Effects of cocaine self-administration history under limited and extended access conditions on in vivo striatal dopamine neurochemistry and acoustic startle in rhesus monkeys

Abstract

Rationale: The transition from infrequent and controlled cocaine use to dependence may involve enduring changes in neurobiology as a consequence of persistent drug use.

Objective: The present study utilized an intravenous drug self-administration protocol of increasing cocaine access to evaluate potential changes in dopamine function in vivo, including changes in sensitivity to psychostimulants.

Materials and methods: Drug-naïve rhesus monkeys were provided limited access (1 h) to cocaine self-administration for 60 days followed by 60 days under an extended access condition (4 h). Basal levels of striatal extracellular dopamine and its metabolites, as well as the effectiveness of cocaine and amphetamine to elevate dopamine, were determined with in vivo microdialysis before the initiation of cocaine self-administration and during limited and extended access. The effect of cocaine and amphetamine on the acoustic startle response was also examined to assess complementary behavioral changes as a function of drug history.

Results: Extended access to cocaine self-administration lead to increased daily intake compared to limited access conditions but did not result in escalated intake over time. However, cocaine- and amphetamine-induced increases in striatal dopamine were diminished as a function of cocaine self-administration history. Surprisingly, there was no effect of drug-taking history on sensitivity to psychostimulant-induced enhancement of startle amplitude.

Conclusions: The present experiments provide evidence of a hypofunctional dopamine system that is not associated with an escalation in drug intake or reflected in measures of acoustic startle.

Fig. 1

Study timeline for each drug access condition including each set of microdialysis and acoustic startle experiments (see the “Materials and methods” section for detailed explanation)

Fig. 2

Average number of cocaine infusions (mean±SEM) earned each week of limited (open squares) and extended access (filled squares) conditions. Also shown is the average number of infusions earned during hour 1 of extended access (filled circles). Inset average number of cocaine infusions (mean±SEM) earned during hour 1 over the first 12 sessions of extended access

Fig. 3

Effects of cocaine (a) and amphetamine (b) on extracellular levels of dopamine before drug self-administration (drug-naïve) and following 10 weeks of limited and extended access (n=3). Dopamine levels are expressed as the mean (±SEM) percentage of baseline levels during 10-min sampling intervals beginning 1 h after probe implantation. Dashed vertical line at time point 0-min represents administration of drug after collection of six baseline samples. The peak percent increase in dopamine in response to both doses of cocaine and amphetamine is indicated for each drug access condition. The asterisk indicates significant difference from the drug-naïve state at time point 20-min

Fig. 4

Effects of cocaine (a) and amphetamine (b) on average startle amplitude for drug-naïve animals (n=6). Drug-naïve subjects were given either saline or drug immediately prior to the start of an experimental session. Graphs depict mean startle amplitude for increasing drug doses as a function of acoustic stimulus intensities (in decibels). Data are collapsed across repeated blocks of stimulus presentation. The asterisk indicates significant difference from saline at each stimulus intensity

Fig. 5

Average startle amplitude as a function of cocaine self-administration history (n=6). For each set of acoustic startle experiments (drug-naïve, limited access, and extended access), subjects were given either saline or drug immediately prior to the start of an experimental session. Graphs depict mean startle amplitude as a function of acoustic stimulus intensities (in decibels) at the midrange dose tested for cocaine (1.0 mg/kg) and amphetamine (0.3 mg/kg) for each set of startle experiments. Data are collapsed across repeated blocks of stimulus presentation. Open circles represent saline in both graphs