The enhancement of glutamate release in the nucleus accumbens of rats with a destroyed hippocampal formation during an emotional conditioned response]

It was shown by means of in vivo microdialysis combined with HPLC/EC analysis that the exocytotoxic lesions of the hippocampal formation impaired the emotional conditioning and led to additional glutamate release in the n. accumbens during acquisition and performance of the conditioned response. Thus, it was shown that the disruption of glutamatergic synaptic transmission in the n. accumbens results in a compensatory increase in the volume glutamatergic transmission in this structure.     

Dopamine-dependent inhibition of glycine release in the rat nucleus accumbens during feeding

Food intake decreased the glycine extracellular level in the rat n.accumbens. Tetrodotoxin prevented the decrease, whereas D,L-threo-beta-hydroxyaspartic acid exerted no effect. Raclopride (D2 dopamine receptor antagonist) increased the glycine extracellular level in food intake. The data obtained suggest that during feeding the glycine release in the n.accumbens is controlled by the D2 dopamine receptors.     

Changes in glutamate release in the rat nucleus accumbens during food and pain reinforcement

In vivo microdialysis combined with HPLC-EC analysis was used to monitor extracellular glutamate in the n. accumbens of Sprague-Dawley rats during footshock and food delivery. The footshock presentation resulted in a delayed increase in extracellular glutamate level, whereas the food intake caused its decrease. The intra-accumbens infusion of glutamate reuptake blocker D,L-threo-beta-hydroxiaspartate (1 mM) completely prevented the food-induced decrease in glutamate level. The intra-accumbens infusion of sodium channel blocker tetrodotoxin (1 microM) led to an increase in glutamate extracellular level in the n. accumbens in response to food intake. The results suggest that the food-induced decrease in glutamate extracellular level in the n. accumbens occurs due to an enhancement of high-affinity glutamate uptake that is probably under the neuronal control during feeding.     

Tetrodotoxine-dependent glycine release in the rat nucleus accumbens during correction of feeding behaviour

Presence of a tone previously paired with a foot-shock in rats during food intake increases the glycine extracellular level in the n. accumbens. The increase will be completely prevented by intra-accumbal infusion of Na-channel blocking agent tetrodotoxine. The findings suggest that glycine mechanisms in the n. accumbens are involved in the correction of feeding behaviour.     

Vesicular and nonvesicular glutamate release in the nucleus accumbens during a forced switch in behavioral strategy

By means of in vivo microdialysis combined with HPLC analysis, we have shown that glutamate extracellular level in the rat n. accumbens increases during a forced switch in behavioral strategy. When infused in the n. accumbens, a Na+ channel blocker tetrodotoxin (TTX, 1 microM) completely prevents this increase whereas a potent cystine/glutamate exchanger blocker (S)-4-carboxyphenylglycine ((S)-4-CPG, 5 microM) has no effect. In contrast, TT (1 microM), infused in the n. accumbens, fails to significantly alter basal level of extracellular glutamate in this region whereas (S)-4-CPG (5 microM) produced a significant decrease. Our data suggest that basal and factional glutamate releases in the n. accumbens are differently regulated. The source of basal glutamate release is a non-vesicular release via cystine/glutamate exchanger. Functional glutamate release observed during a forced switch in behavioral strategy derives from vesicular synaptic pool.     

Inhibition of non-vesicular glutamate release by group III metabotropic glutamate receptors in the nucleus accumbens

