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J F McGinty

Publications and source records attributed to J F McGinty.

At least 19 recordsLinked to original sources
PubMed2006

Extracellular signal-regulated mitogen-activated protein kinase inhibitors decrease amphetamine-induced behavior and neuropeptide gene expression in the striatum.

The aim of this study was to determine whether inhibition of the extracellular-regulated kinase signaling pathway decreases acute amphetamine-induced behavioral activity and neuropeptide gene expression in the rat striatum. Western blotting revealed that extracellular-regulated kinase1/2 phosphorylation was highly induced in the rat striatum 15 min after an acute amphetamine (2.5 mg/kg, i.p.) injection without altering the total amount of extracellular-regulated kinase protein. In a separate experiment, the systemic injection of SL327, a selective inhibitor of extracellular regulated kinase kinase that crosses the blood-brain barrier, 1 h prior to amphetamine administration decreased amphetamine-induced vertical and horizontal activity. Quantitative in situ hybridization histochemistry showed that SL327 abolished the high levels of preproenkephalin and preprodynorphin mRNA induced by amphetamine in the striatum with no alteration of their basal levels. In another set of experiments, the hyperlocomotor activity induced by amphetamine was reduced by pretreatment with intra-striatal infusion of U0126. U0126 also blocked the amphetamine-induced increases in phospho-extracellular-regulated kinase and preproenkephalin and preprodynorphin gene expression in the striatum. These data indicate that activation of the extracellular-regulated kinase cascade contributes to the behavioral effects and changes in striatal neuropeptide gene expression induced by acute amphetamine.

Aminoacetonitrile↗
PubMed2003

Local mu and delta opioid receptors regulate amphetamine-induced behavior and neuropeptide mRNA in the striatum.

The purpose of this study was to investigate the role that mu and delta opioid receptor blockade has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. Intrastriatal infusion of the mu opioid antagonist, H-D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP), or the delta opioid antagonist, H-Tyr-Tic[CH(2)NH]-Phe-Phe-OH (TIPPpsi), significantly decreased amphetamine-induced vertical activity. However, only CTAP reduced amphetamine-induced distance traveled. Quantitative in situ hybridization histochemistry revealed that CTAP blocked amphetamine-induced preprodynorphin and substance P mRNA. However, preproenkephalin mRNA levels in the dorsal striatum were increased to the same extent by CTAP, amphetamine, or a combination of the two drugs. In contrast, TIPPpsi significantly decreased amphetamine-induced mRNA expression of all three neuropeptides. These data indicate that both mu and delta receptor subtypes differentially regulate amphetamine-induced behavior and neuropeptide gene expression in the rat striatum.

Amphetamine↗
PubMed2001

Kappa opioid receptor stimulation decreases amphetamine-induced behavior and neuropeptide mRNA expression in the striatum.

The purpose of this study was to investigate the role that kappa opioid receptor stimulation has upon stimulant-induced behavior and neuropeptide gene expression in the striatum. Acute administration of amphetamine (2.5 mg/kg i.p.) caused an increase in behavioral activity and preprodynorphin, substance P, and preproenkephalin mRNA expression. When amphetamine-treated rats were pretreated with U69593, a kappa agonist (0.16 or 0.32 mg/kg s.c.), there was a significant decrease in behavioral activity. Quantitative in situ hybridization histochemistry revealed that 0.32 mg/kg U69593 significantly decreased amphetamine-induced mRNA expression of all three neuropeptides; however, only the induction of preproenkephalin mRNA was decreased by 0.16 mg/kg. These data suggest that stimulation of kappa receptors decreases acute amphetamine-induced behavior and mRNA expression of neuropeptides in the rat striatum.

Amphetamine↗
PubMed2001

Spinal and supraspinal changes in opioid mRNA expression are related to the onset of pain behaviors following excitotoxic spinal cord injury.

