The islet circadian clock: entrainment mechanisms, function and role in glucose homeostasis.

Circadian regulation of glucose homeostasis and insulin secretion has long been appreciated as an important feature of metabolic control in humans. Circadian disruption is becoming increasingly prevalent in today's society and is likely responsible in part for the considerable rise in type 2 diabetes (T2DM) and metabolic syndrome worldwide. Thus, understanding molecular mechanisms driving the inter-relationship between circadian disruption and T2DM is important in context of disease prevention and therapeutics. In this regard, the goal of this article is to highlight the role of the circadian system, and islet circadian clocks in particular, as potential regulators of ß-cell function and survival. To date, studies have shown that islet clocks respond to changes in feeding patterns, and regulate a multitude of critical cellular processes in insulin secreting ß-cells (e.g. insulin exocytosis, mitochondrial function and response to oxidative stress). Subsequently, either genetic or environmental disruption of normal islet clock performance compromises ß-cell function and leads to loss of glycaemic control. Future work is warranted to further unravel the role of circadian clocks in human islet function in health and contributions to pathogenesis of T2DM.

Disrupted reproduction, estrous cycle, and circadian rhythms in female mice deficient in vasoactive intestinal peptide.

The female reproductive cycle is gated by the circadian timing system and may be vulnerable to disruptions in the circadian system. Prior work suggests that vasoactive intestinal peptide (VIP)-expressing neurons in the suprachiasmatic nucleus (SCN) are one pathway by which the circadian clock can influence the estrous cycle, but the impact of the loss of this peptide on reproduction has not been assessed. In the present study, we first examine the impact of the genetic loss of the neuropeptide VIP on the reproductive success of female mice. Significantly, mutant females produce about half the offspring of their wild-type sisters even when mated to the same males. We also find that VIP-deficient females exhibit a disrupted estrous cycle; that is, ovulation occurs less frequently and results in the release of fewer oocytes compared with controls. Circadian rhythms of wheel-running activity are disrupted in the female mutant mice, as is the spontaneous electrical activity of dorsal SCN neurons. On a molecular level, the VIP-deficient SCN tissue exhibits lower amplitude oscillations with altered phase relationships between the SCN and peripheral oscillators as measured by PER2-driven bioluminescence. The simplest explanation of our data is that the loss of VIP results in a weakened SCN oscillator, which reduces the synchronization of the female circadian system. These results clarify one of the mechanisms by which disruption of the circadian system reduces female reproductive success.

Voltage-operated Ca(2+) and Na(+) channels in the oligodendrocyte lineage.

It is becoming increasingly clear that expression of Ca(2+) and Na(+) channels in the OL lineage is highly regulated and may be functionally related to different stages of development and myelination. Characterization of the mechanisms of voltage-dependent Ca(2+) and Na(+) entry are important because changes in intracellular Ca(2+) and Na(+) are central to practically all cellular activities. In nonexcitable cells, voltage-dependent Ca(2+) influx plays a key role in several important processes, including proliferation, apoptosis, and cell migration. It has been demonstrated that Ca(2+) signaling is essential in the development and functioning of OLs. For example, Ca(2+) uptake is required for the initiation of myelination, and perturbation of Ca(2+) homeostasis, e.g., overwhelming influxes of Ca(2+), leads to demyelination. Although OL progenitor cell Na(+) channels are present at a much lower density, their physiological properties appear to be indistinguishable from those recorded in neurons. Interestingly, recent data indicate that, as with neurons, some white matter OPCs possess the ability to generate Na(+)-dependent action potentials. This Mini-Review focuses on the mechanisms of Ca(2+) and Na(+) signaling in cells within the OL lineage mediated by voltage-operated ion channels, with a particular focus on the relevance of these voltage-dependent currents to oligodendroglial development, myelination, and demyelination. Overall, it is clear that cells in the OL lineage exhibit remarkable plasticity with regard to the expression of voltage-gated Ca(2+) and Na(+) channels and that perturbation of Ca(2+) and Na(+) homeostasis likely plays an important role in the pathogenesis underlying demyelinating diseases.

Role for the NR2B subunit of the N-methyl-D-aspartate receptor in mediating light input to the circadian system.

