AMPA glutamate receptor activation in the posterior zona incerta inhibits amphetamine- and apomorphine-induced stereotypy.

Previous work demonstrated that alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonism in the zona incerta (ZI) dorsal to the subthalamic nucleus inhibits stereotypy in rats. The current investigation was undertaken to determine if AMPA receptors in a more caudal portion of the ZI have a role in the expression of stereotyped behavior. Rats were injected bilaterally with AMPA into the posterior ZI dorsal to the substantia nigra, and immediately given a systemic injection of d-amphetamine (10 mg/kg, s.c.) or apomorphine (1 mg/kg s.c.). AMPA produced a dose-dependent inhibition of stereotypy induced by both drugs which was prevented by the coadministration of the AMPA/kainic acid antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX) (0.5 microgram/0.5 microliter). A dose of AMPA as low as 62.5 ng completely abolished the oral component of stereotypy induced by both apomorphine and amphetamine. This dose of AMPA alone had no significant effect on spontaneous locomotor activity but enhanced the locomotor response stimulated by amphetamine (10 mg/kg, s.c.) due to an inhibition of stereotypy. The finding that activation of AMPA receptors in the posterior ZI inhibits stereotypy shows a contrast to results in the neighboring medial ZI dorsal to the subthalamic nucleus, where blockade of AMPA/kainic acid glutamate receptors with DNQX inhibits stereotypy.

AMPA/kainic acid glutamate receptor antagonism in the zona incerta dorsal to the subthalamic nucleus inhibits amphetamine-induced stereotypy bur not locomotor activity.

The effect of 6,7-dinitroquinoxaline-2,3-dione (DNQX), an alpha-amino-3- hydroxy-5-methyl-4-isoxazole-propionate (AMPA)/kainic acid glutamate receptor antagonist, injected into the zona incerta (ZI) was investigated to determine whether the behavioral responses to systemic amphetamine involve AMPA/kainic acid receptors in this brain region. Rats were injected bilaterally in the ZI with either vehicle or DNQX (1 microgram/0.5 microliter) and immediately given a systemic injection of D-amphetamine (0.5, 1.0 or 10.0 mg/kg, s.c.). Locomotor activity was recorded for 1 h. DNQX did not significantly affect hypermotility stimulated with 0.5 and 1.0 mg/kg amphetamine, but markedly increased the level of locomotor activity elicited by the higher dose, 10 mg/kg. To test the hypothesis that the enhanced locomotor response to high dose amphetamine was due to an inhibition of stereotyped behavior, the effect of DNQX in the ZI on amphetamine and apomorphine-induced stereotypy was investigated. DNQX significantly inhibited stereotypy induced by amphetamine (10 mg/kg) and apomorphine (1 mg/kg), with the onset of inhibition of amphetamine-induced stereotypy corresponding to the onset of enhanced locomotor activity. Ibotenic acid lesions of the ZI produced similar results, having an insignificant effect on locomotor activity stimulated by low dose amphetamine (1 mg/kg) and an attenuation of apomorphine-induced stereotypy which was of a magnitude comparable to that produced by DNQX. Thus, the AMPA/kainic acid subtypes of glutamate receptors in the ZI may be involved in the regulation of motor function mediated via striatal output but not mesolimbically generated locomotor activity.

Activation of AMPA/kainic acid glutamate receptors in the zona incerta stimulates locomotor activity.

Direct injections of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), an AMPA/quisqualic acid receptor agonist, into the medial or posterior zona incerta (ZI) produced a marked stimulation of locomotor activity accompanied by a postural change. Similar responses were obtained by injection of kainic acid (KA) into the same areas. The behavioral effects of AMPA and KA were antagonized by coinjection of 6,7-dinitroquinoxaline-2,3-dione (DNQX), and non-N-methyl-D-aspartate (NMDA) glutamate receptor antagonist. In contrast, injections of NMDA or ibotenic acid failed to significantly stimulate locomotor activity. These results suggest that the AMPA/kainate glutamate receptor subtypes in the zona incerta may have a functional role in regulating locomotor activity.

Dexamethasone potentiates NMDA receptor-mediated neuronal injury in the postnatal rat.

The present study investigated the effect of a synthetic glucocorticoid, dexamethasone, on excitatory amino acid receptor-mediated neurotoxicity in the 7-day-old rat. Pretreatment with dexamethasone (0.7 mg/kg i.p.) 1 h prior to unilateral intrastriatal injection of excitotoxin enhanced damage resulting from N-methyl-D-aspartate (NMDA), but not alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), or kainate receptor activation. The glucocorticoid-induced enhancement of NMDA toxicity was dose dependent. The time of dexamethasone administration appeared critical since only treatment 1 h prior to, but not 24 h prior to, simultaneously with, or 1 h after NMDA injection, affected toxicity. The administration of the adrenal mineralocorticoid aldosterone, or the phospholipase A2 inhibitor mepacrine, did not affect excitotoxicity. Quantitative receptor autoradiography was performed to assess the effect of dexamethasone on NMDA-sensitive [3H]glutamate receptor binding. Neither pretreatment in vivo nor the addition of dexamethasone in vitro affected NMDA-sensitive binding in the striatum. Possible explanations for these observations are discussed.