Wei-Xing Shi

Opposite modulation of cortical N-methyl-d-aspartate receptor-mediated responses by low and high concentrations of dopamine

To examine whether dopamine modulates cortical N-methyl-D-aspartate receptor-mediated glutamate transmission, whole-cell recordings were made from identified pyramidal cells located in layers V and VI of the medial prefrontal cortex of the rat using a slice preparation. In the presence of tetrodotoxin and the absence of Mg2+, a brief local application of N-methyl-D-aspartate evoked an inward current which was blocked by the N-methyl-D-aspartate antagonist dizocilpine maleate but not affected by the non-N-methyl-D-aspartate antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(f)quinoxaline, suggesting that the observed current is mediated by N-methyl-D-aspartate receptors located on recorded cells. Bath application of dopamine produced opposite effects on the N-methyl-D-aspartate current depending on the concentrations of dopamine applied. At low concentrations (<50 microM), dopamine enhanced the N-methyl-D-aspartate current, whereas at higher concentrations, dopamine suppressed the current. The same concentrations of dopamine did not significantly affect the inward current induced by the non-N-methyl-D-aspartate agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid. The enhancing effect of dopamine on the N-methyl-D-aspartate response was mimicked by the D1 agonist SKF38393 and blocked by the D1 antagonist SCH31966, whereas the suppressing effect was mimicked by the D2 agonist quinpirole and blocked by the D2 antagonist eticlopride. The above results suggest that dopamine at low concentrations acts preferentially on D1-like receptors to promote N-methyl-D-aspartate receptor-mediated transmission, while at high concentrations dopamine also activates D2-like receptors, leading to a suppression of the N-methyl-D-aspartate function. This differential modulation of N-methyl-D-aspartate function may have significant implications for understanding behaviors and disorders involving both cortical dopamine- and glutamate-mediated neurotransmission.

Functional Coupling between the Prefrontal Cortex and Dopamine Neurons in the Ventral Tegmental Area

Stimulation of the prefrontal cortex (PFC) has been shown to have an excitatory influence on dopamine (DA) neurons. We report here that, under nonstimulated conditions, the activity of DA neurons in the ventral tegmental area (VTA) also covaries, on a subsecond timescale, with the activity of PFC cells. Thus, in 67% of VTA DA neurons recorded in chloral hydrate-anesthetized rats, the firing of the cell displayed a slow oscillation (SO) that was highly coherent with the activity of PFC neurons. The SO was suppressed by transections immediately caudal to the PFC or by intra-PFC infusion of tetrodotoxin, suggesting that it depends on inputs derived from the PFC. Unexpectedly, the SO in most VTA DA neurons was reversed in phase relative to PFC cell activity, suggesting that at least part of PFC information is transferred to DA neurons indirectly through inhibitory relay neurons. These results, together with those reported previously, suggest that the PFC can act through multiple pathways to exert both excitatory and inhibitory influences on DA neurons. The observed functional coupling between DA and PFC neurons further suggests that these pathways not only allow a bidirectional control of DA neurons by the PFC, but also enable action potential-dependent DA release to be coordinated, on a subsecond timescale, with glutamate release from PFC terminals. Further understanding of this coordinated activity may provide important new insights into brain functions and disorders thought to involve both VTA DA and PFC neurons.

Characterization of dopamine-induced depolarization of prefrontal cortical neurons

Dopamine (DA) has been reported to depolarize neurons in the prefrontal cortex (PFC). To further characterize this effect of DA, we made whole cell recordings from PFC pyramidal cells in rat brain slices. As reported previously, DA depolarized most PFC cells tested. This effect of DA was concentration‐dependent and persisted in the presence of synaptic blockade, indicating a direct effect of DA on the recorded cell. During DA‐induced depolarization, PFC neurons consistently showed an increase in excitability, suggesting that the depolarization is not directly related to DA‐induced inhibition of PFC neurons previously observed in vivo. Surprisingly, the effect of DA was not mimicked or blocked by several commonly used DA agonists and DA antagonists. The α and β antagonists phentolamine and alprenolol and the atypical antipsychotic drug clozapine also showed no significant effect on DA‐induced depolarization. These results suggest that DA‐induced depolarization may be mediated by a nonspecific mechanism. However, it remains possible that there exists a new type of DA receptors in the PFC not sensitive to classical DA agonists and antagonists, particularly given the fact that DA applied in the same manner depolarized only PFC neurons but not those in the striatum or the substantia nigra. Synapse 26:415–422, 1997.

