Impulsive behaviour induced by both NMDA receptor antagonism and GABAA receptor activation in rat ventromedial prefrontal cortex

Abstract

Rationale: Previous work has demonstrated a profound effect of N-methyl-D: -aspartic acid receptor (NMDAR) antagonism in the infralimbic cortex (IL) to selectively elevate impulsive responding in a rodent reaction time paradigm. However, the mechanism underlying this effect is unclear.

Objectives: This series of experiments investigated the pharmacological basis of this effect in terms of excitatory and inhibitory neurotransmission. We tested several pharmacological mechanisms that might produce the effect of NMDAR antagonism via disruption or dampening of IL output.

Methods: Drugs known to affect brain GABA or glutamate function were tested in rats pre-trained on a five-choice serial reaction time task (5-CSRTT) following either their systemic administration or direct administration into the IL.

Results: Systemic lamotrigine administration (15 mg/kg), which attenuates excess glutamate release, did not counteract the ability of the intra-IL NMDAR antagonist 3-((R)-2-carboxypiperazin-4-yl)-propyl-L: -phosphonic acid ((R)-CPP) to increase premature responding on the 5-CSRTT. Putative elevation of local extracellular glutamate via intra-IL infusions of the selective glutamate reuptake inhibitor DL: -threo-β-benzyloxyaspartate as well as local α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonism also had no effect on this task. However, intra-IL infusions of the GABA(A) receptor agonist muscimol produced qualitatively but not quantitatively comparable increases in impulsive responding to those elicited by (R)-CPP. Moreover, the GABA(A) receptor antagonist bicuculline blocked the increase in impulsivity produced by (R)-CPP when infused in the IL.

Conclusions: These findings implicate glutamatergic and GABAergic mechanisms in the IL in the expression of impulsivity and suggest that excessive glutamate release may not underlie increased impulsivity induced by local NMDA receptor antagonism.

Figures

Fig. 1

Composite diagram illustrating the placement of injector tips in PL cortex (light grey) and IL cortex (dark grey) across all experiments. Adapted from Paxinos and Watson (from Bregma: top +3.7 mm; middle +3.2 mm; bottom +2.7 mm)

Fig. 2

Percentage of premature responding in the 5-CSRTT following the infusion of 50 ng/side (R)-CPP into IL cortex in rats pretreated with either 15 mg/kg LTG or vehicle (n = 6). (Asterisk) indicates main effect of drug 2 (veh+veh, LTG+veh vs. veh+(R)-CPP, LTG+(R)-CPP)

Fig. 3

Proportion of premature responses (arcsine transformation) following either the administration of PBS or muscimol into the PL (n = 6) or IL (n = 7). Asterisk indicates p < 0.05 compared to the PBS control condition. Mean raw scores (SEM) of percentage premature responding. PL, percentage premature responding: mean = 3.7% (0.07); muscimol, percentage premature responding: mean = 8.8% (3.4). IL, percentage premature responding: mean = 8.4% (2.1); muscimol, percentage premature responding: mean = 33.9% (7.3)

Fig. 4

Percentage of premature responding in the 5-CSRTT following the infusion of 50 ng/side (R)-CPP into IL cortex in rats pretreated with either 50 ng/side bicuculline or vehicle (n = 6). Asterisk indicates main effect of drug 1 (veh+veh, veh+(R)-CPP vs. BIC+veh, BIC+(R)-CPP) and number sign indicates main effect of drug 2 (veh+veh, BIC+veh vs. veh+(R)-CPP, BIC+(R)-CPP). Plus sign indicates significance with respect to veh+veh