Previous Exposure to VTA Amphetamine Enhances Cocaine Self-Administration under a Progressive Ratio Schedule in an NMDA, AMPA/Kainate, and Metabotropic Glutamate Receptor-Dependent Manner

Self Cite

103

100

The effect of previous exposure to psychostimulants on the subsequent self-administration of cocaine as well as reinstatement of this behavior by priming infusions of AMPA into the nucleus accumbens (NAcc) was examined. Rats were exposed to five injections, one injection every third day, of either saline or amphetamine (AMPH: 1.5 mg/kg, i.p.). Starting 10 days later, they were trained to selfadminister cocaine (0.3 mg/kg/infusion, i.v.) and subsequently tested under a progressive ratio (PR) schedule for 4 consecutive days. As expected, rats exposed to AMPH worked more and obtained more cocaine infusions than saline exposed controls on the PR test sessions. Following daily extinction sessions during which saline was substituted for cocaine, the effect of priming infusions of AMPA (0.0, 0.08, or 0.8 nmol/0.5 ml/side) into the NAcc was then examined on two tests: one conducted 4 days after the last cocaine PR test session (2-3 weeks after the last AMPH exposure injection) and the next 4 weeks later. Consistent with previous reports, NAcc AMPA dosedependently reinstated cocaine seeking on both tests regardless of exposure condition. Importantly, this priming effect of NAcc AMPA was significantly enhanced in AMPH compared to saline exposed rats on the first test conducted 2-3 weeks after AMPH. On the second test, conducted 4 weeks after cocaine, reinstatement was similarly enhanced in both groups to levels observed on the first test in AMPH exposed rats. These results indicate that both noncontingent (AMPH) and contingent (cocaine) exposure to psychostimulants enhances the reinstatement of cocaine seeking by NAcc AMPA and appears to do so in a time-dependent manner.

Section: Cocaine Self-administration Trainingsupporting

confidence: 91%

Section: Cocaine Self-administration Testing Under the Pr Schedule Ofsupporting

confidence: 91%

Previous Exposure to Psychostimulants Enhances the Reinstatement of Cocaine Seeking by Nucleus Accumbens AMPA

Suto

Tanabe

Austin

et al. 2004

Self Cite

103

100

“…The present data showing that the 1 and 7 day deprivation groups show almost identical changes in DA terminal function indicates that these neurochemical effects do not account for the behavioral results. These data, showing a dramatic loss of cocaine effects on DA, are in contrast to accepted theories that equate increased behavioral response to cocaine with increased DA terminal responsiveness (Kalivas and Duffy, 1993;Suto et al, 2003). Previous reports have shown enhanced cocaine-induced DA levels using a variety of other dosing protocols and have associated enhanced DA levels with increased cocaine reinforcement (Vezina, 2004).…”

Section: Discussioncontrasting

confidence: 61%

Reduced Dopamine Terminal Function and Insensitivity to Cocaine Following Cocaine Binge Self-Administration and Deprivation

Mateo

Läck

Morgan

et al. 2005

124

139

Despite large numbers of studies describing neuroadaptations caused by chronic cocaine exposure, there remains considerable uncertainty as to whether alterations in dopamine (DA) neurotransmission are responsible for progression into an addicted state. Highintake, 24-h access cocaine self-administration (SA, 10 days) followed by an extended (7 days), but not 1 day deprivation period produces an increased motivation to SA cocaine as measured by a progressive ratio protocol. Following binge cocaine SA and deprivation, the status of DA terminals in the nucleus accumbens (NAc) was investigated using microdialysis in freely moving rats and voltammetry in brain slices. At 1 and 7 days following binge cocaine SA, baseline extracellular DA concentrations in the NAc core were decreased by 40 and 55% of control levels, in the 1 and 7 day deprivation groups, respectively. Acute cocaine (1.5 mg/kg, i.v.) administration increased extracellular DA (350%) in the NAc core of naïve animals but failed to significantly increase DA at 1 or 7 days following binge cocaine SA. The shell of the NAc showed a similar lack of effect of cocaine. Analysis of DA terminals in brain slices showed that cocaine was markedly less effective in inhibiting DA uptake at 1 and 7 days of cocaine deprivation (max. effect 40% of control). Electrically stimulated DA release was decreased at 1 day and further decreased at 7 days of deprivation (67 and 49% of control, respectively). The rate of DA uptake was increased (150% of control) following binge SA, irrespective of deprivation period. Finally, presynaptic autoreceptors were subsensitive at both time points, as measured by the ability of quinpirole, a D2-like DA receptor agonist, to inhibit DA release. Thus, the NAc was hypodopaminergic and DA terminals were less sensitive to cocaine following binge cocaine SA and deprivation.

“…It has also been demonstrated that rats receiving experimenter-administered stimulants, which produces a sensitized locomotor response, acquire selfadministration faster and/or at lower doses (Horger et al, 1990(Horger et al, , 1992Schenk et al, 1991). Animals treated this way also respond to higher breakpoints when subsequently tested on a PR schedule (Mendrek et al, 1998;Lorrain et al, 2000;Covington and Miczek, 2001;Suto et al, 2002Suto et al, , 2003Vezina et al, 2002). Taken together, there appear to be links between locomotor sensitization and sensitization to the reinforcing effects of cocaine.…”

Section: Discussionmentioning

confidence: 98%

Rapid and Persistent Sensitization to the Reinforcing Effects of Cocaine

Morgan

Liu

Roberts

2005

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 Â 5 days) resulted in sensitization, whereas relatively higher intake (60 or 100 mg/kg/day Â 5 days) suppressed the development of sensitization. In contrast, this higher level of intake (60 mg/kg/day Â 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.