Biomedical subjects

C K Meshul

Publications and source records attributed to C K Meshul.

At least 19 recordsLinked to original sources

PubMed2001

Dopamine D4 receptor-deficient mice display cortical hyperexcitability.

The dopamine D(4) receptor (D(4)R) is predominantly expressed in the frontal cortex (FC), a brain region that receives dense input from midbrain dopamine (DA) neurons and is associated with cognitive and emotional processes. However, the physiological significance of this dopamine receptor subtype has been difficult to explore because of the slow development of D(4)R agonists and antagonists the selectivity and efficacy of which have been rigorously demonstrated in vivo. We have attempted to overcome this limitation by taking a multidimensional approach to the characterization of mice completely deficient in this receptor subtype. Electrophysiological current and voltage-clamp recordings were performed in cortical pyramidal neurons from wild-type and D(4)R-deficient mice. The frequency of spontaneous synaptic activity and the frequency and duration of paroxysmal discharges induced by epileptogenic agents were increased in mutant mice. Enhanced synaptic activity was also observed in brain slices of wild-type mice incubated in the presence of the selective D(4)R antagonist PNU-101387G. Consistent with greater electrophysiological activity, nerve terminal glutamate density associated with asymmetrical synaptic contacts within layer VI of the motor cortex was reduced in mutant neurons. Taken together, these results suggest that the D(4)R can function as an inhibitory modulator of glutamate activity in the FC.

4-Aminopyridine↗

PubMed2000

Haloperidol reverses the changes in striatal glutamatergic immunolabeling following a 6-OHDA lesion.

We reported previously that 3 months following a unilateral lesion of the nigrostriatal pathway with 6-hydroxydopamine (6-OHDA), there was a decrease in the extracellular level of striatal glutamate as determined by in vivo microdialysis. This resulted in an accumulation or increase in the density of nerve terminal glutamate immunolabeling (Meshul et al., 1999). We also reported on blockade of dopamine D-2 receptors with haloperidol resulting in ultrastructural changes within the striatum consistent with increased functioning of the glutamatergic corticostriatal pathway (Meshul and Tan 1994). We hypothesized that administration of haloperidol to 6-OHDA-lesioned rats may be capable of activating the corticostriatal pathway and thereby counteracting the effects of the unilateral nigrostriatal lesion. Striatal glutamatergic function was evaluated using electron microscopy and quantitative glutamate immunocytochemistry. Starting 1 month after a unilateral lesion of the nigrostriatal pathway with 6-OHDA, haloperidol (0.5 mg/kg/d) was administered for the next 2 months. Within the dorsolateral caudate nucleus, the main area of innervation from the motor cortex, haloperidol blocked the 6-OHDA-induced increase in the density of nerve terminal glutamate immunolabeling. Within all three experimental groups (6-OHDA, haloperidol, 6-OHDA/haloperidol) there was an increase in the mean percentage of striatal asymmetrical synapses containing a perforated postsynaptic density. In addition, haloperidol treatment resulted in a reduction in the number of apomorphine-induced contralateral rotations in unilaterally 6-OHDA lesioned rats. The data suggests that the decrease in striatal glutamatergic function 3 months following a unilateral 6-OHDA lesion can be reversed by daily haloperidol treatment. This finding is discussed in terms of current therapy for Parkinson's disease. Synapse 36:129-142, 2000. Published 2000 Wiley-Liss, Inc.

Animals↗

PubMed2000

Alterations in rat striatal glutamate synapses following a lesion of the cortico- and/or nigrostriatal pathway.

Ultrastructural changes within the ipsilateral dorsolateral striatum were investigated 1 month following a unilateral ablation of the rat frontal cortex (CTX), removing corticostriatal input, or injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), into the substantia nigra pars compacta, removing nigrostriatal input. In addition, a combined ipsilateral cortical and 6-OHDA lesion (CTX/6-OHDA) was carried out. We find that following a CTX, 6-OHDA, or CTX/6-OHDA lesion, there was a significant decrease in the density of striatal nerve terminal glutamate immunoreactivity compared to the control group. There was also a significant increase in all three lesion groups in the mean percentage of asymmetrical synapses associated with a perforated postsynaptic density. There was a large increase within the CTX/6-OHDA-lesioned group and a smaller but still significant increase in the CTX-lesioned group in the percentage of terminals or boutons with multiple synaptic contacts (i.e., multiple synaptic boutons, MSBs), compared to either the 6-OHDA or the control group. There was no change in any of these measurements within the contralateral striatum. There was a significant decrease in the number of apomorphine-induced contralateral rotations in the CTX/6-OHDA versus the 6-OHDA-lesioned group. Animals receiving just the single CTX or 6-OHDA lesion recovered in motor function compared to the control group as measured by the Rotorod test, while the CTX/6-ODA-lesioned group recovered to less than 50% of the control level. The data suggest that following a CTX and/or 6-OHDA lesion, there is an increase in striatal glutamatergic function. The large increase in the percentage of MSBs in the combined lesion group suggests that dopamine or other factors released by the dopamine terminals assist in regulating synapse formation.