Previous in vitro studies have shown that group III metabotropic glutamate receptors (mGluRs) regulate synaptic glutamate release. The present study used microdialysis to characterize this regulation in vivo in rat nucleus accumbens. Reverse dialysis of the group III mGluR agonist l-(+)-2-amino-4-phosphonobutyric acid (L-AP4) decreased, whereas the antagonist (R,S)-alpha-methylserine-O-phosphate (MSOP) increased the extracellular level of glutamate. The decrease by L-AP4 or the increase by MSOP was antagonized by co-administration of MSOP or L-AP4, respectively. Activation of mGluR4a by (1S,3R,4S)-1-aminocyclopentane-1,2,4-tricarboxylic acid or mGluR6 by 2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid had no effect on extracellular glutamate. (R,S)-4-Phosphonophenylglycine (PPG), another group III agonist with high affinity for mGluR4/6/8, reduced extracellular glutamate only at high concentrations capable of binding to mGluR7. The increase in extracellular glutamate by MSOP was tetrodotoxin-independent, and resistant to both the L-type and N-type Ca2+ channel blockers. L-AP4 failed to block 30 mm K+-induced vesicular glutamate release. Blockade of glutamate uptake by d,l-threo-beta-benzyloxyaspartate caused a Ca2+-independent elevation in extracellular glutamate that was reversed by L-AP4. Finally, (S)-4-carboxyphenylglycine, an inhibitor of cystine-glutamate antiporters, attenuated the L-AP4-induced reduction in extracellular glutamate. Together, these data indicate that group III mGluRs regulate in vivo extracellular glutamate in the nucleus accumbens by inhibiting non-vesicular glutamate release.     

Citrulline extracellular level in the nucleus accumbens during feeding behaviour

In Sprague-Dawley rats, by means of in vivo microdialysis combined with HPLC analysis it was shown that a consumption of a novel food did not produce any changes in extracellular levels ofcitrulline (an NO-co-product) in the medial n. accumbens. In contrast, the rejection of the novel food caused a rise of the extracellular citrulline level in this brain area which can be completely prevented by intra-accumbal infusion of 0.5 mM 7-nitroindazple, a neuronal NO-synthase inhibitor. The data obtained reveal for the first time that new food rejection (but not its consumption) is characterized by neuronal NO-synthase activation and, very likely, NO production in the medial nucleus accumbens.     

Nociceptin differentially affects morphine-induced dopamine release from the nucleus accumbens and nucleus caudate in rats

The effects induced by nociceptin on morphine-induced release of dopamine (DA), 3,4-dihydroxyphenilacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens and nucleus caudate were studied in rats by microdialysis with electrochemical detection. Nociceptin administered intracerebroventricularly (i.c.v.) at doses of 2, 5 and 10 nmol/rat changed neither DA nor metabolites release in the shell of the nucleus accumbens or in the nucleus caudate. Morphine administered intraperitoneally (i.p.) (2, 5, and 10 mg/kg) increased DA and metabolites release more in the shell of the nucleus accumbens than in the nucleus caudate. When nociceptin (5 or 10 nmol) was administered 15 min before morphine (5 or 10 mg/kg), it significantly reduced morphine-induced DA and metabolites release in the shell of the nucleus accumbens, whereas only a slight, nonsignificant reduction was observed in the nucleus caudate. Our data indicate that nociceptin may regulate the stimulating action associated with morphine-induced DA release more in the nucleus accumbens than in the nucleus caudate, and are consistent with recent observations that nociceptin reversed ethanol- and morphine-induced conditioned place preference. Therefore, the nociceptin-induced reduction of DA release stimulated by morphine in the nucleus accumbens, and the results obtained with nociceptin in the conditioned place preference procedure suggest a role for nociceptin in the modulation of the behavioral and neurochemical effects of abuse drugs.     

Adenosine receptor-mediated modulation of dopamine release in the nucleus accumbens depends on glutamate neurotransmission and N-methyl-D-aspartate receptor stimulation