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells that utilize glutamate as a neurotransmitter. A variety of evidence suggests that the release of glutamate then activates N-methyl-D-aspartate (NMDA) receptors within the SCN and triggers a signaling cascade that ultimately leads to phase shifts in the circadian system. In this study, we first sought to explore the role of the NR2B subunit in mediating the effects of light on the circadian system of hamsters and mice. We found that localized microinjection of the NR2B subunit antagonist ifenprodil into the SCN region reduces the magnitude of light-induced phase shifts of the circadian rhythm in wheel-running activity. Next, we found that the NR2B message and levels of phospho-NR2B vary with time of day in SCN tissue using semiquantitative real-time polymerase chain reaction and western blot analysis, respectively. Functionally, we found that blocking the NR2B subunit with ifenprodil significantly reduced the magnitude of NMDA currents recorded in SCN neurons. Ifenprodil also significantly reduced the magnitude of NMDA-induced Ca2+ changes in SCN cells. Together, these results demonstrate that the NR2B subunit is an important component of NMDA receptor-mediated responses within SCN neurons and that this subunit contributes to light-induced phase shifts of the mammalian circadian system.

Disrupted neuronal activity rhythms in the suprachiasmatic nuclei of vasoactive intestinal polypeptide-deficient mice.

Vasoactive intestinal polypeptide (VIP), acting via the VPAC(2) receptor, is a key signaling pathway in the suprachiasmatic nuclei (SCN), the master clock controlling daily rhythms in mammals. Most mice lacking functional VPAC(2) receptors are unable to sustain behavioral rhythms and lack detectable SCN electrical rhythms in vitro. Adult mice that do not produce VIP (VIP/PHI(-/-)) exhibit less severe alterations in wheel-running rhythms, but the effects of this deficiency on the amplitude, phasing, or periodicity of their SCN cellular rhythms are unknown. To investigate this, we used suction electrodes to extracellularly record multiple- and single-unit electrical activity in SCN brain slices from mice with varying degrees of VIP deficiency, ranging from wild-type (VIP/PHI(+/+)) to heterozygous (VIP/PHI(+/-)) and VIP/PHI(-/-) animals. We found decreasing proportions of rhythmic cells in SCN slices from VIP/PHI(+/+) ( approximately 91%, n = 23) through VIP/PHI(-/+) ( approximately 71%, n = 28) to VIP/PHI(-/-) mice (62%; n = 37) and a parallel trend toward decreasing amplitude in the remaining rhythmic cells. SCN neurons from VIP/PHI(-/-) mice exhibited a broad range in the period and phasing of electrical rhythms, concordant with the known alterations in their behavioral rhythms. Further, treatment of VIP/PHI(-/-) slices with a VPAC(2) receptor antagonist significantly reduced the proportion of oscillating neurons, suggesting that VPAC(2) receptors still become activated in the SCN of these mice. The results establish that VIP is important for appropriate periodicity and phasing of SCN neuronal rhythms and suggest that residual VPAC(2) receptor signaling promotes rhythmicity in adult VIP/PHI(-/-) mice.

Brain-derived neurotrophic factor regulation of N-methyl-D-aspartate receptor-mediated synaptic currents in suprachiasmatic nucleus neurons.

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells. Previous work raises the possibility that brain-derived neurotrophic factor (BDNF) and its high-affinity receptor TrkB may be important as modulators of this excitatory input into the SCN. To test this possibility, we used whole-cell patch-clamp methods to measure excitatory currents in rat SCN neurons. These currents were evoked by electrical stimulation of the optic nerve. We found that the amplitude of the N-methyl-D-aspartate (NMDA) component of the evoked excitatory postsynaptic currents (NMDA-EPSC) was increased by application of BDNF. The neurotrophin also increased the magnitude of NMDA-evoked currents in SCN neurons. The BDNF enhancement of the NMDA-EPSC was blocked by treatment with the neurotrophin receptor antagonist K252a as well as treatment with the soluble form of the TrkB receptor engineered as an immunoadhesin (TrkB IgG). Finally, the BDNF enhancement was lost in brain slices treated with the NR2B antagonist ifenprodil. The results demonstrate that BDNF and TrkB receptors are important regulators of retinal glutamatergic synaptic transmission within the SCN.

Brain-derived neurotrophic factor and neurotrophin receptors modulate glutamate-induced phase shifts of the suprachiasmatic nucleus.