Excitotoxic spinal cord injury (SCI) causes anatomic, physiologic and molecular changes within the spinal cord and brain. Intraspinal injection of quisqualic acid (QUIS) produces an excitotoxic injury that leads to the onset of behavioral syndromes, believed to be related to the clinical condition of chronic pain. The opioid system, classically involved in the suppression of pain transmission, has been associated with the onset of pain-related behaviors and changes in spinal opioid peptide expression have been demonstrated in various models of SCI and chronic pain. Recently, changes in opioid peptide expression have been demonstrated in both spinal and supraspinal areas following excitotoxic SCI. Therefore, the purpose of this study was to examine changes in opioid peptide gene expression as they relate to the onset of pain behaviors following excitotoxic SCI. Male, Long-Evans rats were given an intraspinal injection of 1.2 microl of 125 mM QUIS and allowed to survive for 10 days, a duration sufficient for the development of pain-related behaviors. Animals were assessed daily for the presence of excessive grooming behavior, i.e. self-directed biting and scratching resulting in damage to superficial and deeper layers of the skin. Animals were also tested for thermal hypersensitivity using a cold plate apparatus on days 5, 7, and 10 following QUIS injection. After sacrifice, quantitative in situ hybridization was performed on regions of the spinal cord surrounding the lesion site as well as whole brain sections through various levels of the thalamus and cortex. Spinal preproenkephalin (PPE) and preprodynorphin (PPD) expression was significantly increased in animals that developed excessive grooming behaviors vs. those that did not. For PPE, this difference was seen bilaterally, in areas of cord caudal to the site of injury. For PPD, this difference was seen only ipsilateral to the site of injection, rostral to the site of injury. In addition, PPE expression in the anterior cingulate cortex and PPD expression in the contralateral parietal cortex were significantly higher in grooming vs. non-grooming animals. These results support previous conclusions that both spinal and supraspinal regulation of endogenous opioid peptide expression plays a role in the response to or onset of post-SCI pain. These results also suggest that the opioid peptides are regulated independently and serve different functions in response to SCI.

Animals↗
PubMed2001

Intrastriatal GABA(A) receptor blockade does not alter dopamine D(1)/D(2) receptor interactions in the intact rat striatum.

The purpose of this study was to investigate the effects of intrastriatal blockade of GABA(A) receptors on dopamine D(1)/D(2) receptor interactions in the intact rat striatum. Muscarinic receptors mediate the ability of the D(2) receptor antagonist, eticlopride, to block an increase in striatonigral neuropeptide messenger RNA stimulated by the full D(1) agonist, SKF-82958. However, because D(2) receptor antagonists activate striatopallidal neurons, it is possible that increased GABA release from local medium spiny axon collaterals also contributes to the ability of eticlopride to block the effects of SKF-82958. This hypothesis was addressed by infusing the GABA(A) receptor antagonist, bicuculline, into the dorsal striatum in rats treated with eticlopride and SKF-82958. In contrast to the actions of the muscarinic antagonist, scopolamine, bicuculline did not affect the increase in behaviors induced by SKF-82958 or the ability of eticlopride to block them. Quantitative in situ hybridization demonstrated that bicuculline did not significantly affect basal preprodynorphin messenger RNA, nor did it affect the ability of eticlopride to decrease SKF-82958-induced preprodynorphin messenger RNA. However, the level of the preprodynorphin hybridization signal in bicuculline plus SKF-82958-treated rats was significantly lower than in saline plus SKF-82958-treated rats. In contrast, bicuculline, eticlopride or SKF-82958 by themselves increased basal preproenkephalin messenger RNA. However, there was no significant interaction among bicuculline, eticlopride and SKF-82958 on preproenkephalin messenger RNA levels.These data indicate that blockade of striatal GABA(A) receptors has only a subtle effect on acute dopamine agonist-induced changes in gene expression. These results are discussed in the context of local intrastriatal interactions.

Animals↗
PubMed2001

The role of kainic acid/AMPA and metabotropic glutamate receptors in the regulation of opioid mRNA expression and the onset of pain-related behavior following excitotoxic spinal cord injury.