Animals↗

PubMed2000

Kappa opioid receptor immunoreactivity in the nucleus accumbens and caudate-putamen is primarily associated with synaptic vesicles in axons.

A rabbit polyclonal antiserum, raised against a C-terminal oligopeptide of the mouse kappa opioid receptor, was used to localize the cellular distribution of kappa receptors in the dorsal and ventral striatum of rats with light and electron microscopic immunocytochemistry. Prominent, diffuse kappa receptor immunoreactivity was present in the nucleus accumbens, particularly in the shell, ventral caudate-putamen and olfactory tubercle. The density of receptor immunoreactivity decreased in more dorsal areas of the caudate-putamen. In contrast, neuronal cell bodies stained clearly in the dorsal endopiriform nucleus, claustrum and layer VI of the adjacent cerebral cortex. Observations at the electron microscopic level in the dorsomedial shell of the nucleus accumbens and caudate-putamen revealed that the kappa receptor immunoreactivity was predominantly located in axons, often associated with synaptic vesicles, remote from the terminal or preterminal area. The few terminals which were labeled made slightly more asymmetrical than symmetrical contacts and the percentage of asymmetrical contacts observed was greater in the caudate than in the accumbens. A small number of postsynaptic spines was labeled; most of them were contacted by asymmetrical terminals. No labeling was observed in dendritic shafts.Thus, the predominant localization of kappa receptor immunoreactivity in axons is consistent with its role as a major inhibitor of glutamate and dopamine release in the dorsal and ventral striatum.

Animals↗

PubMed1999

Glutamate uptake in mice bred for ethanol withdrawal severity.

RATIONALE: Withdrawal seizure-prone and withdrawal seizure-resistant mice were selectively bred to exhibit differences in handling-induced convulsion severity during ethanol withdrawal. The glutamatergic system has been implicated in seizure activity as well as ethanol withdrawal symptoms. OBJECTIVE: This study assessed L-[3H]glutamate uptake into hippocampal synaptosomes prepared from withdrawal seizure-prone and- resistant mice. METHODS: Glutamate uptake was characterized following repeated handling-induced convulsions, during acute intoxication, and during peak withdrawal following chronic ethanol exposure. RESULTS: Hippocampal synaptosomal L-[3H]glutamate uptake did not differ between convulsion- and ethanol-naive withdrawal seizure-prone and- resistant mice. Furthermore, exposure to convulsions or to a hypnotic dose of ethanol (4 g/kg) did not alter L-[3H]glutamate uptake. However, withdrawal from 72 h of ethanol exposure significantly increased L-[3H]glutamate uptake in both mouse lines as compared to their respective ethanol-naive controls. CONCLUSIONS: These data suggest that glutamate uptake is influenced by chronic ethanol exposure similarly in both withdrawal seizure-prone and- resistant mice. The observed increases in glutamate uptake during withdrawal may be associated with compensatory mechanisms triggered by chronic intoxication and are independent of the selected differences for withdrawal severity.

Alcoholic Intoxication↗

PubMed1999

Time-dependent changes in striatal glutamate synapses following a 6-hydroxydopamine lesion.