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells. Previous work raised the possibility that brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related receptor kinase may be important as modulators of this excitatory input into the SCN. In order to test this possibility, we used whole-cell patch-clamp methods to measure spontaneous excitatory currents in mouse SCN neurons. We found that the amplitude and frequency of these currents were increased by BDNF and decreased by the neurotrophin receptor inhibitor K252a. The neurotrophin also increased the magnitude of currents evoked by application of N-methyl-d-aspartate and amino-methyl proprionic acid. Next, we measured the rhythms in action potential discharge from the SCN brain slice preparation. We found that application of K252a dramatically reduced the magnitude of phase shifts of the electrical activity rhythm generated by the application of glutamate. By itself, BDNF caused phase shifts that resembled those produced by glutamate and were blocked by K252a. The results demonstrate that BDNF and neurotrophin receptors can enhance glutamatergic synaptic transmission within a subset of SCN neurons and potentiate glutamate-induced phase shifts of the circadian rhythm of neural activity in the SCN.

Selective deficits in the circadian light response in mice lacking PACAP.

Previous studies indicate that light information reaches the suprachiasmatic nucleus through a subpopulation of retinal ganglion cells that contain both glutamate and pituitary adenylyl cyclase-activating peptide (PACAP). Although the role of glutamate in this pathway has been well studied, the involvement of PACAP and its receptors is only beginning to be understood. To investigate the functions of PACAP in vivo, we developed a mouse model in which the gene coding for PACAP was disrupted by targeted homologous recombination. RIA was used to confirm a lack of detectable PACAP protein in these mice. PACAP-deficient mice exhibited significant impairment in the magnitude of the response to brief light exposures with both light-induced phase delays and advances of the circadian system impacted. This mutation equally impacted phase shifts induced by bright and dim light exposure. Despite these effects on phase shifting, the loss of PACAP had only limited effects on the generation of circadian oscillations, as measured by rhythms in wheel-running activity. Unlike melanopsin-deficient mice, the mice lacking PACAP exhibited no loss of function in the direct light-induced inhibition of locomotor activity, i.e., masking. Finally, the PACAP-deficient mice exhibited normal phase shifts in response to exposure to discrete dark treatments. The results reported here show that the loss of PACAP produced selective deficits in the light response of the circadian system.

Cellular communication and coupling within the suprachiasmatic nucleus.

In mammals, the part of the nervous system responsible for most circadian behavior can be localized to a pair of structures in the hypothalamus known as the suprachiasmatic nucleus (SCN). Importantly, when SCN neurons are removed from the organism and maintained in a brain slice preparation, they continue to generate 24h rhythms in electrical activity, secretion, and gene expression. Previous studies suggest that the basic mechanism responsible for the generation of these rhythms is intrinsic to individual cells in the SCN. If we assume that individual cells in the SCN are competent circadian oscillators, it is obviously important to understand how these cells communicate and remain synchronized with each other. Cell-to-cell communication is clearly necessary for conveying inputs to and outputs from the SCN and may be involved in ensuring the high precision of the observed rhythm. In addition, there is a growing body of evidence that a number of systems-level phenomena could be dependent on the cellular communication between circadian pacemaker neurons. It is not yet known how this cellular synchronization occurs, but it is likely that more than one of the already proposed mechanisms is utilized. The purpose of this review is to summarize briefly the possible mechanisms by which the oscillatory cells in the SCN communicate with each other.

NMDA-evoked calcium transients and currents in the suprachiasmatic nucleus: gating by the circadian system.

A variety of evidence suggests that the effects of light on the mammalian circadian system are mediated by glutamatergic mechanisms and that the N-methyl- D-aspartate (NMDA) receptor plays an important role in this regulation. One of the fundamental features of circadian oscillators is that their response to environmental stimulation varies depending on the phase of the daily cycle when the stimuli are applied. For example, the same light treatment, which can produce phase shifts of the oscillator when applied during subjective night, has no effect when applied during the subjective day in animals held in constant darkness (DD). We examined the hypothesis that the effects of NMDA on neurons in the suprachiasmatic nucleus (SCN) also vary from day to night. Optical techniques were utilized to estimate NMDA-induced calcium (Ca2+) changes in SCN cells. The resulting data indicate that there was a daily rhythm in the magnitude and duration of NMDA-induced Ca2+ transients. The phase of this rhythm was determined by the light-dark cycle to which the rats were exposed with the Ca2+ transients peaking during the night. This rhythm continued when animals were held in DD. gamma-Aminobutyric acid (GABA)ergic mechanisms modulated the NMDA response but were not responsible for the rhythm. Finally, there was a rhythm in NMDA-evoked currents in SCN neurons that also peaked during the night. This study provides the first evidence for a circadian oscillation in NMDA-evoked Ca2+ transients in SCN cells. This rhythm may play an important role in determining the periodic sensitivity of the circadian systems response to light.