Neurotensin modulates autoreceptor mediated dopamine effects on midbrain dopamine cell activity

Interactions of neurotensin (NT) with midbrain dopamine (DA) neurons were studied in rats using microiontophoretic techniques. Local ejection of NT significantly increased (greater than 30%) the firing rate of a few DA cells (12/106). In most cases, however, iontophoretic NT produced no significant change in spontaneous activity. On the other hand, in these same cells, NT significantly attenuated the inhibition induced by either DA or quinpirole, a specific D2 agonist. Inhibition induced by DA was not attenuated by either glutamate or cholecystokinin, although both of them increase the firing rate of DA cells. The effect of NT appears to be selective as NT attenuated DA-induced inhibition without a measurable effect on either GABA-induced inhibition or glutamate-induced excitation of the same DA cells. Combined, these results suggest that NTs effect on DA cell activity is primarily a neuromodulatory one. As both NT and D2 receptors in midbrain DA cell areas are primarily located on DA cells, the above results also suggest that the observed interaction between NT and DA occurred at the DA cell level.

Actions of Neurotensin: A Review of the Electrophysiological Studies

Three effects of NT were observed on midbrain DA cells. The modulatory effect of NT, that is, the attenuation of DA-induced inhibition, has been most extensively examined. Studies indicate that this effect of NT was not simply due to a nonspecific excitation. NT selectively attenuated DA-induced inhibition without affecting either GABA-induced inhibition or glutamate-induced excitation of the same cells, and the attenuation of DA-induced inhibition could be observed at the doses at which the basal activity of DA cells was not changed by NT. The attenuation of DA-induced inhibition by NT is also unlikely to result from the formation of a DA-NT complex, since neuromedin N, which competes with NT for the same receptor but does not bind to DA, mimicked the effects, and neurotensin(1-11), which forms a complex with DA but is inactive in competing for NT receptors, did not. The similarities between the effects of NT and those of 8-bromo-cAMP and forskolin suggest that intracellular cAMP and protein kinase A may be involved. This suggestion was supported by the findings that IBMX (an inhibitor of phosphodiesterases) potentiated the effect of NT; and SQ22536 (an inhibitor of adenylate cyclase) and H8 (an inhibitor of protein kinase A) antagonized it. Phorbal-12,13-dibutyrate (an activator of protein kinase C) did not mimic the effect of neurotensin, and H7 (an inhibitor of protein kinase C) did not reduce the effect, suggesting that protein kinase C is unlikely to be involved in the modulatory effect of neurotensin. Experiments in vitro indicated that the excitatory effect of NT on DA cells occurred at higher concentrations (> 10 nM) than those needed for producing the modulatory effect. Its persistence during DA receptor blockade by sulpiride suggests that this effect was not entirely mediated by an attenuation of the inhibition induced by endogenously released DA. At even higher concentrations (> 100 nM), a sudden cessation of cell activity preceded by an increase in firing rate was observed. Whether this effect of NT was due to depolarization inactivation or a toxic effect of the peptide at high concentrations remains to be determined. In most other areas studied, the excitatory effect of NT was most commonly observed. In many areas, this excitatory effect was apparently a direct postsynaptic effect of NT. However, different mechanisms may be involved (see Table 1). For example, in some areas NT acted through a decrease in membrane conductance, while in others no change or an increase in the membrane conductance was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Endogenous DA-mediated feedback inhibition of DA neurons: Involvement of both D1- and D2-like receptors

To investigate the role of D1‐like receptors in endogenous dopamine (DA)‐mediated feedback control of DA neurons in vivo, single unit recordings were made from rat nigral DA cells using low cerveau isolé preparations. The D2 antagonist raclopride, but not the D1 antagonist SCH23390, increased baseline activity of DA neurons, suggesting that spontaneously released DA acts primarily through D2‐like receptors to inhibit DA cells. However, feedback inhibition induced by an increased DA release by d‐amphetamine (1 mg/kg, i.v.) was partially reversed by SCH23390. The same inhibition, on the other hand, was always completely reversed by raclopride, suggesting that the D1‐mediated portion of the inhibition depends upon co‐activation of D2‐like receptors. In rats with forebrain hemitransections, d‐amphetamine‐induced inhibition was markedly decreased and the remaining inhibition was not blocked by SCH23390, supporting the suggestion that D1‐D2 co‐activation‐induced inhibition is mediated through long feedback pathways. In chloral hydrate‐anesthetized rats, d‐amphetamine‐induced inhibition was also insensitive to SCH23390; however, the degree of the inhibition was not reduced. Combined with previous studies, these data suggest that chloral hydrate not only inactivates the D1 feedback pathway but also enables the D2 feedback pathway to operate independently of D1‐like receptors. Conversely, in parkinsonian animals D1 receptor activation alone has been reported to inhibit DA cells. Taken together, these results suggest that a major portion of endogenous DA‐mediated feedback inhibition is due to concurrent activation of D1‐ and D2‐like receptors. However, this D1–D2 interdependence may alter under certain conditions and may play a role in the pathophysiology of Parkinsons disease. Synapse 35:111–119, 2000.

Enhancement of NMDA-induced current by the putative NR2B selective antagonist ifenprodil.