The goal of this study was to investigate changes in glutamatergic synapses in the striatum of rats at two different time-points following a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. One month following this lesion of the nigrostriatal pathway, there was an increase (70%) in the mean percentage of asymmetrical synapses within the dorsolateral striatum containing a discontinuous, or perforated, postsynaptic density, possibly suggesting an increase in glutamatergic activity. This was correlated, in the same brain region, with a decrease (44%) in the density of glutamate immunoreactivity within nerve terminals associated with all asymmetrical synapses and also with those terminals associated with a perforated postsynaptic density. These morphological changes were consistent with an increase (>two-fold) in the basal extracellular level of striatal glutamate, as measured by in vivo microdialysis. The density of GABA immunolabeling within symmetrical nerve terminals was increased (25%) at this one month time-period. Dopamine levels within the lesioned striatum were >99% depleted. However, at three months, while an increase in the mean percentage of striatal perforated synapses was maintained, a significant increase (50%) in the density of striatal nerve terminal glutamate immunolabeling within all asymmetrical synapses and those associated with a perforated postsynaptic density was observed. This was correlated with a small, but significant, decrease (32%) in the basal extracellular level of striatal glutamate. The density of GABA immunolabeling within nerve terminals associated with a symmetrical contact remained elevated at this three month time-period, while striatal dopamine levels remained depleted. While the density of nerve terminal GABA immunolabeling remained elevated at both the one and three month time-periods, there appeared to be a differential effect on glutamatergic synapses. The in vivo microdialysis data suggest that glutamate synapses were more active at a basal level at one month and become less active compared to the control group at the three month time-period. These data suggest that there are compensatory changes in glutamatergic synapses within the striatum following a 6-hydroxydopamine lesion that appear to be independent of the level of striatal dopamine or GABA. We propose that changes in the activity of the thalamo-cortico-striatal pathway may help to explain the differential time-course change in striatal glutamatergic synaptic activity.

Animals↗

PubMed1999

High-dose methamphetamine treatment alters presynaptic GABA and glutamate immunoreactivity.

The goal of this study was to determine if high-dose methamphetamine treatment altered presynaptic immunoreactivity for the amino acid neurotransmitters GABA and glutamate within the basal ganglia. Methamphetamine (15 mg/kg every 6 h, four doses) treatment in rats resulted in severe hyperthermia and a long-lasting (four weeks) depletion of striatal dopamine content (>80%). Severe dopamine loss correlated with a decrease in the density of presynaptic immunolabeling for GABA one week post-drug, and an increase after four weeks. Although no changes were seen in presynaptic striatal glutamate immunoreactivity, there was a significant increase in the percentage of glutamate-immuno-positive terminals associated with perforated postsynaptic densities. Rats given the same dose of methamphetamine but prevented from becoming hyperthermic showed less severe dopamine depletions and a lack of ultrastructural or immunocytochemical changes. In addition, induction of hyperthermia in the absence of drug decreased immunolabeling within mitochondria, but had no effect on dopamine content, morphology or nerve terminal immunoreactivity. Altered presynaptic GABA immunolabeling and terminal size were found in both the striatum and globus pallidus, suggesting that dynamic changes occur in the striatopallidal pathway following methamphetamine-induced dopamine loss. In addition, ultrastructural changes in glutamate-positive synapses which have been correlated with increased synaptic activity were found. These results are similar to changes in GABA and glutamate synapses that follow nigrostriatal dopamine loss in 6-hydroxydopamine-lesioned animals and in Parkinson's disease, and provide the first direct evidence that methamphetamine-induced dopamine loss alters the GABAergic striatopallidal pathway. Exposure to either methamphetamine or prolonged hyperpyrexia decreased mitochondrial Immunoreactivity, indicating that hyperthermia may contribute to methamphetamine toxicity by affecting energy stores.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Prolonged survival of adult rat pancreatic islets transfected with E1A-12S adenovirus.

It has been reported that various mutants of the E1A-adenovirus can activate quiescent differentiated cells to start proliferating. The aim of this study was to determine whether transfection with E1A-12S could extend the life span and functionality of pancreatic islets in culture. Rat pancreatic islets were isolated and transfected with retrovirus containing the adenovirus E1A-12S, E1A-13S, or control vectors. Transfection with the retroviral E1A-13S mutant produced extensive islet necrosis compared with nontransfected islets. Islets transfected with the control E1A mutant Ad5-dl312 vector (containing no E1A-12S or E1A-13S segments) were similar to nontransfected islets in their characteristics. We found that the E1A-12S transfected islets maintained greater viability, insulin granule structure, and glucose-induced insulin responsiveness over a 6-week period compared with mock or control islets. At 6 weeks of culture, the E1A-12S transfected islets also had fewer apoptotic cells compared with nontransfected islets. These data suggest that adenovirus E1A-12S can extend the functional life span of cultured rat pancreatic islets.