Rhythmic coupling among cells in the suprachiasmatic nucleus.

In mammals, the part of the nervous system responsible for most circadian behavior can be localized to a pair of structures in the hypothalamus known as the suprachiasmatic nucleus (SCN). Previous studies suggest that the basic mechanism responsible for the generation of these rhythms is intrinsic to individual cells. There is also evidence that the cells within the SCN are coupled to one another and that this coupling is important for the normal functioning of the circadian system. One mechanism that mediates coordinated electrical activity is direct electrical connections between cells formed by gap junctions. In the present study, we used a brain slice preparation to show that developing SCN cells are dye coupled. Dye coupling was observed in both the ventrolateral and dorsomedial subdivisions of the SCN and was blocked by application of a gap junction inhibitor, halothane. Dye coupling in the SCN appears to be regulated by activity-dependent mechanisms as both tetrodotoxin and the GABA(A) agonist muscimol inhibited the extent of coupling. Furthermore, acute hyperpolarization of the membrane potential of the original biocytin-filled neuron decreased the extent of coupling. SCN cells were extensively dye coupled during the day when the cells exhibit synchronous neural activity but were minimally dye coupled during the night when the cells are electrically silent. Immunocytochemical analysis provides evidence that a gap-junction-forming protein, connexin32, is expressed in the SCN of postnatal animals. Together the results are consistent with a model in which gap junctions provide a means to couple SCN neurons on a circadian basis.

Circadian modulation of calcium levels in cells in the suprachiasmatic nucleus.

There is reason to believe that resting free calcium concentration [Ca2+]i in neurons in the suprachiasmatic nucleus (SCN) may vary with the circadian cycle. In order to start to examine this hypothesis, optical techniques were utilized to estimate resting Ca2+ levels in SCN cells in a rat brain slice preparation. [Ca2+]i measured from the soma was significantly higher in the day than in the night. Animals from a reversed light-dark cycle were used to confirm that the phase of the rhythm was determined by the prior light-dark cycle. The rhythm in Ca2+ levels continued to be expressed in tissue collected from animals maintained in constant darkness, thus confirming the endogenous nature of this variation. Interestingly, the rhythm in Ca2+ levels was not observed when animals were housed in constant light. Finally, the rhythm in Ca2+ levels was prevented when slices were exposed to tetrodotoxin (TTX), a blocker of voltage-sensitive sodium channels. Similar results were obtained with the voltage-sensitive Ca2+ channel blocker methoxyverapamil. These observations suggest a critical role for membrane events in driving the observed rhythm in Ca2+. Conceptually, this rhythm can be thought of as an output of the circadian oscillator. Because [Ca2+]i is known to play a critical role in many cellular processes, the presence of this rhythm is likely to have many implications for the cell biology of SCN neurons.

Serotonin modulation of calcium transients in cells in the suprachiasmatic nucleus.

Information about environmental lighting conditions is conveyed to the suprachiasmatic nucleus (SCN), at least in part, via a glutamatergic fiber pathway originating in the retina, known as the retinohypothalamic tract (RHT). Previous work indicates that serotonin (5HT) can inhibit this pathway, although the underlying mechanisms are unknown. The authors became interested in the possibility that 5HT can inhibit the glutamatergic regulation of Ca2+ in SCN neurons and, by this mechanism, modulate light-induced phase shifts of the circadian system. To start to examine this hypothesis, optical techniques were used to measure Ca2+ levels in SCN cells in a brain slice preparation. First, it was found that 5HT produced a reversible and significant inhibition of Ca2+ transients evoked by synaptic stimulation. Next, it was found that 5HT did not alter the magnitude or duration of Ca2+ transients evoked by the bath application of glutamate or N-methyl-D-aspartate acid (NMDA) in the presence of tetrodotoxin (TTX). The authors feel that the simplest explanation for these results is that 5HT can act presynaptically at the RHT/SCN synaptic connection to inhibit the release of glutamate. The demonstration that 5HT can have a dramatic modulatory action on synaptic-evoked Ca2+ transients measured in SCN neurons adds support to the notion that the serotonergic innervation of the SCN may function to regulate environmental input to the circadian system. In addition, it was found that the administration of higher concentrations of 5HT can increase Ca2+ in at least a subpopulation of SCN neurons. This effect of 5HT was concentration dependent and blocked by a broad-spectrum 5HT antagonist (metergoline). In addition, both TTX and the gamma-amino-N-butyric acid (GABA) receptor blocker bicuculline inhibited the 5HT-induced Ca2+ transients. Therefore, the interpretation of this data is that 5HT can act within the SCN to alter GABAergic activity and, by this mechanism, cause changes in intracellular Ca2+. It is also suggested that this 5HT-induced Ca2+ increase might play a role in 5HT-induced phase shifts of the SCN circadian oscillator.

