Acute cocaine induced deficits in cognitive performance in rhesus macaque monkeys treated with baclofen

Abstract

Rationale: Acute and/or chronic exposure to cocaine can affect cognitive performance, which may influence rate of recovery during treatment.

Objective: Effects of the GABA-B receptor agonist baclofen were assessed for potency to reverse the negative influence of acute, pre-session, intravenous (IV) injection of cocaine on cognitive performance in Macaca mulatta nonhuman primates.

Methods: Animals were trained to perform a modified delayed match to sample (DMS) task incorporating two types of trials with varying degrees of cognitive load that had different decision requirements in order to correctly utilize information retained over the delay interval. The effects of cocaine (0.2, 0.4, and 0.6 mg/kg, IV) alone and in combination with baclofen (0.29 and 0.40 mg/kg, IV) were examined with respect to sustained performance levels. Brain metabolic activity during performance of the task was assessed using PET imaged uptake of [(18) F]-fluorodeoxyglucose.

Results: Acute cocaine injections produced a dose-dependent decline in DMS performance selective for trials of high cognitive load. The GABA-receptor agonist baclofen, co-administered with cocaine, reversed task performance back to nondrug (saline IV) control levels. Simultaneous assessment of PET-imaged brain metabolic activity in prefrontal cortex (PFC) showed alterations by cocaine compared to PFC metabolic activation in nondrug (saline, IV) control DMS sessions, but like performance, PFC activation was returned to control levels by baclofen (0.40 mg/kg, IV) injected with cocaine.

Conclusions: The results show that baclofen, administered at a relatively high dose, reversed the cognitive deficits produced by acute cocaine intoxication that may have implications for use in chronic drug exposure.

Fig. 1

DMS task and cognitive performance. a Behavioral paradigm of DMS task. Object trial and spatial trial reward contingencies signaled by circle and square, respectively. Object trial: correct match phase response was to select the same image presented in sample phase irrespective of where it occurred on the screen which was also occupied by other ‘distracter’ images. Spatial trial: correct match response required selection of the image that occupied the same spatial position on the screen where the sample image was presented. Trials within a single session (n=100) consisted of delay intervals of 1–60 s combined randomly with two to seven images in the match phase. b DMS task performance as a function of increased cognitive demand (number of images in match phase of DMS task) for object and spatial type trials shown in (a). Performance on spatial trials was significantly worse than object trials for all trials with >3 images to choose from in the match phase. Asterisks: object vs. spatial trials *F_(1,486) =7.96, p<0.01, **F_(1,486)=11.04, p<0.001

Fig. 2

Effects of cocaine administration on object vs. spatial trials. Differential performance on object and spatial trials as a function of number of images in the match phase of the task was dose-dependently decreased by increased doses (0.2, 0.4, and 0.6 mg/kg, IV) of cocaine administered 10 min prior to start of session. Effects were more pronounced on object (upper) vs. spatial (lower) trials. *F_(1,486)=7.15, p<0.01; **F_(1,486)=12.44, p<0.001, cocaine vs. saline sessions

Fig. 3

Reversal by baclofen, of effects of cocaine on DMS performance. a Object trials: comparison of performance on cocaine only (0.6 mg/kg, IV), baclofen only (0.40 mg/kg, IV), and cocaine + baclofen in the same doses, with vehicle (saline) administration on object trials. Baclofen (0.29 mg/kg, 0.40 mg/kg, IV) injected 20 min prior to cocaine (0.6 mg/kg, IV) administration at 10 min before start of session. *F_(1,486)=7.09, p<0.01; **F_(1,486)=13.75, **p<0.001, vs. cocaine 0.6 mg/kg. b Spatial trials: effects of the same doses of cocaine and baclofen alone and baclofen + cocaine on performance on spatial trials. The higher dose of baclofen (0.40 mg/kg, IV) was significantly different from the lower dose (0.29 mg/kg, IV) in reversing the effects of cocaine, especially when more images were presented on spatial trials. *F_(1,486)=7.26, p<0.01, **F_(1,486)=11.79, p<0.001, compared to cocaine 0.6 mg/kg. ^##F_(1,486)=12.31, p<0.001 compared to saline

Fig. 4

Average [¹⁸F]-FDG PET difference images from NHPs (n=6 animals) performing DMS task show changes in brain activation (LCMR) following treatment with drugs vs. vehicle (saline) sessions. a Difference maps show cocaine injection (0.6 mg/kg, IV) increased activation of prefrontal (left) and medial parietal cortex (right) during DMS performance. Regions in red show increased metabolic activity. Effects are plotted on representative MRIs of the same brain areas. b Difference maps for sessions in which baclofen (0.40 mg/kg, IV) was administered prior to cocaine (0.6 mg/kg, IV) injection (Fig. 3) relative to images from sessions with cocaine alone in (a). Areas shown activated by cocaine alone in (a) were not differentially increased in baclofen + cocaine sessions. Areas of increased activation relative to cocaine alone sessions are shown in red and include the dorsal striatum (left) and posterior hippocampus (right). c Difference map shows effect of baclofen (0.4 mg/kg, IV) administered alone prior to saline delivery at the time of cocaine administration in other sessions (a, b). Increased activation of prefrontal cortex, similar to cocaine alone (a), is shown relative to normal saline vehicle alone sessions. Probability thresholds set to p<0.05 at the voxel level and corrected at the cluster level (p<0.001, corrected)