Ifenprodil has been widely used as an antagonist selective for NMDA receptors containing the NR2B subunit. Evidence suggests, however, that ifenprodil also increases NMDA receptor affinity. Using rat brain slices, we found that ifenprodil enhanced NMDA‐induced current in both cortical and subcortical areas examined. To test whether the effect is due to an increase in NMDA receptor affinity, we compared the effect of ifenprodil on currents induced by different concentrations of NMDA. Consistent with the hypothesis, the enhancing effect (percent increase) was relatively constant at low NMDA concentrations. As NMDA concentration increased, however, the effect decreased. To test whether the effect is blocked when NMDA binding sites are saturated with NMDA, high concentrations of NMDA were applied. To partially block Ca2+ influx and prevent cells from deteriorating, the experiments were performed in the presence of either MK801 or kynurenate, two noncompetitive antagonists. Under such conditions, ifenprodil not only failed to potentiate NMDA currents, but consistently suppressed the current. When the same concentration of NMDA was applied in the presence of the competitive antagonist CGP37849, ifenprodil regained its ability to potentiate NMDA currents. Furthermore, the higher the concentration of CGP37849 the more the NMDA current was potentiated by ifenprodil. These results, combined with previous studies, suggest that the enhancing effect is due to an increase in NMDA receptor affinity and is specific for responses induced by low NMDA concentrations. As NMDA concentration increases, the affinity‐enhancing effect decreases. Consequently, the channel‐suppressing effect becomes more prominent. Synapse 37:56–63, 2000.

Effects of Lesions in the Medial Prefrontal Cortex on the Activity of Midbrain Dopamine Neurons

To determine whether lesions in the prefrontal cortex (PFC) alter the activity of midbrain dopamine (DA) neurons, single unit recordings were made from DA neurons in control and lesioned rats. PFC lesions, obtained by local injection of ibotenic acid into the medial PFC, had no effect on either firing rate or bursting activity of DA neurons in the ventral tegmental area (VTA). However, the number of spontaneously active DA neurons in the VTA was significantly decreased. In the substantia nigra (SN), the same lesions increased the firing rate and had no effect on either the bursting activity of the number of active DA cells. These results suggest that PFC lesions alter the activity of DA neurons. However, VTA and SN DA neurons may respond differently to PFC lesions.

Effects of Scopolamine on Dopamine Neurons in the Substantia Nigra: Role of the Pedunculopontine Tegmental Nucleus

Previous neurochemical and behavioral studies suggest that muscarinic receptor antagonism has an excitatory effect on the nigrostriatal dopamine (DA) system. Using in vivo extracellular single unit recording, this study examined whether blockade of the muscarinic receptor by scopolamine alters the firing properties of DA neurons in the substantia nigra (SN). Scopolamine was administered either systemically or locally to DA neurons using microiontophoresis. Surprisingly, scopolamine did not cause any significant change in either the firing rate or pattern of the spontaneously active DA neurons. However, systemic injection of scopolamine significantly increased the number of active DA neurons in the SN. Local infusion of scopolamine into the pedunculopontine tegmental nucleus (PPT) mimicked the effect induced by systemically administered scopolamine, significantly increasing the number of active DA neurons without altering the firing rate and pattern. These results suggest that the reported increase in striatal DA release induced by scopolamine is in part mediated by activation of silent nigral DA neurons. The experiments with PPT local infusion further suggest that part of the effect of scopolamine may be due to its blockade of the inhibitory muscarinic autoreceptors on PPT cholinergic cells. The latter effect may lead to activation of quiescent DA neurons by increasing acetylcholine (ACh) release in the SN or in other brain areas providing inputs to DA neurons. Further understanding of the mechanism of action of scopolamine may help us further understand the role of ACh in both the pathophysiology and treatment of DA‐related disorders including schizophrenia and Parkinsons disease. Synapse 63:673–680, 2009.

Dynamic modulation of NMDA‐induced responses by ifenprodil in rat prefrontal cortex

Ifenprodil is known to inhibit channel opening of NMDA receptors containing the NR2B subunit. However, it has also been shown to increase NMDA receptor affinity for glutamate‐site agonists, including NMDA. The coexistence of the two opposing effects may explain why ifenprodil can either enhance or suppress an NMDA response depending on the level of NMDA binding and thus the NMDA concentration. Using whole cell recordings in rat prefrontal cortical slices, we report here that the effect of ifenprodil also depends on the speed and the direction of change of NMDA concentration. As shown previously, ifenprodil increased the inward current induced by low concentrations of NMDA applied through a local Y‐tube perfusion system. However, the rising phase of the current was less enhanced compared to the falling phase. Increasing the speed of rising of NMDA concentration further reduced the enhancing effect of ifenprodil. When pressure ejection was used to produce even faster NMDA responses, the entire rising phase including the peak of the response was suppressed by ifenprodil, while the falling phase remained enhanced. These results are consistent with the suggestion that ifenprodil decreases both the association and dissociation rates of NMDA from NMDA receptors, and suggest that ifenprodil affects slow and fast NMDA responses in different manners. In particular, this study suggests that ifenprodil inhibits the rising phase of a fast NMDA response by suppressing both channel opening and the association of NMDA with NMDA receptors and that this inhibition can occur even when the level of NMDA binding is low. Synapse 39:313–318, 2001.