Metabotropic glutamate receptor modulation of excitotoxicity in the neostriatum: role of calcium channels.

We have previously shown that metabotropic glutamate receptor (mGluR) activation can attenuate N-methyl-d-aspartate (NMDA)-induced excitotoxic injury in the neostriatum both in vivo and in vitro. Our earlier studies made use of the non-subtype selective mGluR agonist 1-amino-cyclopentane-1,3-dicarboxylic acid (tACPD). In the present study, we extended these observations by identifying the subtype of mGluR involved. Using selective mGluR agonists, we provide evidence that the Group II mGluRs are responsible for inhibition of NMDA excitotoxicity in the neostriatum. In addition, we provide evidence that the inhibitory effects of tACPD on excitotoxicity are dependent upon calcium influx as they are blocked by a low calcium solution as well as the broad-spectrum calcium channel blocker cadmium. The tACPD-induced attenuation was also blocked by omega-conotoxin GVIA suggesting participation of N-type calcium channels. Whole cell voltage clamp recordings were made to directly determine the effects of mGluRs on voltage-gated calcium channels in neostriatal neurons. As predicted, both tACPD and the Group II agonist 3C4HPG inhibited calcium currents in neostriatal neurons. Again this effect was blocked by omega-conotoxin GVIA. Overall the results suggest that mGluR regulation of voltage-gated calcium channels can limit NMDA toxicity in the neostriatum.

Dopaminergic modulation of early signs of excitotoxicity in visualized rat neostriatal neurons.

Cell swelling induced by activation of excitatory amino acid receptors is presumably the first step in a toxic cascade that may ultimately lead to cell death. Previously we showed that bath application of N-methyl-D-aspartate (NMDA) or kainate (KA) produces swelling of neostriatal cells. The present experiments examined modulation of NMDA and KA-induced cell swelling by dopamine (DA) and its receptor agonists. Nomarski optics and infra-red videomicroscopy were utilized to visualize neostriatal medium-sized neurons in thick slices from rat pups (12-18 postnatal days). Increase in somatic cross-sectional area served as the indicator of swelling induced by bath application of glutamate receptor agonists. NMDA induced cell swelling in a dose-dependent manner. Activation of DA receptors in the absence of NMDA did not produce swelling. DA and the D1 receptor agonist SKF 38393, increased the magnitude of swelling produced by NMDA. This effect was reduced in the presence of the D1 receptor antagonist, SCH 23390. In contrast, activation of D2 receptors by quinpirole decreased the magnitude of NMDA-induced cell swelling. DA slightly attenuated cell swelling induced by activation of KA receptors. Quinpirole produced a significant concentration-dependent reduction in KA-induced swelling while SKF38393 increased KA-induced swelling, but only at a low concentration of KA. Together, these results provide additional support for the hypothesis that the direction of DA modulation depends on the glutamate receptor subtype, as well as the DA receptor subtype activated. One possible consequence of these observations is that endogenous DA may be an important contributing factor in the mechanisms of cell death in Huntington's disease.

Postnatal development of glutamate receptor-mediated responses in the neostriatum.

