Evidence for a modulatory effect of sulbutiamine on glutamatergic and dopaminergic cortical transmissions in the rat brain.

Chronic treatment of rats by sulbutiamine induced no change in density of N-methyl-D-aspartate (NMDA) and (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in the cingular cortex, but a significant decrease of the kainate binding sites, as measured by quantitative autoradiography. In the same treated animals, an increase of D1 dopaminergic (DA) binding sites was measured both in the prefrontal and the cingular cortex, while no modification of the D2 binding sites was detected. Furthermore, an acute sulbutiamine administration induced a decrease of kainate binding sites but no change of the density of D1 and D2 DA receptors. Acute sulbutiamine injection led to a decrease of the DA levels in the prefrontal cortex and 3,4-dihydroxyphenylacetic acid levels in both the cingular and the prefrontal cortex. These observations are discussed in terms of a modulatory effect of sulbutiamine on both dopaminergic and glutamatergic cortical transmissions.

Mediodorsal thalamic evoked responses in the rat prefrontal cortex: influence of the mesocortical DA system.

The prefrontal cortex (PFC) receives a dopaminergic (DA) innervation from the ventral tegmental area (VTA) and is reciprocally connected with the mediodorsal thalamic nucleus (MD). The present study was performed in anaesthetized rats to determine the influence of the mesocortical DA system on excitatory responses evoked in the PFC by stimulation of MD: (1) short latency (< 4 ms) responses resulting from activation of the MD-PFC pathway; (2) long latency responses (> 10 ms) resulting from activation of recurrent collaterals of PFC neurons projecting to MD. Local DA application and VTA stimulation did not affect short latency responses but blocked long latency responses. These results suggest that the mesocortical DA system inhibits excitations by recurrent collaterals of the PFC-MD neurones but not the excitatory MD inputs to the PFC.

Excitatory responses evoked in prefrontal cortex by mediodorsal thalamic nucleus stimulation: influence of anaesthesia.

The prefrontal cortex and the mediodorsal thalamic nucleus are reciprocally connected through excitatory amino acid pathways. Cortical excitatory responses resulting from activation of either the mediodorsal thalamic nucleus-prefrontal cortex pathway (short latency) or the recurrent collaterals of prefrontal cortex-mediodorsal thalamic nucleus neurons (long latency) can be discriminated mainly by their latency. The present study was undertaken to compare the effects of halothane and ketamine anaesthesia on these cortical excitatory responses and to establish their pharmacological characteristics using microiontophoretic application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and D,L-2-amino-5-phosphonovaleric acid (APV), the specific antagonists of D,L-alpha-amino-3-hydroxy-5-methyl-4-isoxalone propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors respectively. The number of prefrontal cortex cells which presented short or long latency excitatory responses was smaller in halothane- than in ketamine-anaesthetized rats. Whatever the anaesthetic used, short latency responses were blocked by CNQX and not affected by APV. Long latency responses were mainly blocked by APV and occasionally by CNQX in halothane-anaesthetized rats, while they were only blocked by CNQX in ketamine-anaesthetized animals. Therefore, halothane seems to preferentially reduce evoked responses mediated by AMPA receptors while ketamine completely abolishes evoked responses involving NMDA receptors. Moreover, the present data confirm that excitatory responses resulting from the activation of the mediodorsal thalamic nucleus-prefrontal cortex pathway are mainly mediated by AMPA receptors. In addition, they demonstrate that cortical responses linked to the activation of recurrent collaterals from prefrontal cortex-mediodorsal thalamic nucleus neurons involve both AMPA and NMDA receptors.

Anatomical and electrophysiological evidence for an excitatory amino acid pathway from the thalamic mediodorsal nucleus to the prefrontal cortex in the rat.