Intraspinal injection of quisqualic acid, a mixed kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid and metabotropic glutamate receptor agonist, produces an excitotoxic injury that leads to the onset of both spontaneous and evoked pain behavior as well as changes in spinal and cortical expression of opioid peptide mRNA, preprodynorphin and preproenkephalin. What characteristics of the quisqualic acid-induced injury are attributable to activation of each receptor subtype is unknown. This study attempted to define the role of activation of the kainic acid/2-amino-3(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) and metabotropic glutamate receptor subtypes in the regulation of opioid peptide expression and the onset of spontaneous and evoked pain-related behavior following excitotoxic spinal cord injury by comparing quisqualic acid-induced changes with those created by co-injection of quisqualic acid and the kainic acid/AMPA antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline, (NBQX) or the metabotropic antagonist, (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA). Therefore, 42 male Long-Evans adult rats were divided into seven treatment groups and received intraspinal microinjections of saline (sham), 0.5% dimethylsulphoxide (sham), quisqualic acid (1.2 microl, 125 mM), NBQX (1.2 microl, 60 microM), AIDA (1.2 microl, 250 microM), quisqualic acid/NBQX (1.2 microl, 125 mM/60 microM), or quisqualic acid/AIDA (1.2 microl, 125 mM/250 microM) directed at spinal levels thoracic 12-lumbar 2. Behavioral observations of spontaneous and evoked pain responses were completed following surgery. After a 10-day survival period, animals were killed and brain and spinal cord tissues were removed and processed for histologic analysis and in situ hybridization. Both AIDA and NBQX affected the quisqualic acid-induced total lesion volume but only AIDA caused a decrease in the percent tissue damage at the lesion epicenter. Preprodynorphin and preproenkephalin expression is increased in both spinal and cortical areas in quisqualic acid-injected animals versus sham-, NBQX or AIDA-injected animals. NBQX did not affect quisqualic acid-induced spinal or cortical expression of preprodynorphin or preproenkephalin except for a significant decrease in preproenkephalin expression in the spinal cord. In contrast, AIDA significantly decreases quisqualic acid-induced preprodynorphin and preproenkephalin expression within the spinal cord and cortex. AIDA, but not NBQX, significantly reduced the frequency of, and delayed the onset of, quisqualic acid-induced spontaneous pain-related behavior. From these data we suggest that both the kainic acid/AMPA and metabotropic glutamate receptor subtypes are involved in the induction of the excitotoxic cascade responsible for quisqualic acid-induced neuronal damage and changes in opioid peptide mRNA expression, while metabotropic glutamate receptors may play a more significant role in the onset of post-injury pain-related behavior.

Animals↗
PubMed2001

Cyclic AMP and mitogen-activated protein kinases are required for glutamate-dependent cyclic AMP response element binding protein and Elk-1 phosphorylation in the dorsal striatum in vivo.

Dopaminergic and glutamatergic signalling cascades are integrated in striatal medium spiny neurones by cyclic AMP response-element binding protein and Elk-1 phosphorylation. Phosphorylated cyclic AMP response-element binding protein and phosphorylated Elk-1 contribute to c-fos expression by binding to the calcium and cyclic AMP response-element and the serum response element, respectively, in the c-fos promoter. The role of cyclic AMP and mitogen-activated protein kinase signalling cascades in glutamate-induced cyclic AMP response-element binding protein and Elk-1 phosphorylation and Fos expression was investigated using semiquantitative immunocytochemistry in vivo. Intracerebroventricular infusion of the sodium channel blocker, tetrodotoxin, decreased the glutamate-induced increase in phosphorylated cyclic AMP response-element binding protein, phosphorylated Elk-1, and Fos immunoreactivity. Intracerebroventricular infusion of the mitogen-activated and extracellular signal-regulated kinase inhibitor, PD98059, the p38 mitogen-activated protein kinase inhibitor, SB203580, or the cyclic AMP inhibitor, Rp-8-Br-cAMPS, decreased glutamate-induced phosphorylated cyclic AMP response-element binding protein, phosphorylated Elk-1, and Fos immunoreactivity. Simultaneous infusion of glutamate and Sp-8-Br-cAMPS, a cyclic AMP analogue, augmented induction of Fos immunoreactivity but not phosphorylated cyclic AMP response-element binding protein or phosphorylated Elk-1 immunoreactivity. These data indicate that cyclic AMP and mitogen-activated protein kinase signalling cascades are necessary for glutamate to induce cyclic AMP response-element binding protein and Elk-1 phosphorylation and Fos expression in the striatum. Furthermore, neuronal activity plays an important role in glutamate-induced signalling cascades in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Absorption, distribution, metabolism, and excretion of a respirable antisense oligonucleotide for asthma.

EPI-2010 is a respirable antisense oligonucleotide (RASON), which selectively attenuates discordantly overexpressed adenosine A(1) receptors in allergic lung (Nature 1997;385:721). In the present study, aerosolized [(35)S]-labeled EPI-2010 (5 mg exposure; specific activity 0.055 Ci/mmol) was administered to normal rabbits by endotracheal tube to assess biodistribution, route of elimination, and potential cardiovascular toxicity. The animals were killed at 0, 6, 24, 48, and 72 h after inhalation of EPI-2010. Duplicate aliquots from different tissues and samples were solubilized and assessed for radioactivity. Approximately 1.4% of the total aerosolized EPI-2010 was deposited into the lung. The concentration of the drug in the lung at 0, 6, 24, 48, and 72 h was 64.0 +/- 1.5, 67.0 +/- 4.4, 32.0 +/- 3.7, 23.4 +/- 1.4, and 2.1 +/- 0.5 microg equivalents, respectively. Only a small amount of the radioactivity was detected in extrapulmonary tissues. By 72 h, 67.5% of the administered dose was excreted in the urine, which represented the major pathway of elimination. In postlabeling studies, intact full-length EPI-2010 could only be detected in the lung. Autoradiographic analysis after inhalation of [(35)S]-labeled EPI-2010 showed a relatively uniform deposition of drug throughout the lung. The aerosolized EPI-2010 did not have any significant systemic effects on the cardiovascular system as determined by Cardiomax-II analysis. This pattern of distribution and the lack of effect on cardiovascular function support the concept that RASONs offer the potential to safely address respiratory targets for which systemic distribution and systemic bioavailability may be contraindicated.