Three experimental approaches were used to examine the maturation of N-methyl-D-aspartate (NMDA) receptors in the neostriatum and compare their developmental profile to that of the non-NMDA receptors [alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainate (KA)]. The first, and least conventional approach utilized infrared videomicroscopy to measure NMDA-induced swelling in single cells in a brain slice. The results demonstrated that NMDA receptors display an incremental pattern of postnatal development with no responses at postnatal day (PND) 3, weak responses at PND 7, the largest responses by PND 14 and slight decreases at PNDs 21 and 28. At PNDs 3 and 7, KA-induced cell swelling was proportionately greater than NMDA-induced cell swelling suggesting earlier maturation of this non-NMDA receptor subtype. The second approach used whole-cell patch clamp analysis to examine NMDA currents and compare their maturation to AMPA/KA-induced currents. Though the data are still preliminary, a very similar developmental pattern emerged. NMDA-induced currents were small and developed slowly after PND 7. In contrast, AMPA/KA-induced currents were larger and appeared to develop earlier. Finally, dizocilpine (MK-801) binding was measured in homogenates of neostriatal tissue. The ontogeny of binding resembled a step function with increases between PNDs 3 and 7 and PNDs 14 and 21. Binding peaked at PND 28 and then declined slightly in the adult (PND 60). The affinity of MK-801 for the receptor did not change during postnatal development. These findings demonstrate the pattern of functional development of glutamate receptors in the neostriatum. The NMDA receptor subtype displays minimal functional development until PND 14. In contrast, neostriatal AMPA/KA receptor function appears to precede NMDA receptor function.

Dopaminergic modulation of NMDA-induced whole cell currents in neostriatal neurons in slices: contribution of calcium conductances.

The present experiments were designed to examine dopamine (DA) modulation of whole cell currents mediated by activation of N-methyl-D-aspartate (NMDA) receptors in visualized neostriatal neurons in slices. First, we assessed the ability of DA, D1 and D2 receptor agonists to modulate membrane currents induced by activation of NMDA receptors. The results of these experiments demonstrated that DA potentiated NMDA-induced currents in medium-sized neostriatal neurons. Potentiation of NMDA currents occurred at three different holding potentials, although it was more pronounced at -30 mV. It was mediated by D1 receptors, because it was mimicked by D1 agonists and blocked by exposure to a D1 antagonist. Activation of D2 receptors produced inconsistent effects on NMDA-induced membrane currents. Either decreases, increases, or no effects on NMDA currents occurred. Second, we examined the contributions of intrinsic, voltage-dependent conductances to DA potentiation of NMDA currents. Blockade of K+ conductances did not prevent DA enhancement of NMDA currents. However, voltage-activated Ca2+ conductances provided a major contribution to DA modulation. The dihydropyridine L-type Ca2+ channel blockers, nifedipine, and methoxyverapamil (D-600), markedly reduced but did not totally eliminate the ability of DA to modulate NMDA currents. The D1 receptor agonist SKF 38393 also enhanced Ba2+ currents in neostriatal neurons. Together, these findings provide evidence for a complex interplay between DA, NMDA receptor activation and dihydropyridine-sensitive Ca2+ conductances in controlling responsiveness of neostriatal medium-sized neurons.

Histamine modulates NMDA-dependent swelling in the neostriatum.

In the present study, infrared differential interference contrast videomicroscopy was used to examine the effect of histamine on N-methyl-D-aspartate-induced swelling in neostriatal neurons in a brain slice preparation. Histamine caused a concentration-dependent increase in swelling evoked by N-methyl-D-aspartate. By itself, histamine did not cause swelling. Electrical stimulation also caused N-methyl-D-aspartate-dependent swelling which was enhanced by histamine. In addition, histamine was found to enhance N-methyl-D aspartate-induced swelling from postnatal day 7 to 28 but not at postnatal day 3. Finally, this histamine-induced enhancement was prevented by treatment with either the H2 receptor antagonist cimetidine or with the potassium channel blocker tetraethylammonium chloride. Overall, these findings suggest that histamine modulates N-methyl-D-aspartate receptor function in the neostriatum through a H2 receptor-mediated regulation of potassium channels.

Metabotropic glutamate receptor activation selectively limits excitotoxic damage in the intact neostriatum.

The present study was designed to compare the protective consequences of activation of metabotropic glutamate receptors (mGluRs) on N-methyl-D-aspartate (NMDA)- and kainic acid (KA)-induced excitotoxicity in vivo. Pretreatment with the mGluR agonist ISR,3RS-1-aminocyclo-pentane-1,3-dicarboxylic acid (tACPD) limited the anatomical and behavioral consequences of the intrastriatal administration of the NMDA agonist quinolinic acid (QA). In contrast, pretreatment with tACPD did not alter the effects of intrastriatal injection of KA.