Performance of the DMS task showed differential performance levels within sessions across all variables including duration of delay, number of images, as well in relation to the type of match phase selection rule (object or spatial position) present on each trial. Therefore the task included a combination of short-term memory (retention of the sample phase information) and cognitive decision making (selection of the appropriate target in the match phase) present on each trial which provoked a wide range of performance related directly to the above three factors that influenced cognitive demand and involvement of appropriately related brain structures (Hampson et al. 2004
). Results across all animals (n
=6) were consistent in showing differential performance levels on object vs. spatial trials in terms of different levels of cognitive demand defined by the number of images (# images) in the match phase of the DMS task. The overall ANOVA was significant (F(131,486)
= 30.83, p
<0.001), as were the main effects of trial type (F(1,486)
<0.001), cocaine dose (F(3,486)
< 0.001), baclofen dose (F(2,486)
<0.001), and number of images (F(5, 486)
<0.001). All interactions were significant to at least the p
<0.05 level except for four-way “trial type × baclofen dose × # images” (p
=0.09), therefore comparisons reported below were justified on the basis of the interaction terms in the ANOVA model. Pairwise comparison utilized linear contrasts constructed within the overall ANOVA to compare specific effects.
The type of trial signified by the start signal () effectively controlled overall performance levels and it is clear from that spatial trials were more difficult than object trials. Performance on object trials was significantly higher than on spatial trials for all trials with more than three images in the match phase, as revealed by a significant interaction between trial type vs. number of images (F(5,486)=46.52, p<0.001). This same distinction was apparent when the task was performed following acute administration of cocaine () in which there was a dose-dependent (0.20, 0.40, and 0.60 mg/kg) decrease in performance on both object and spatial trials but with a greater decrement in performance of spatial trials. These dose-dependent influences were significant as indicated by the fact that and the effects of cocaine for 0.4 and 0.6 mg/kg increased as a function of task demand () revealed by a significant interaction between cocaine dose level and number of images (F(15,486)=9.45, p<0.001). Finally, the same dose of cocaine was more influential on spatial vs. object trials as evidenced by the significant interaction between trial type and cocaine dose (F(3,486)=15.35, p<0.001), specifically indi cated in by the differences in performance on spatial vs. object trials with five to seven images (linear contrast: F(1,486)= 16.39, p<0.001). These dose-dependent alterations in cognitive performance produced by cocaine administration formed the basis for testing baclofen to see if it could reverse the effects if administered 20 min prior to the time in which cocaine was delivered prior to the start of the session.
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 (more ...)
shows results for cocaine only (0.6 mg/kg), cocaine + baclofen (0.29 mg/kg and 0.40 mg/kg), and baclofen + vehicle (saline) for both object () and spatial trials (). As previously demonstrated (), cocaine alone (0.60 mg/kg) at this dose influenced performance in a task-dependent manner with more of a difference in performance between spatial vs. object trials in cocaine alone vs. saline sessions (linear contrast: difference of cocaine 0.60 mg/kg vs. saline on object vs. spatial trials, F(1,486)=21.85, p<0.001). Doses of pre-administered baclofen (0.29 and 0.40 mg/kg) were assessed for their ability to reverse the effects of this dose (0.60 mg/kg) of cocaine. In sessions with baclofen (0.40 mg/kg) + cocaine (0.60 mg/kg), baclofen reversed deficits in performance produced by cocaine (0.60 mg/kg) alone as revealed by a significant difference in cocaine vs. baclofen + cocaine (F(1,486)=19.48, p<0.001, overall linear contrast) performance summed over both trial types (object vs. spatial). Improvement of cocaine impaired performance by pre-injection of baclofen (0.4 mg/kg) on object trials () was significantly greater if the trials were more difficult in terms of number (five to seven) of images (linear contrast; cocaine + baclofen (0.40 mg/kg) vs. cocaine alone F(1,486)= 7.28, p<0.01). Performance on the same (five to seven images) trials in the more difficult spatial version of the DMS task () was even more improved by the higher dose (0.40 mg/kg) of baclofen (linear contrast; cocaine alone 0.60 mg/kg vs. cocaine + baclofen (0.40 mg/kg) F(1,486)= 13.22, p<0.001). The dose dependence of baclofen reversal of cocaine effects was demonstrated by the fact that cocaine reduced performance on trials with higher cognitive load (four to seven images) were not significantly improved by the low dose (0.29 mg/kg) of baclofen (linear contrast, average over four to seven images; cocaine alone vs. baclofen 0.29 + cocaine, F(1,486)=3.62, NS), but the higher dose of baclofen (0.40 mg/kg) significantly reduced cocaine effects on performance on all trials with more than three images (linear contrast average over four to seven images—cocaine alone vs. baclofen 0.40 + cocaine 0.60, F(1,486)=15.83, p<0.001) as shown in . The high dose of baclofen (0.40 mg/kg) was also more effective in reducing the effects of cocaine on spatial vs. object trials when assessed across all trial types (interaction: trial type × cocaine vs. saline × cocaine + baclofen 0.29 and 0.4 mg/kg; F(5,486)=8.24, p<0.001) in . Interestingly, on the most difficult spatial DMS trials in which seven images appeared in the match phase of the task (), baclofen administered alone with saline significantly improved performance above all other conditions including saline controls (; baclofen, 0.40 mg/kg + saline, ##F(1,486)=12.31, p<0.001).
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 (more ...)
F]-FDG PET imaging was utilized to investigate differences in local cerebral metabolic rate in brain areas known to be engaged during the DMS task (Porrino et al. 2005
; Deadwyler et al. 2007
). The difference maps in (n
=6 animals) show regions in red that indicate increases in LCMR following whole brain analyses with probability thresholds set to p
<0.01 at the voxel-level and corrected at the cluster level (p
<.001, corrected). In agreement with other reports the effect of the acute cocaine injection (0.6 mg/kg) was to increase activation during DMS performance in the dorsolateral prefrontal ( left image) and medial parietal cortical ( right image) areas relative to activity during sessions with saline injection (Porrino et al. 2001
; Hoshi and Tanji 2004
; Fogassi et al. 2005
; Volkow et al. 2005
; Bradberry 2007
; Hampson et al. 2011
; Parvaz et al. 2011
). shows difference maps of brain areas activated in the same animals during cocaine (0.6 mg/kg) DMS sessions preceded by treatment with baclofen (0.4 mg/kg). Unlike sessions with cocaine alone, neither were differentially activated during the task but there was increased activation of dorsal striatum (left) and posterior temporal lobe (right), when the same animals were pretreated with baclofen (). The lack of differential activation in prefrontal and parietal cortices indicates that the effect of pretreatment with baclofen prior to cocaine sessions was similar to the effect of cocaine alone. However, the basis for this lack of differential activation by cocaine + baclofen was revealed in sessions in which scans were taken from the same animals treated with baclofen (0.4 mg/kg) alone (shown in ) and compared to saline sessions. The difference brain map in shows that baclofen alone was capable of increasing activity in prefrontal cortex during the task in the same regions affected by pre-injection of cocaine alone (). Therefore, this similar activation pattern from both drugs alone (baclofen or cocaine) in prefrontal cortex () was the basis for the lack of registration of differential activation in when both drugs were administered together in the same session.
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 (more ...)