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.     

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.     

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 motivational and emotional factors on glutamate release in the nucleus accumbens of rats during feeding

Food intake was shown to decrease the glutamate extracellular level in the nucleus accumbens in both deprived and non-deprived Spraque-Dawly rats. Feeding combined with presentation of a tone previously paired with foot shock caused an increase in the glutamate extracellular level in deprived rats only, whereas the tone alone had no effect. The data suggest that emotional and motivational variations exert co-operative effect on the glutamate release in the nucleus accumbens during feeding.     

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.     

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.     

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.     

Role of tissue plasminogen activator in the sensitization of methamphetamine-induced dopamine release in the nucleus accumbens

We have previously demonstrated that repeated, but not acute, methamphetamine (METH) treatment increases tissue plasminogen activator (tPA) activity in the brain, which is associated with the development of behavioral sensitization to METH. In this study, we investigated whether the tPA-plasmin system is involved in the development of sensitization in METH-induced dopamine release in the nucleus accumbens (NAc). There was no difference in acute METH-induced increase in extracellular dopamine levels in the NAc between wild-type and tPA-deficient (tPA−/−) mice. Repeated METH treatment resulted in a significant enhancement of METH- induced dopamine release in wild-type mice, but not tPA−/− mice. Microinjection of exogenous tPA or plasmin into the NAc of wild-type mice significantly potentiated acute METH- induced dopamine release. Degradation of laminin was evident in brain tissues incubated with tPA plus plasminogen or plasmin in vitro although tPA or plasminogen alone had no effect. Immunohistochemical analysis revealed that microinjection of plasmin into the NAc reduced laminin immunoreactivity without neuronal damage. Our findings suggest that the tPA-plasmin system participates in the development of behavioral sensitization induced by repeated METH treatment, by regulating the processes underlying the sensitization of METH-induced dopamine release in the NAc, in which degradation of laminin by plasmin may play a role.     

Mediolateral gradient of the nucleus accumbens nitrergic activation during exploratory behavior

In Sprague-Dawley rats, by means of in vivo microdialysis combined with HPLC analysis it has been shown that an exploratory behavior in a new environment is accompanied by a rise in extracellular levels of citrulline (an NO co-product) in the mediolateral regions of the n. accumbens with the maximum observed in the medial n. accumbens. Infusions of 7-nitroindazole (0.5 mM), a neuronal NO synthase inhibitor, into the medial n. accumbens prevented the exploration-induced rise of extracellular citrulline levels in this area. The second presentation of the same chamber did not produce any significant changes of extracellular citrulline levels in the medial n. accumbens, although there was a tendency of a small increase. The presentation of a familiar chamber did not affect citrulline extracellular levels in this area. The data obtained indicate for the first time that exploratory activity in a new environment is accompanied by the nitrergic activation in the entire n. accumbens with the maximal activation in the medial part of this brain area.     

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.     

Stimulation of prefrontal cortex at physiologically relevant frequencies inhibits dopamine release in the nucleus accumbens

The prefrontal cortex (PFC) is thought to provide an excitatory influence on the output of mesoaccumbens dopamine neurons. The evidence for this influence primarily arises from findings in the rat that chemical or high-intensity and high-frequency (60-200 Hz) electrical stimulations of PFC increase burst activity of midbrain dopamine neurons, and augment terminal release of dopamine in the nucleus accumbens. However, PFC neurons in animals that are engaged in PFC-dependent cognitive tasks increase their firing frequency from a baseline of 1-3 Hz to 7-10 Hz, suggesting that the commonly used high-frequency stimulation parameters of the PFC may not be relevant to the behavioral states that are associated with PFC activation. We investigated the influence of PFC activation at lower physiologically relevant frequencies on the release of dopamine in the nucleus accumbens. Using rapid (5-min) microdialysis measures of extracellular dopamine in the nucleus accumbens, we found that although PFC stimulation at 60 Hz produces the expected increases in accumbal dopamine release, the same amplitude of PFC stimulation at 10 Hz significantly decreased these levels. These results indicate that activation of PFC, at frequencies that are associated with increased cognitive demand on this region, inhibits the mesoaccumbens dopamine system.     