Administration, Inhalation↗
PubMed2000

Delta opioid receptors regulate calcium-dependent, amphetamine-evoked glutamate levels in the rat striatum: an in vivo microdialysis study.

Blockade of opioid receptors decreases amphetamine-induced behaviors and dopamine release in the striatum. Use of selective opioid receptor ligands has indicated that these effects are mediated by delta opioid receptors (DORs). However, the site of action of delta receptors and the influence of delta receptor antagonists on other neurotransmitters released by amphetamine are unknown. Therefore, the effect of reverse microdialysis of the selective delta opioid antagonist, naltrindole, on extracellular striatal glutamate levels evoked by amphetamine (2.5 mg/kg, i.p.) was investigated. Naltrindole (10-100 microM) decreased amphetamine-evoked glutamate levels in a concentration-dependent manner. The selective delta agonist, [D-Pen(2,5)]-enkephalin (100, 500 microM), reversed the effect of naltrindole, confirming that delta receptors mediated this effect. The amphetamine-evoked increase in extracellular glutamate levels was determined to be 39% calcium-sensitive by lowering the calcium concentration in the perfusate. Under these conditions, naltrindole had no effect on the calcium-independent component of amphetamine-evoked glutamate levels. These data indicate that intrastriatal DORs modulate a calcium-dependent, amphetamine-evoked component of extracellular glutamate levels that may depend on activation of a transsynaptic basal ganglia-thalamo-cortical loop.

Amphetamine↗
PubMed2000

Opioid peptide messenger RNA expression is increased at spinal and supraspinal levels following excitotoxic spinal cord injury.

Spinal cord injury in rats is known to cause anatomical, physiological and molecular changes within the spinal cord. These changes may account for behavioral syndromes that appear following spinal cord injury, syndromes believed to be related to the clinical condition of chronic pain. Intraspinal injection of quisqualic acid produces an excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury. In addition, recent studies have demonstrated changes in blood flow, neuronal excitability and gene expression in the brain following excitotoxic injury, indicating that behavioral changes may result from modification of neuronal substrates at supraspinal levels of the neuraxis. Because changes in spinal opioid peptide expression have been demonstrated in models of traumatic spinal cord injury and chronic pain, the present study investigated messenger RNA expression of the opioid peptides, preproenkephalin and preprodynorphin, at spinal and supraspinal levels following excitotoxic spinal cord injury. Male, Long-Evans rats were given three intraspinal injections of quisqualic acid (total 1.2 microl, 125mM). After one, three, five, seven or 10days, animals were killed and quantitative in situ hybridization performed on regions of the spinal cord surrounding the lesion site, as well as whole-brain sections through various levels of the thalamus. Preproenkephalin and preprodynorphin expression was increased in spinal cord areas adjacent to the site of quisqualic injection and in cortical regions associated with nociceptive function, preproenkephalin in the cingulate cortex and preprodynorphin in the parietal cortex, both ipsilaterally and contralaterally at various time-points following injury. These results further our knowledge of the secondary events that occur following spinal cord injury, specifically implicating supraspinal opioid systems in the CNS response to spinal cord injury.

Animals↗
PubMed2000

N-Methyl-D-aspartate receptors and p38 mitogen-activated protein kinase are required for cAMP-dependent cyclase response element binding protein and Elk-1 phosphorylation in the striatum.