3T3 Cells↗

PubMed1999

Glial differences between naïve withdrawal seizure-prone and -resistant mice.

BACKGROUND: Withdrawal seizure-prone (WSP) and withdrawal seizure-resistant (WSR) mice were bred in replicate (i.e., WSP-1 and WSP-2) to exhibit differences in handling-induced convulsion severity during ethanol withdrawal. METHODS: We examined the role of the glutamatergic system in susceptibility to ethanol-withdrawal convulsions in naive mice by measuring the density of immunolabeling for several glutamate transporters and the glutamate-metabolizing enzyme, glutamine synthetase. The density of glial fibrillary acidic protein immunolabeling (a marker of glial structure) and cytochrome oxidase activity (a marker of neuronal activity) were also characterized in naive mice. RESULTS: We observed a significantly greater density of immunolabeling for the glial transporter, glutamate/aspartate transporter, in CA1 subfield of the hippocampus (CA1) of naive WSP-2 mice as compared to WSR-2 mice. No other significant differences were observed. However, as compared to WSR mice, naive WSP mice exhibited a trend toward (a) greater immunolabeling for the glial glutamate transporter, glutamate transporter-1, in CA3, (b) greater immunolabeling for glial-specific glutamate-metabolizing enzyme, glutamine synthetase, in CA1 (replicate-2 only), and (c) less immunolabeling for the glial structural protein, glial fibrillary acidic protein, in all brain regions tested. In contrast, no trends or significant differences in the labeling density for the neuronal transporter, excitatory amino acid carrier 1, or the neuronal activity marker, cytochrome oxidase, were observed between the selected lines. CONCLUSIONS: These data suggest that the glutamatergic system and glia may play a pivotal role in the increased susceptibility to handling-induced convulsions observed in WSP mice.

ATP-Binding Cassette Transporters↗

PubMed1998

Cocaine-induced changes in glutamate and GABA immunolabeling within rat habenula and nucleus accumbens.

We previously reported that subchronic administration of cocaine for 5 days via slow-release pellets results in pronounced degeneration in the lateral habenula (LHB) and its primary efferent tract, the fasciculus retroflexus [Ellison (1992): Brain Res 598:353-356; Ellison and Switzer (1993): Neuroreport 5:17-20]. The lateral habenula receives both GABA and glutamate afferents. In order to test the hypothesis that the cocaine-induced degeneration of the fasciculus retroflexus may be related to changes in synaptic activity of either GABA or glutamate nerve terminals within the LHB, the density of nerve terminal immunolabeling of either neurotransmitter was quantified after 5 days of chronic drug administration followed by either 1 or 14 days off the drug. The shell of the nucleus accumbens (NACs) was also analyzed, since this area is thought to be associated with the reward aspects of addictive stimulant drug administration and was previously shown not to be associated with fiber degeneration. We found that cocaine treatment resulted in a significant decrease in the density of nerve-terminal GABA immunolabeling located within the LHB in animals taken off the drug for either 1 or 14 days, while there was no change in the density of glutamate immunolabeling. In the NACs, there was a decrease in the density of glutamate immunolabeling within nerve terminals 1 day but not 14 days after cocaine administration. There was no change in the density of GABA immunolabeling within the NACs following the 1 or 14 day-off period. These results suggest that there are long-term changes in the density of GABA immunolabeling within the LHB and that the effects seen in glutamate synapses within the NACs are transitory. The long-term decrease in GABA immunolabeling within the LHB is consistent with the hypothesis that a decrease in inhibitory synaptic activity, leading to increased excitatory influence on LHB neurons, may result in neurotoxicity and the subsequent degeneration of the fasciculus retroflexus.

Animals↗

PubMed1998

Reduced glutamate immunolabeling in the nucleus accumbens following extended withdrawal from self-administered cocaine.

