Modafinil reverses phencyclidine-induced deficits in cognitive flexibility, cerebral metabolism, and functional brain connectivity

Abstract

Objective: In the present study, we employ mathematical modeling (partial least squares regression, PLSR) to elucidate the functional connectivity signatures of discrete brain regions in order to identify the functional networks subserving PCP-induced disruption of distinct cognitive functions and their restoration by the procognitive drug modafinil.

Methods: We examine the functional connectivity signatures of discrete brain regions that show overt alterations in metabolism, as measured by semiquantitative 2-deoxyglucose autoradiography, in an animal model (subchronic phencyclidine [PCP] treatment), which shows cognitive inflexibility with relevance to the cognitive deficits seen in schizophrenia.

Results: We identify the specific components of functional connectivity that contribute to the rescue of this cognitive inflexibility and to the restoration of overt cerebral metabolism by modafinil. We demonstrate that modafinil reversed both the PCP-induced deficit in the ability to switch attentional set and the PCP-induced hypometabolism in the prefrontal (anterior prelimbic) and retrosplenial cortices. Furthermore, modafinil selectively enhanced metabolism in the medial prelimbic cortex. The functional connectivity signatures of these regions identified a unifying functional subsystem underlying the influence of modafinil on cerebral metabolism and cognitive flexibility that included the nucleus accumbens core and locus coeruleus. In addition, these functional connectivity signatures identified coupling events specific to each brain region, which relate to known anatomical connectivity.

Conclusions: These data support clinical evidence that modafinil may alleviate cognitive deficits in schizophrenia and also demonstrate the benefit of applying PLSR modeling to characterize functional brain networks in translational models relevant to central nervous system dysfunction.

Fig. 1.

Modafinil Reverses the Impaired Ability of Phencyclidine (PCP)-Experienced Animals to Switch Attentional Set. Data were analyzed using Mann-Whitney U test with Bonferroni post hoc correction for multiple comparisons. ⁺ Denotes P < .05 significant difference from control (Vehicle.Vehicle) animals and * denotes P < .05 significant difference from PCP-experienced animals who receive acute vehicle (PCP.Vehicle).

Fig. 2.

(A) Phencyclidine (PCP)-Experienced Animals Display a Reversal Deficit That Specifically Manifests at the Third Reversal (Rev3) That Is Not Reversed by Acute Modafinil Treatment. †Denotes significant difference from control (Vehicle.Vehicle) animals at the same discrimination stage (t test with Bonferroni post hoc correction). Data for errors, punishments, perseverative responding, and regressive errors were square root (sqrt) transformed to give the data a normal distribution (B) PCP-experienced animals commit a significantly higher level of regressive errors, as evidenced by a higher proportion of dropout across all trial levels following punishment-induced reorientation of digging behavior (main pretreatment effect, 2-way repeated measures ANOVA, F_(1,34) = 4.188, P = .049). (C) PCP-treated animals commit more errors in Rev3 (1-way ANOVA; PCP main effect F_(2,41) = 3.275, P = .048). *Denotes significant (P < .05) difference from control (Vehicle.Vehicle) animals (post hoc Tukeys test, P < .05, q = 3.537). Despite a trend toward a higher number of errors in PCP.Modafinil–treated animals in comparison to control animals, these failed to reach significance (P > .05, q = 2.143). (D) PCP-treated animals do not experience significantly more punishments in Rev3 (1-way ANOVA F_(2,41) = 1.597, P = .2148). (E) PCP pretreatment did not significantly alter the likelihood of perseverative responding in Rev3. Animals in all groups perform below the 50% chance level (sqrt 0.5 = 0.7) of remaining with the incorrect bowl following punishment, suggesting that animals are less likely than chance to remain with the incorrect bowl following punishment.

Fig. 3.

Representative Alterations in Cerebral Metabolism Produced by Subchronic Phencyclidine (PCP) and Acute Modafinil Treatment. Modafinil reverses PCP-induced deficits in overt cerebral metabolism in the anterior prelimbic and retrosplenial cortices and enhances metabolism in the medial prelimbic cortex (layer 1). PCP-induced deficits in metabolism in the orbital (dorsolateral and lateral) cortex and dorsal reticular thalamus were not reversed by modafinil. * Denotes P < .05 and ** denotes P < .01 significant difference from control (Vehicle.Vehicle). ⁺ Denotes P < .05 and ⁺⁺ denotes P < .01 significant difference from PCP.Vehicle animals (1-way ANOVA with Newman-Keuls post hoc test).

Fig. 4.

Table Summarizing Functional Connectivity Alterations of the (A) Anterior Prelimbic, (B) Retrosplenial, and (C) Medial Prelimbic (Layer 1) Cortices Following Subchronic Phencyclidine (PCP) Treatment and the Acute Treatment of PCP-Experienced Animals With Modafinil. Data shown as significant alterations in the variable importance to the projection statistic generated by partial least squares regression analysis. Significance between experimental groups was set at P < .05 and determined using 1-way ANOVA with Newman-Keuls post hoc test. Gray shading denotes a significant PCP-induced alteration in functional connectivity, which is not corrected by acute modafinil treatment. Light orange denotes a PCP-induced alteration in functional connectivity, which is corrected to control (Vehicle.Vehicle) levels by modafinil treatment. Dark orange shading denotes a PCP-induced alteration in functional connectivity, which is corrected by and then is further enhanced to a level beyond that seen in control (Vehicle.Vehicle) animals by acute modafinil. Green denotes a significant effect of modafinil in a brain region where subchronic PCP experience does not significantly alter connectivity. Red denotes a region in which the effect of modafinil is additive to that of subchronic PCP treatment. Detailed significant alterations between the different experimental groups are shown in table S6 in supplementary material.