In vivo cyclic adenosine monophosphate (cAMP)-induced N-methyl-D-aspartate receptor and mitogen-activated protein kinase activation was investigated in the dorsal striatum by semiquantitative immunocytochemistry. Intracerebroventricular infusion of 8-bromo-adenosine 3',5'-cyclic monophosphorothioate, Sp isomer (Sp-8-Br-cAMPS), increased phosphorylated cAMP-responsive element binding protein, phosphorylated Elk-1 and Fos immunoreactivity in a dose-dependent manner. Intracerebroventricular infusion of the N-methyl-D-aspartate antagonist, MK801, decreased, but tetrodotoxin or the mitogen-activated extracellular-regulated kinase inhibitor, PD98059, did not affect Sp-8-Br-cAMPS-induced phosphorylated c-AMP-responsive element binding protein, phosphorylated Elk-1, phosphorylated extracellular-signal-regulated kinase and Fos immunoreactivity. The p38 mitogen-activated protein kinase inhibitor, SB203580, decreased the Sp-8-Br-cAMPS-induced increase in all markers, except phosphorylated extracellular-signal-regulated kinase, in a dose-dependent manner. We suggest that N-methyl-D-aspartate receptors couple c-AMP to phosphorylation events and immediate early gene induction in the nucleus of striatal medium spiny neurons. These events are mediated by crosstalk between protein kinase A and mitogen-activated protein kinase cascades in vivo.

8-Bromo Cyclic Adenosine Monophosphate↗
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

Autoradiographic evidence that intrastriatal administration of adenosine A(1) receptor antisense oligodeoxynucleotide decreases adenosine A(1) receptors in the rat striatum and cortex.

In this study, the effect of a phosphorothioated A(1) adenosine receptor antisense oligodeoxynucleotide on A(1) receptor density and mRNA in the striatum and cortex of rats was determined. Receptor autoradiography and in situ hybridization revealed a reduction in striatal and cortical A(1) receptor density and cortical A(1) receptor mRNA, respectively, in antisense-treated brains but not in those treated with a mismatch oligonucleotide. There was no change in A(2) receptor binding. These data imply that the corticostriatal pathway synthesizes A(1) receptors and transports them to its terminals.

Adenosine↗
PubMed1999

The role of dorsal striatal GABA(A) receptors in dopamine agonist-induced behavior and neuropeptide gene expression.

The purpose of this study was to investigate whether GABA(A) receptors in the dorsal striatum regulate basal or stimulant-induced behaviors. Correspondingly, the question of possible GABA(A) receptor control of neuropeptide mRNA expression in nigrostriatal neurons was addressed. The GABA(A) receptor antagonist, bicuculline, was unilaterally or bilaterally microinjected into the dorsal striatum of rats in a series of 3 studies. In the first study, unilateral administration of 10-50 ng/microliter of bicuculline did not alter behavior. However, 250 ng/microliter bicuculline produced motor dyskinesias and/or seizures. In the second study, 100 ng/microliter bicuculline administered unilaterally prior to saline or amphetamine treatment, produced mild twitching in 61% of rats but did not affect amphetamine (2.5 mg/kg, i.p.)-induced behavioral activity, specifically rearing and sniffing. In the third study, 75 ng/microliter of bicuculline was administered unilaterally or bilaterally into the striatum in two separate experiments. Administration of bicuculline either unilaterally or bilaterally produced mild transient twitching of the forelimbs but did not affect behaviors induced by the selective D(1) receptor agonist SKF-82958 (0.5 mg/kg, s.c.). Three hours after unilateral bicuculline administration, the brains were removed and processed for quantitative in situ hybridization. Bicuculline did not significantly affect the basal or SKF-82958-induced increase in preprodynorphin or substance P mRNA expression in striatonigral neurons on the side of injection. These data suggest that blockade of GABA(A) receptors in the dorsal striatum does not affect dopamine agonist-stimulated behaviors or neuropeptide mRNA expression in striatonigral neurons in the rat striatum.

Animals↗
PubMed1999

Regulation of neurotransmitter interactions in the ventral striatum.

Transsynaptic activation of neuronal circuits originating in the basal forebrain contributes to psychostimulant-evoked dopamine and glutamate release and consequent changes in medium spiny neuronal gene expression in the ventral striatum. New evidence from microdialysis studies indicates that amphetamine-induced dopamine and glutamate release in vivo is partially calcium dependent. The calcium-dependent component is totally blocked by a kappa opioid receptor agonist, indicating that endogenous opioids may regulate dopamine-glutamate interactions in the ventral striatum. Further, muscarinic receptor blockade increases, and muscarinic receptor stimulation decreases, dialysate glutamate levels in the striatum. Pre- and postsynaptic muscarinic receptors contribute to the ability of the muscarinic antagonist, scopolamine, to augment D1 receptor-stimulated immediate early and neuropeptide gene expression. Moreover, scopolamine prevents a D2 antagonist from blocking D1 agonist-induced gene expression, indicating that activation of cholinergic interneurons contributes to D1/D2 interactions in the striatum. Thus, transsynaptic activity and presynaptic muscarinic and kappa opioid receptors regulate dopamine and glutamate interactions that switch on and off multiple intracellular signaling cascades. Changes in immediate early and neuropeptide gene expression that result from activation of these cascades are mediated by such nuclear transcription factors as phosphorylated cyclase response element-binding protein. In addition, a novel signaling pathway involving the RAR/RXR nuclear hormone receptor complex is implicated in the control of dopamine receptor and neuropeptide gene expression in the striatum.

