likely to push the addiction process forward is also the most reinforcing dose and the one animals are most drawn toward if given a choice.…”

“…The upper curve represents animals that were tested for 2 weeks using conditions that produced an escalation of final ratios; that is, they were given access to cocaine on a PR schedule reinforced with a high unit dose of cocaine (1.5 mg/kg/inj) delivered relatively rapidly (~5 sec). When other doses were subsequently tested, it was apparent that the escalating effects carried over to other doses causing an upward and leftward shift in the dose response curve [14].An upward and leftward shift in a dose-response curve is referred to as 'reverse tolerance' or 'sensitization'. Note that the term sensitization describes a change in a very specific drug response and is not a conclusion regarding a more global modification.…”

“…Liu et al [55] found that higher final ratios are not necessarily observed in LgA animals. Additionally, under certain conditions, escalating the rate of cocaine intake can suppress the development of final ratio escalation that occurs during PR training [14]. Therefore, it remains unclear whether LgA and PR training produce parallel escalations in both drug intake and the effort an animal is willing to expend to obtain cocaine.…”