Adenosine, by acting on adenosine A(1) and A(2A) receptors, exerts opposite modulatory roles on striatal extracellular levels of glutamate and dopamine, with activation of A(1) inhibiting and activation of A(2A) receptors stimulating glutamate and dopamine release. Adenosine-mediated modulation of striatal dopaminergic neurotransmission could be secondary to changes in glutamate neurotransmission, in view of evidence for a preferential colocalization of A(1) and A(2A) receptors in glutamatergic nerve terminals. By using in vivo microdialysis techniques, local perfusion of NMDA (3, 10 microm), the selective A(2A) receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine (CGS 21680; 3, 10 microm), the selective A(1) receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 300, 1000 microm), or the non-selective A(1)-A(2A) receptor antagonist in vitro caffeine (300, 1000 microm) elicited significant increases in extracellular levels of dopamine in the shell of the nucleus accumbens (NAc). Significant glutamate release was also observed with local perfusion of CGS 21680, CPT and caffeine, but not NMDA. Co-perfusion with the competitive NMDA receptor antagonist dl-2-amino-5-phosphonovaleric acid (APV; 100 microm) counteracted dopamine release induced by NMDA, CGS 21680, CPT and caffeine. Co-perfusion with the selective A(2A) receptor antagonist MSX-3 (1 microm) counteracted dopamine and glutamate release induced by CGS 21680, CPT and caffeine and did not modify dopamine release induced by NMDA. These results indicate that modulation of dopamine release in the shell of the NAc by A(1) and A(2A) receptors is mostly secondary to their opposite modulatory role on glutamatergic neurotransmission and depends on stimulation of NMDA receptors. Furthermore, these results underscore the role of A(1) vs. A(2A) receptor antagonism in the central effects of caffeine.     

Comparison in changes of glutamate level in the rat nucleus accumbens induced by D1- and D2-dopamine receptors during feeding

The influence of dopamine D1- and D2-like receptors blockage on glutamate level in the n. accumbens of Sprague-Dawly rats during feeding was investigated by in vivo microdialysis combined with HPLC-EC analysis. Food intake resulted in a decrease in extracellular glutamate level. Infusion of D1-like dopamine receptor-blocker (SCH-23390, 0.01 mM) into the n. accumbens did not change this effect. Infusion of D2-like dopamine receptor-blocker (raclopride, 0.1 mM) into the n. accumbens caused an increase in extracellular glutamate level during feeding. The findings suggest, that decrease in extracellular glutamate level in n. accumbens is caused by dopamine D2-like, but not D1-like receptors activation.     

Glutamate release in the nucleus accumbens during competitive presentation of aversive and appetitive stimuli

By means of in vivo microdialysis combined with HPLC analysis, we have shown that extracellular glutamate level in the rat n. accumbens increases during a simultaneous presentation of a palatable diet and a tone previously paired with a footshock, the magnitude of the extracellular glutamate increase being proportional to the latency of food taking. In contrast, extracellular glutamate level remains unchanged when the diet is presented after the conditioned aversive stimulus or when the tone is given alone. These data suggest that the glutamate release evoked by the competitive presentation of the diet and the conditioned aversive stimulus appears to be related to the inhibition of a planned feeding response, whereas the choice between behavioural strategies may not contribute to this phenomenon.     

Conditioned reflex dopamine release in the nucleus accumbens in rats with disrupted hippocampal formation

Lesion of the hippocampal formation affects in different ways the dopamine release in response to the two phases of emotional conditioning: increases the acquisition and exerts no effect on the expression of the reflex in rats.     

Enhancement of glutamate release in the extracellular space of nucleus accumbens during presentation of aversive or neutral stimuli instead of food reinforcement

By means of in vivo microdialysis combined with HPLC/EC analysis it was shown that presentation to a rat of an inedible object (a piece of rubber) or an aversive object (food of bitter taste) instead of expected food caused a marked increase in extracellular glutamate level in n. accumbens. In rats not expecting food reinforcement, extracellular glutamate remained unchanged during presentation of these objects. Our findings suggest that dissociation between the expected biological value of a presented object and its real significance may be an important determinant for glutamate release control in n. accumbens during food behavior.     