Coordinated activity of ventral tegmental neurons adapts to appetitive and aversive learning

Our understanding of how value-related information is encoded in the ventral tegmental area (VTA) is based mainly on the responses of individual putative dopamine neurons. In contrast to cortical areas, the nature of coordinated interactions between groups of VTA neurons during motivated behavior is largely unknown. These interactions can strongly affect information processing, highlighting the importance of investigating network level activity. We recorded the activity of multiple single units and local field potentials (LFP) in the VTA during a task in which rats learned to associate novel stimuli with different outcomes. We found that coordinated activity of VTA units with either putative dopamine or GABA waveforms was influenced differently by rewarding versus aversive outcomes. Specifically, after learning, stimuli paired with a rewarding outcome increased the correlation in activity levels between unit pairs whereas stimuli paired with an aversive outcome decreased the correlation. Paired single unit responses also became more redundant after learning. These response patterns flexibly tracked the reversal of contingencies, suggesting that learning is associated with changing correlations and enhanced functional connectivity between VTA neurons. Analysis of LFP recorded simultaneously with unit activity showed an increase in the power of theta oscillations when stimuli predicted reward but not an aversive outcome. With learning, a higher proportion of putative GABA units were phase locked to the theta oscillations than putative dopamine units. These patterns also adapted when task contingencies were changed. Taken together, these data demonstrate that VTA neurons organize flexibly as functional networks to support appetitive and aversive learning.     

Organization of interneuronal relationships in the nucleus accumbens during impulsive and self-control behavior in cats

Under conditions of a choice between a high-valuable delayed and a low-valuable immediate food rewards, cats were divided into 3 groups on the basis of their individual strategy of behavior: (1) choosing predominantly the high-valuable reward because of inhibition of the instrumental response (capable of self-control), (2) choosing predominantly the immediate low-valuable reward (impulsive), and (3) with a mixed pattern of reactions (ambivalent). Coherent activity of nucleus accumbens neurons which was a characteristic of interactions between nearby cells was assessed by the method of crosscorrelation. It was found that the total number of interneuronal interactions in cats capable of self-control exceeded that displayed by impulsive cats. In those rare cases when impulsive cats performed long-latency responses not typical of them, the number of interneuronal interactions was the same as during the self-control behavior. In animals of different groups, the number of interneuronal interactions was higher during erroneous responses as compared to correctly performed reactions. The results suggest an important role of systemic activity of neurons in the nucleus accumbens in the organization of the long-latency reaction pattern, characteristic of self-control behavior.     

In vivo regulation of dopamine and noradrenaline release by alpha2A-adrenoceptors in the mouse nucleus accumbens

The present study investigated the role of alpha2A-adrenoceptor (alpha2A-AR) subtype in the regulation of noradrenaline (NA) and dopamine (DA) release in the nucleus accumbens (NAc). The effect of locally infused and systemically injected alpha2-AR agonist, dexmedetomidine (DMT), and alpha2-AR antagonist, atipamezole, on NA and DA release was investigated in alpha2A-AR knockout and control mice by using in vivo microdialysis. In addition, we compared the drug effects on DA and NA release in the NAc to their effect on locomotor activity. Baseline NA and DA concentrations did not differ between genotypes. Local infusion of DMT decreased, in a concentration-dependent manner, NA, but not DA, levels in the control mice. However, systemic injection of DMT decreased both NA and DA levels in the control mice. In both cases DMT had no effects on transmitter release in alpha2A-AR knockout mice. Our results suggest that alpha2-ARs regulate the release of NA, but not DA, at the terminal level in the NAc. However, alpha2-ARs regulate DA release in the NAc indirectly by their effect on DA neurones in the ventral tegmental area via an unknown mechanism. In both cases the regulation is mediated by alpha2A-adrenoceptor subtype. Also the modulation of locomotor activity by alpha2-AR agonist and antagonist seems to be mediated via alpha2A-adrenoceptors.     

Roles of octopaminergic and dopaminergic neurons in appetitive and aversive memory recall in an insect

Background  

In insect classical conditioning, octopamine (the invertebrate counterpart of noradrenaline) or dopamine has been suggested to mediate reinforcing properties of appetitive or aversive unconditioned stimulus, respectively. However, the roles of octopaminergic and dopaminergic neurons in memory recall have remained unclear.     

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.