Alterations in the density of GABA and glutamate immunolabeling within nerve terminals in the shell region of the nucleus accumbens were assessed in rats withdrawn from intravenous cocaine exposure. Four groups of rats were used: one group self-administered cocaine (0.42 mg/kg/infusion) in daily 3-h sessions for approximately 2 weeks, two additional groups received either saline or cocaine in a noncontingent fashion, and a fourth comprised a drug-naive, age-matched control group. Immunogold electron microscopy was used to quantify presynaptic terminal GABA and glutamate density within the vesicular and mitochondrial pools approximately 18 days following the last drug or saline exposure in the treatment groups. A significant 27.7% decrease in vesicular glutamate density within asymmetrical nerve terminals was observed in animals that self-administered cocaine as compared to controls. This group also showed an 18.6% decrease in vesicular nerve terminal glutamate immunolabeling as compared to animals that were administered a similar total dose of cocaine in a response-independent fashion. No significant changes in the density of nerve terminal GABA vesicular immunolabeling were observed in any groups. For both transmitters, no differences were detected in the density of immunolabeling within the presynaptic mitochondrial (i.e., metabolic) pool. These results demonstrate that glutamate density is suppressed in the shell region of the nucleus accumbens following withdrawal from 2 weeks of cocaine exposure. The findings also suggest that the motivational aspects that accompany self-administration may participate in this reduction.

Animals↗

PubMed1997

Immunocytochemical analysis of glutamate and GABA in selectively bred mice.

Withdrawal Seizure Prone (WSP) and Withdrawal Seizure Resistant (WSR) mice have been selectively bred for differential ethanol withdrawal handling-induced convulsions (HICs). In addition, it has been observed that WSP mice exhibit drug-naive HICs. This latter finding suggests that WSP and WSR mice differ in their susceptibility to HICs. Alterations in the glutamate and gamma-aminobutyric acid (GABA) systems have been implicated in convulsive activity and have been proposed to underlie the manifestation of ethanol withdrawal symptoms. It is therefore possible that WSP and WSR mice are genetically different with respect to their glutamatergic and/or GABAergic systems. To test this hypothesis, we have analyzed WSP and WSR mice that are both drug- and HIC-naive for differences in the density of nerve terminal glutamate and GABA immunoreactivity within the CA1 subfield of the hippocampus (CA1) and layer II of the somatosensory cortex (SSC). The major finding of this study is that drug- and HIC-naive WSP mice exhibit a significantly greater density of presynaptic glutamate immunoreactivity associated with asymmetric synapses within the CA1, but not the SSC, when compared to WSR mice. The density of GABA immunoreactivity within nerve terminals associated with symmetric synapses does not differ between the selected lines in either brain region. Since prior drug exposure and HICs cannot account for the observed differences in these naive mice, the results strongly suggest that the density of nerve terminal glutamate immunoreactivity within the CA1 is a reflection of inherent genetic differences between WSP and WSR mice. Furthermore, an elevated density of presynaptic glutamate immunoreactivity may be an underlying neurochemical correlate to increased susceptibility to drug-naive and ethanol withdrawal convulsions.

Animals↗

PubMed1997

Methamphetamine alters presynaptic glutamate immunoreactivity in the caudate nucleus and motor cortex.

It has been suggested that methamphetamine (METH)-induced neurotoxicity requires the activation of both dopamine (DA) and glutamate (GLU) systems. To investigate the possibility that METH-induced increases in extracellular GLU, as measured by in vivo microdialysis [Nash and Yamamoto (1992) Brain Res., 581:237-243], arise from neuronal stores, postembedding immunogold electron microscopy was used to measure the density of presynaptic GLU immunoreactivity within the striatum, the shell of the nucleus accumbens, and the motor cortex. Rats were treated with METH (5 mg/kg), or an equivalent volume of saline (SAL), every 2 h for a total of four injections. No ultrastructural evidence of terminal degeneration was observed. Significant decreases in the density of nerve terminal GLU immunolabeling occurred 12 h following METH administration within the primary motor cortex and the ventrolateral caudate/putamen, and a trend towards depletion was seen within the dorsolateral caudate/putamen. Although GLU immunolabeling within the shell of the nucleus accumbens was unaffected, DA content was decreased in all regions examined 1 week following METH treatment. The lack of degeneration, coupled with a partial recovery of DA levels, suggests that moderate doses of METH may inhibit DA biosynthesis without widespread terminal loss. Furthermore, METH administration results in a decrease in presynaptic GLU that correlates both temporally and anatomically with delayed GLU overflow, suggesting that neuronally derived GLU may play a role in METH-induced neurotoxicity. However, there does appear to be a dissociation between DA loss and altered GLU immunocytochemistry within the nucleus accumbens.

Animals↗

PubMed1997

A rat model of chronic pressure-induced optic nerve damage.