Regulation of 3H-dopamine release by presynaptic GABA and glutamate heteroreceptors in the synaptosomes of the rat nucleus accumbens

The influence of GABA, muscimol, delta-aminolevulinic acid (DALA), baclofen and L-glutamate on K+-evoked release of 3H-dopamine (3H-DA) from the rat brain n. accumbens crude synaptosomal fraction was studied in superfusion experimental conditions. Both GABA-receptor agonists--GABA and muscimol (50 microM) depressed the 3H-DA release by bicuculline- and picrotoxin-sensitive manner. On the contrary, glutamate, DALA and baclofen led to the increase in 3H-DA efflux independently of the presence of GABA-receptor antagonists. While the action of glutamate was antagonized by glutamate-receptor blocker--glutamic acid diethyl ester (GDEE), the effects of DALA and baclofen were suppressed upon adding to superfusion medium of GABA uptake inhibitors (nipecotic acid and 2,4-diaminobutyric acid) but not GDEE. The data obtained demonstrate that 3-H-DA secretion from n. accumbens is inhibited by GABA- and stimulated by glutamate-heteroreceptors. At the same time the mechanism of interaction between baclofen, DALA and GABA-uptake blockers effects with 3H-DA release needs special investigations.     

Effects of N-acetylaspartylglutamate (NAAG) peptidase inhibition on release of glutamate and dopamine in prefrontal cortex and nucleus accumbens in phencyclidine model of schizophrenia

The "glutamate" theory of schizophrenia emerged from the observation that phencyclidine (PCP), an open channel antagonist of the NMDA subtype of glutamate receptor, induces schizophrenia-like behaviors in humans. PCP also induces a complex set of behaviors in animal models of this disorder. PCP also increases glutamate and dopamine release in the medial prefrontal cortex and nucleus accumbens, brain regions associated with expression of psychosis. Increased motor activation is among the PCP-induced behaviors that have been widely validated as models for the characterization of new antipsychotic drugs. The peptide transmitter N-acetylaspartylglutamate (NAAG) activates a group II metabotropic receptor, mGluR3. Polymorphisms in this receptor have been associated with schizophrenia. Inhibitors of glutamate carboxypeptidase II, an enzyme that inactivates NAAG following synaptic release, reduce several behaviors induced by PCP in animal models. This research tested the hypothesis that two structurally distinct NAAG peptidase inhibitors, ZJ43 and 2-(phosphonomethyl)pentane-1,5-dioic acid, would elevate levels of synaptically released NAAG and reduce PCP-induced increases in glutamate and dopamine levels in the medial prefrontal cortex and nucleus accumbens. NAAG-like immunoreactivity was found in neurons and presumptive synaptic endings in both regions. These peptidase inhibitors reduced the motor activation effects of PCP while elevating extracellular NAAG levels. They also blocked PCP-induced increases in glutamate but not dopamine or its metabolites. The mGluR2/3 antagonist LY341495 blocked these behavioral and neurochemical effects of the peptidase inhibitors. The data reported here provide a foundation for assessment of the neurochemical mechanism through which NAAG achieves its antipsychotic-like behavioral effects and support the conclusion NAAG peptidase inhibitors warrant further study as a novel antipsychotic therapy aimed at mGluR3.     

Effects of nucleus accumbens lesions in rats on spatial preference in an open field

Selective lesions placed in three different regions of the nucleus accumbens were performed to assess their effects on spatial preference in the rat. Histological verification allowed to establish three groups of lesioned animals: medial, intermediate and lateral. Sham operations involved all procedures except the passing of a current. All animals were tested once prior to operation and twice postoperatively. Sherman's directionality score (DS) was adopted. Positive values indicate right side preference and negative ones leftward bias. Statistical analysis revealed that rats used in this study showed a nonsignificant spontaneous right side preference in the open field (DS = +0.08). Medial and intermediate lesions increased the right side bias (DS = +0.37), whereas lateral lesioned animals reversed their preoperative rightward bias and showed a significant left side preference (DS = -0.48). These results suggest a participation of the nucleus accumbens in spatial preference and are considered to be due to the well known uneven distribution of the afferent and efferent fiber systems within the nucleus.     

