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

• Published in: Psychopharmacology 2012, Vol.219 (2), p.401-410
• Main Authors: Murphy, Emily R., Fernando, Anushka B. P., Urcelay, Gonzalo P., Robinson, Emma S. J., Mar, Adam C., Theobald, David E. H., Dalley, Jeffrey W., Robbins, Trevor W.
• Format: Article
• Language: English
• Subjects: alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - administration & dosage; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid - pharmacology; Animals; Animals, Outbred Strains; Aspartic Acid - administration & dosage; Aspartic Acid - pharmacology; Bicuculline - administration & dosage; Bicuculline - pharmacology; Biomedical and Life Sciences; Biomedicine; Choice Behavior - drug effects; Choice Behavior - physiology; GABA-A Receptor Agonists - pharmacology; GABA-A Receptor Agonists - physiology; Impulsive Behavior - chemically induced; Impulsive Behavior - physiopathology; Lamotrigine; Male; Microinjections; Muscimol - administration & dosage; Muscimol - pharmacology; Neurosciences; Original Investigation; Pharmacology/Toxicology; Piperazines - administration & dosage; Piperazines - antagonists & inhibitors; Piperazines - pharmacology; Prefrontal Cortex - drug effects; Prefrontal Cortex - physiology; Psychiatry; Rats; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - physiology; Serial Learning - drug effects; Serial Learning - physiology; Triazines - pharmacology
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-011-2572-1

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 - thre o-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.