To develop unilateral, chronically elevated intraocular pressure in rats, episcleral veins were injected with hypertonic saline and the intraocular pressure was monitored with a Tono-Pen XL tonometer. Histologic analyses of eyes with differing degrees and durations of intraocular pressure elevation were performed to ascertain the effects of these pressures on the optic nerve. Out of 20 consecutive animals, nine had elevations of intraocular pressure following a single injection, while subsequent injections raised intraocular pressure in seven others. One eye became hypotonous. In the remaining animals, subsequent injections sufficient to raise intraocular pressure were deliberately withheld, to determine the possible direct effects of injections on the optic nerve. Mean sustained pressure elevations ranged from 7 to 28 mm Hg and the retinal vasculature remained perfused in all eyes. Optic nerve cross sections from eyes without intraocular pressure elevation appeared identical to those from uninjected eyes, while nerves from eyes with the greatest intraocular pressure rise demonstrated axonal damage that involved 100% of the neural area. Eyes with either less severe pressure elevations or shorter durations showed partial damage, ranging from 0.5% to 10.4% of the neurla area. In 70% of these nerves, damage was concentrated in the superior temporal region. Within the optic nerve head, often associated with astrocytes, axons contained abnormal accumulations of membrane-bound vesicles and mitochondria. The anterior chamber angles showed sclerosis of the trabecular meshwork with anterior synechiae, but Schlemm's canal, collector channels and aqueous veins appeared patent. Unilateral sclerosis of the trabecular meshwork produces sustained elevation of intraocular pressure in rats with optic nerve damage that in many ways resembles that seen in human glaucoma. Understanding the mechanism of nerve damage in this model may provide new insights into the pathogenesis of human glaucoma.

Animals↗

PubMed1996

Characterization and distribution of basic fibroblast growth factor-containing cells in the rat hippocampus.

Basic fibroblast growth factor (bFGF), a member of the heparin-binding growth factor family, is present in relatively high levels in the brain where it may play an important role in the maintenance, repair, and reorganization of the tissue. Although bFGF is associated mainly with astrocytes throughout most of the central nervous system (CNS), a narrow but prominent band of pyramidal neurons, which coincides with the CA2 subregion of Ammon's horn in the hippocampus, stains intensely for bFGF. In order to gain an understanding of which cells express bFGF and whether or not BFGF is a good marker for CA2 neurons, we have used a mouse monoclonal antibody directed against recombinant human bFGF to characterize the distribution and localization of bFGF expression in the hippocampus. We find that about one-quarter of the neurons in CA2 are bFGF positive, and they appear smaller and have more irregular-shaped nuclei than their unstained counterparts. In addition, all glial fibrilary acidic protein (GFAP)-positive astrocytes in the hippocampus stain for bFGF, and the distribution of these astrocytes is heterogeneous in the hippocampus. Finally, in both astrocytes and CA2 pyramidal neurons, bFGF immunoreactivity is localized primarily in the nucleus and to a lesser extent in the cytoplasm and processes of stained cells.

Animals↗

PubMed1996

Activation of corticostriatal pathway leads to similar morphological changes observed following haloperidol treatment.

Treatment with haloperidol, a dopamine receptor D-2 antagonist, for one month resulted in an increase in the mean percentage of asymmetric synapses containing a discontinuous, or perforated, postsynaptic density (PSD) [Meshul et al. (1994) Brain Res., 648:181-195] and a change in the density of striatal glutamate immunoreactivity within those presynaptic terminals [Meshul and Tan (1994) Synapse, 18:205-217]. We speculated that this haloperidol-induced change in glutamate density might be due to an activation of the corticostriatal pathway. To determine if activation of this pathway leads to similar morphological changes previously described following haloperidol treatment, GABA (10(-5) M, 0.5 microliters) was injected into the thalamic motor (VL/VM) nuclei daily for 3 weeks. This treatment resulted in an increase in the mean percentage of striatal asymmetric synapses containing a perforated PSD and an increase in the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated or non-perforated PSD. Subchronic injections of GABA into the thalamic somatosensory nuclei (VPM/VPL) had no effect on the mean percentage of synapses with perforated PSDs but resulted in a small, but significant, increase in density of glutamate immunoreactivity. Using in vivo microdialysis, an acute injection of GABA (10(-5) M, 15 microliters) into VL/VM resulted in a prolonged rise in the extracellular level of striatal glutamate. The increase in asymmetric synapses with perforated PSDs and in glutamate immunoreactivity within nerve terminals of the striatum following either subchronic haloperidol treatment or GABA injections into VL/VM suggest that an increase in glutamate release may be a common factor in these two experiments. It is possible that the extrapyramidal side effects associated with haloperidol treatment may be due, in part, to an increase in release of glutamate within the corticostriatal pathway.

