Behavioral arousal and increased dopamine efflux after blockade of NMDA-receptors in the prefrontal cortex are dependent on activation of glutamatergic neurotransmission

Abstract

Blockade of NMDA/glutamate receptors induces altered behavior in humans and experimental animals. At the same time a differential activation of dopaminergic (DA) systems has been reported. To study the involvement of the medial prefrontal cortex (mPFC) in these effects, we used bilateral perfusions of the rat mPFC with the competitive NMDA-antagonist D-AP-5 and simultaneous determination of spontaneous behavior and local DA efflux.

D-AP-5 concentration-dependently induced arousal and motor activity and also increased DA efflux. These effects were shown to have a similar time-scale but no causal relationship: combined D1/D2 receptor blockade in the mPFC did not inhibit the behavioral activation. As bilateral perfusion of the nucleus accumbens with D-AP-5 resulted in similar behavioral effects, but no change in DA efflux, we conclude that DA is not involved in the behavioral activation induced by these local perfusions.

However, local blockade of non-NMDA glutamate receptors or stimulation of GABA-B receptors completely blocked the effects on behavior and DA efflux, suggesting that the arousal and locomotor activity induced by NMDA receptor blockade in mPFC is primarily dependent on activation of glutamatergic mechanisms. The mPFC appears to be an important site of action for NMDA antagonists to induce behavioral alterations.

Introduction

The non-competitive antagonist of NMDA/glutamate receptors, ketamine, has recently been shown to induce schizophrenia-like symptoms in healthy volunteers and in schizophrenic patients and, consequently, the involvement of NMDA receptors in schizophrenic states has received much attention (Abi-Saab et al., 1998, Jentsch and Roth, 1999). This is in line with experimental research in rodents where central or peripheral administration of NMDA-antagonists has been shown to produce effects that resemble some symptoms of schizophrenia, such as impaired sensorimotor gating, selective cognitive deficits and augmented locomotor responses to stress and stimulants (Review: Jentsch and Roth (1999).

In many studies the ventral striatum or nucleus accumbens (NAC) is considered as a pivotal structure in the actions of NMDA antagonists and in the interactions between glutamatergic and dopaminergic (DA) mechanisms that may determine these effects (Iversen, 1995).

However, the prefrontal cortex (PFC) has been implicated in the schizophreniform actions of NMDA antagonists in humans (Breier et al., 1997, Lahti et al., 1995). Experimental research in rodents also points to the involvement of the PFC and its DAergic innervation in addition to the NAC in the above-mentioned effects of NMDA-antagonists. Bilateral injections of competitive (O’Neill and Liebman, 1987) and noncompetitive (Jentsch et al., 1998) antagonists in the medial PFC (mPFC) induced hyperactivity while lesions of the mPFC, on the other hand, blocked the hyperactivity induced by peripheral administration of the noncompetitive antagonist phencyclidine (PCP) (Jentsch et al., 1998). Both local and peripheral application of NMDA antagonists induced deficits in working memory, measured in tasks that are typically sensitive to disruption of PFC function (Aura and Riekkinen, 1999, Verma and Moghaddam, 1996). The PFC DA system might be involved in these effects as the hyperactivity induced by intra-PFC application was blocked by peripheral DA antagonists (O’Neill et al., 1988), as were the effects of ketamine on working memory in a T-maze (Verma and Moghaddam, 1996). NMDA antagonists also increase DA metabolism (Bowers and Hoffman, 1984, Hata et al., 1990) and in vivo extracellular DA concentrations (Wedzony et al., 1993, Nishijima et al., 1994) selectively in the PFC compared to striatal areas.

However, a dissociation between effects on DA efflux in mPFC and behavioral effects was noted after peripheral administration of PCP (Adams and Moghaddam, 1998) and it was suggested that changes in glutamate transmission in mPFC underlie the effects of ketamine on cortical DA efflux and spatial delayed alternation behavior (Moghaddam et al., 1997).

These data indicate the need for further studies on the relation between blockade of NMDA receptors, DA efflux and behavioral activation. Local administration of NMDA-antagonists in mPFC (and NAC) should be the best way to study this relation directly and is well suited for an integrated approach, i.e. during intra cerebral drug application both behavior and in vivo efflux are studied. Therefore, we used bilateral placement of dialysis cannulae with direct on-line measurements of catecholamine efflux in mPFC and video registration of behavior before, during and after application of the competitive NMDA-antagonist D-AP-5.

Nishikawa et al. (1991) put forward the hypothesis that the stimulating effects of NMDA-receptor blockade on DA efflux might be explained by the removal of a NMDA-receptor dependent inhibition of DA efflux. This inhibitory mechanism might incorporate GABAergic interneurons. We extend this hypothesis, for which supportive data were presented by Yonezawa et al. (1998), to the effects on spontaneous behavior. Thus, we tried to antagonize the effects of the local NMDA-receptor block by coadministration of either a GABA-B agonist, as this has been reported to control DA efflux (Santiago et al., 1993) or of a non-NMDA receptor antagonist, because these also have been shown to inhibit the stimulating effects of NMDA antagonists (Hauber and Andersen, 1993). Then, we combined D-AP-5 perfusion with local DA receptor blockade, to investigate the role of local DA mechanisms in the behavioral effects. We also present more extensive data on the effects of simultaneous competitive stimulation of NMDA receptors which has been reported to block behavioral effects (Contreras, 1990) and effects on DA efflux (Feenstra et al., 1995).

Part of this work has been presented at a meeting of the Britsh Pharmacological Society, (British Journal of Pharmacology, 114: 328P; 1995).