谷氨酸及NMDA受体拮抗剂MK-801对大鼠伏核痛兴奋神经元电活动的影响

本文研究了谷氨酸(glutamic acid,Glu)及其NMDA受体拮抗剂5-甲基二氢丙环庚烯亚胺马来酸(MK-801)对人鼠伏核(nucleus accumbens,NAc)痛兴奋神经元(pain-excitation neurons,PEN)痛诱发反应的影响。电刺激坐骨神经作为伤害性刺激,用玻璃微电极记录NAc的PEN放电,观察脑室内注射Glu和NAc内注射MK-801对大鼠NAc中PEN伤害性诱发活动的影响。结果显示,伤害性刺激可使NAc的PEN电活动增强;脑室内注射Glu(10nmol／10μl)可使NAc的PEN伤害性诱发放电频率增加;NAc内注射MK-801(1．0nmol／0．5μl)可阻断这种作用;MK-801本身也可部分抑制PEN伤害性诱发反应。上述结果表明,Glu对PEN伤害性反应的易化作用是通过NMDA受体介导的：Glu和NMDA受体参与NAc伤害性信息传递的调制。     

Glutamatergic regulation of citrulline extracellular level in the nucleus accumbens during acquisition and expression of conditioned emotional response

In Spregue-Dawley rats, by means of in vivo microdialysis combined with HPLC analysis, it was shown that acquisition and expression of conditioned emotional response increased extracellular level of citrulline: a nitric oxide coproduct, in the nucleus accumbens. Intraaccumbal infusion of MK-801 (100 microM): an NMDA antagonist, markedly attenuated the increase in extracellular citrulline in the n. accumbens produced by acquisition of the response, and completely prevented its conditioned rise observed during expression of the response. The data obtained suggest that, during acquisition and expression of the conditioned emotional response, glutamatergic input to the n. accumbens might act via NMDA receptors to stimulate NO production within this brain area.     

Regulation of nucleus accumbens dopamine release by the dorsal raphe nucleus in the rat

The effects of microinfusingl-glutamate, serotonin (5-HT), (±)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH DPAT; a 5-HT_1A agonist), and muscimol (a GABA_A agonist) into the dorsal raphe nucleus on the extracellular levels of 5-HT, dopamine (DA) and their metabolites in the nucleus accumbens were studied in unanesthetized, freely moving, adult male Wistar rats, using the technique of microdialysis coupled with small-bore HPLC. Administration of 0.75 gl-glutamate produced a 25–50% increase (P<0.05) in the extracellular levels of both 5-HT and DA. On the other hand, infusion of 8-OH DPAT and, to a lesser extent, 5-HT produced a significant (P<0.05) decrease in the extracellular levels of both 5-HT and DA. Muscimol (0.25 or 0.50 g) had little effect on the extracellular concentrations of 5-HT or DA following its administration. In general, the extracellular levels of the major metabolites of 5-HT and DA in the nucleus accumbens were not altered by microinfusion of any of the agents. The data indicate that (a) the 5-HT neurons projecting to the nucleus accumbens from the dorsal raphe nucleus can be activated by excitatory amino acid receptors and inhibited by stimulation of 5-HT_1A autoreceptors, and (b) the dorsal raphe nucleus 5-HT neuronal system may regulate the ventral tegmental area DA projection to the nucleus accumbens.Special issue dedicated to Dr. Morris H. Aprison     

Effects of CCK-8 in the nucleus accumbens

The electrophysiological effects of CCK-8 were studied in the rabbit nucleus accumbens. CCK-8 was found to influence neurotransmitter (modulator) systems so as to enhance their action. For example, CCK-8 enhanced the effects of stimulation of the glutaminergic pathways, the fimbria. In addition, when CCK-8 was co-administered with dopamine and acetylcholine, their suppressive effect on the fimbria evoked response was enhanced. Therefore, CCK-8 appears to be capable of enhancing the influence of multiple neurotransmitter (modulator) systems.