Animals↗

PubMed1996

Correlation of vacuous chewing movements with morphological changes in rats following 1-year treatment with haloperidol.

Long-term treatment with the typical antipsychotic drug, haloperidol, can lead to a sometimes irreversible motor disorder, tardive dyskinesia (TD). It has been hypothesized that increased release of glutamate due to prolonged neuroleptic drug treatment may result in an excitotoxic lesion in specific neuronal populations within the basal ganglia, leading to TD. We reported that treatment with haloperidol for 1 month results in an increase in the mean percentage of striatal asymmetric synapses containing a perforated postsynaptic density (PSD) and that these synapses are glutamatergic. Using quantitative immunocytochemistry, we found that depending on how long the animals had been off haloperidol following subchronic (30 d) treatment, there was either a decrease (1 day off) or increase (3-4 days off) in the density of glutamate immunolabeling within the presynaptic terminals of synapses with perforated PSDs. Using a rat model for TD, animals in the current study were treated for 1 year with haloperidol and spontaneous oral dyskinesias (i.e. vacuous chewing movements, VCMs) were recorded. In these long-term treated animals we wanted to determine if there was a correlation between glutamate function, as measured by changes in synapses with perforated PSDs and the density of nerve terminal glutamate immunoreactivity, and VCM behavior. In drug treated rats which demonstrated either a high or low rate of VCMs, there was a significant increase in the mean percentage of asymmetric synapses in the dorsolateral striatum with perforated PSDs in both haloperidol-treated groups compared to vehicle-treated rats. There was a small but significant increase in the density of glutamate immunolabeling within striatal nerve terminals of the high VCM group compared to the low VCM group. There was, however, no difference in the density of glutamate immunolabeling between the high VCM group compared to the vehicle-treated animals. One reason for this lack of difference was partially due to a significant increase in nerve terminal area within the high VCM group compared to either the low VCM- or vehicle-treated groups. The larger nerve terminal size in the high VCM group may be due to a small but sustained increase in glutamate neurotransmitter release with the ability of the terminal to maintain its supply of glutamate, while the terminals in the low VCM group showed evidence of glutamate depletion. This finding would be consistent with the hypothesis that increased glutamatergic activity may be associated with TD.

Animals↗

PubMed1996

Effects of subchronic clozapine and haloperidol on striatal glutamatergic synapses.

Subchronic treatment with haloperidol increases the number of asymmetric glutamate synapses associated with a perforated postsynaptic density in the striatum. To characterize these synaptic changes further, the effects of subchronic (28 days) administration of an atypical antipsychotic, clozapine (30 mg/kg, s.c.), or a typical antipsychotic, haloperidol (0.5 mg/kg, s.c.), on the binding of [3H] MK-801 to the NMDA receptor-linked ion channel complex and on the in situ hybridization of riboprobes for NMDAR2A and 2B subunits and splice variants of the NMDAR1 subunit were examined in striatal preparations from rats. The density of striatal glutamate immunogold labeling associated with nerve terminals of all asymmetric synapses and the immunoreactivity of those asymmetric synapses associated with a perforated postsynaptic density were also examined by electron microscopy. Subchronic neuroleptic administration had no effect on [3H] MK-801 binding to striatal membrane preparations. Both drugs increased glutamate immunogold labeling in nerve terminals of all asymmetric synapses, but only haloperidol increased the density of glutamate immunoreactivity within nerve terminals of asymmetric synapses containing a perforated postsynaptic density. Whereas subchronic administration of clozapine, but not haloperidol, resulted in a significant increase in the hybridization of a riboprobe that labels all splice variants of the NMDAR1 subunit, both drugs significantly decreased the abundance of NMDAR1 subunit mRNA containing a 63-base insert. Neither drug altered mRNA for the 2A subunit, but clozapine significantly increased hybridization of a probe for the 2B subunit. The data suggest that some neuroleptic effects may be mediated by glutamatergic systems and that typical and atypical antipsychotics can have varying effects on the density of glutamate in presynaptic terminals and on the expression of specific NMDA receptor splice variant mRNAs. Alternatively, NMDAR1 subunit splice variants may differentially respond to interactions with glutamate.

Alternative Splicing↗