This study was undertaken to identify the neurotransmitter of the projection from the thalamic mediodorsal nucleus (MD) to the prefrontal cortex (PFC) using both retrograde transport of D-[3H]aspartate and electrophysiological approaches in the rat. Unilateral microinjections of D-[3H]aspartate performed into the prelimbic area of the PFC resulted in dense labelling of numerous cells in the ipsilateral MD. Excitatory responses were observed in PFC neurons after electrical stimulation of the MD. However, since cortical neurons project to the MD, these excitatory responses could have resulted either from the activation of the MD-PFC pathway and/or from the activation of recurrent collaterals of antidromically driven cortico-thalamic fibres. The conduction time of each of these two reciprocal pathways was determined by antidromic activation. Short latency excitatory responses resulted from activation of the MD-PFC pathway. They were predominantly observed in PFC neurons located in layer III and evoked at low frequency stimulation (0.3-1 Hz). These excitatory responses disappeared or were replaced by longer latency responses when higher frequency stimulations (3-10 Hz) were used. MD-evoked responses were blocked by the iontophoretic application of the AMPA receptor antagonist CNQX into the PFC. These results indicate that the MD-PFC pathway utilizes glutamate and/or aspartate as the neurotransmitter and that its activation induces excitation in PFC neurons through AMPA receptors. Even though the local application of the NMDA receptor antagonist APV was ineffective, a contribution of these receptors in MD-PFC transmission cannot be excluded.

Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminergic and GABAergic components.

The medial prefrontal cortex of the rat receives dopamine and non-dopaminergic projections from the ventral tegmental area. Both electrical stimulation of the ventral tegmental area and local application of dopamine induce an inhibition of the spontaneous activity of most prefrontal cortical neurons, including efferent neurons. In the present study, the techniques of extracellular recording and microiontophoresis were used in anesthetized rats in order to determine whether these dopamine- and ventral tegmental area-induced inhibitory responses involve GABAergic components. Prefrontal cortex output neurons were identified by antidromic activation from subcortical structures. The inhibitory responses evoked by the local application of dopamine were blocked by the iontophoretic application of the D2 antagonist sulpiride, and the GABAA antagonist bicuculline in 89 and 57% of the cases, respectively. In addition, sulpiride and bicuculline abolished the inhibition induced by ventral tegmental area stimulation in 54 and 51% of the prefrontal cortical cells tested, respectively. The implication of a non-dopaminergic mesocortical system in the ventral tegmental area-induced inhibition was further analysed using rats pre-treated with alpha-methylparatyrosine to deplete dopamine stores. The proportion of prefrontal cortical cells inhibited by ventral tegmental area stimulation was markedly reduced (39%) in alpha-methylparatyrosine-treated rats, when compared to controls (86%). Remaining ventral tegmental area-induced inhibition was no longer affected by sulpiride, but in all cases blocked by the local microiontophoretic application of bicuculline. The present results suggest that: (1) the dopamine-induced inhibition of prefrontal cortex neurons could involve cortical GABAergic interneurones; (2) the non-dopaminergic mesocortical system exerts also an inhibitory influence on prefrontal cortical cells and appears to be GABAergic.

Inhibitory influence of the mesocortical dopaminergic neurons on their target cells: electrophysiological and pharmacological characterization.

Both dopaminergic (DA) and noradrenergic (NA) systems exert an inhibitory influence on the activity of prefrontal cortical neurons (PFC). As NA-containing fibers run close to the dorsal ventral tegmental area (VTA), electrical stimulation of the VTA might coactivate both DA and NA systems. In the present study extracellular recordings and microiontophoresis were used in anesthetized rats to analyze first whether the inhibitory cortical responses to VTA stimulation and DA application were mediated by DA or adrenergic receptors. Inhibitory responses elicited by DA application or VTA stimulation were observed in PFC output neurons identified by antidromic activation from subcortical structures. Both types of inhibitory effects were reversed by the DA antagonist sulpiride, but not by the adrenergic antagonists prazosin (alpha-1), yohimbine (alpha-2) or propranolol (beta). NA and the beta agonist isoproterenol inhibited the activity of PFC cells and these effects were antagonized by propranolol, but neither by prazosin and yohimbine nor by the DA antagonist sulpiride. Thus, the inhibitory influence of the mesocortical DA system in the PFC involves DA, but not NA, recognition sites. The DA receptor subtype mediating the inhibitory effects of VTA stimulation and DA application in the PFC was analyzed further. VTA- and DA-evoked inhibitory responses were antagonized by the D2 selective antagonists (-)-sulpiride, LUR 2366 and RIV 2093, but not by the D1 selective antagonist SCH23390. In addition, the DA-induced inhibitory response was mimicked by the selective D2 agonist LY 171555 but not by the selective D1 agonist SKF 38393. Surprisingly, haloperidol, which is also a potent D2 antagonist, failed to consistently block DA- and VTA-induced inhibitory effects. The present results indicate that the inhibition of PFC cells by mesocortical DA neurons is mediated via a subtype of DA receptors which is particularly sensitive to benzamides.