Animals↗
PubMed1999

Presynaptic kappa-opioid and muscarinic receptors inhibit the calcium-dependent component of evoked glutamate release from striatal synaptosomes.

In addition to cytosolic efflux, reversal of excitatory amino acid (EAA) transporters evokes glutamate exocytosis from the striatum in vivo. Both kappa-opioid and muscarinic receptor agonists suppress this calcium-dependent response. These data led to the hypothesis that the calcium-independent efflux of striatal glutamate evoked by transporter reversal may activate a transsynaptic feedback loop that promotes glutamate exocytosis from thalamo- and/or corticostriatal terminals in vivo and that this activation is inhibited by presynaptic kappa and muscarinic receptors. Corollaries to this hypothesis are the predictions that agonists for these putative presynaptic receptors will selectively inhibit the calcium-dependent component of glutamate released from striatal synaptosomes, whereas the calcium-independent efflux evoked by an EAA transporter blocker, L-trans-pyrrolidine-2,4-dicarboxylic acid (L-trans-PDC), will be insensitive to such receptor ligands. Here we report that a muscarinic agonist, oxotremorine (0.01-10 microM), and a kappa-opioid agonist, U-69593 (0.1-100 microM), suppressed the calcium-dependent release of glutamate that was evoked by exposing striatal synaptosomes to the potassium channel blocker 4-aminopyridine. The presynaptic inhibition produced by these ligands was concentration dependent, blocked by appropriate receptor antagonists, and not mimicked by the delta-opioid agonist [D-Pen2,5]-enkephalin. The finding that glutamate efflux evoked by L-trans-PDC from isolated striatal nerve endings was entirely calcium independent supports the notion that intact basal ganglia circuitry mediates the calcium-dependent effects of this agent on glutamate efflux in vivo. Furthermore, because muscarinic or kappa-opioid receptor activation inhibits calcium-dependent striatal glutamate release in vitro as it does in vivo, it is likely that both muscarinic and kappa receptors are inhibitory presynaptic heteroceptors expressed by striatal glutamatergic terminals.

4-Aminopyridine↗
PubMed1999

The kappa-opioid agonist, U-69593, decreases acute amphetamine-evoked behaviors and calcium-dependent dialysate levels of dopamine and glutamate in the ventral striatum.

The effects of a kappa-opioid receptor agonist on acute amphetamine-induced behavioral activation and dialysate levels of dopamine and glutamate in the ventral striatum were investigated. Amphetamine (2.5 mg/kg i.p.) evoked a substantial increase in rearing, sniffing, and hole-poking behavior as well as dopamine and glutamate levels in the ventral striatum of awake rats. U-69593 (0.32 mg/kg s.c.) significantly decreased the amphetamine-evoked increase in behavior and dopamine and glutamate levels in the ventral striatum. Reverse dialysis of the selective kappa-opioid receptor antagonist, nor-binaltorphimine, into the ventral striatum antagonized the effects of U-69593 on amphetamine-induced behavior and dopamine and glutamate levels. Reverse dialysis of low calcium (0.1 mM) into the ventral striatum decreased basal dopamine, but not glutamate, dialysate levels by 91% 45 min after initiation of perfusion. Strikingly, 0.1 mM calcium perfusion significantly reduced the 2.5 mg/kg amphetamine-evoked increase in dopamine and glutamate levels in the ventral striatum, distinguishing a calcium-dependent and a calcium-independent component of release. U-69593 did not alter the calcium-independent component of amphetamine-evoked dopamine and glutamate levels. These data are consistent with the view that a transsynaptic mechanism augments the increase in dopamine and glutamate levels in the ventral striatum evoked by a moderately high dose of amphetamine and that stimulation of kappa-opioid receptors suppresses the calcium-dependent component of amphetamine's effects.

Amphetamine↗