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.     

Opposite modulatory roles for adenosine A1 and A2A receptors on glutamate and dopamine release in the shell of the nucleus accumbens. Effects of chronic caffeine exposure

Previous studies have demonstrated opposing roles for adenosine A1 and A2A receptors in the modulation of extracellular levels of glutamate and dopamine in the striatum. In the present study, acute systemic administration of motor-activating doses of the A2A receptor antagonist MSX-3 significantly decreased extracellular levels of dopamine and glutamate in the shell of the rat nucleus accumbens (NAc) and counteracted both dopamine and glutamate release induced by systemic administration of motor-activating doses of either the A1 receptor antagonist CPT or caffeine. Furthermore, exposure to caffeine in the drinking water (1 mg/mL, 14 days) resulted in tolerance to the effects of systemic injection of CPT or caffeine, but not MSX-3, on extracellular levels of dopamine and glutamate in the NAc shell. The present results show: first, the existence of opposite tonic effects of adenosine on extracellular levels of dopamine and glutamate in the shell of the NAc mediated by A1 and A2A receptors; second, that complete tolerance to caffeine's dopamine- and glutamate-releasing effects which develops after chronic caffeine exposure is attributable to an A1 receptor-mediated mechanism. Development of tolerance to the dopamine-releasing effects of caffeine in the shell of the NAc may explain its weak addictive properties and atypical psychostimulant profile.     

GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A2A receptors

Glial cell line-derived neurotrophic factor (GDNF) affords neuroprotection in Parkinson's disease in accordance with its ability to bolster nigrostriatal innervation. We previously found that GDNF facilitates dopamine release in a manner dependent on adenosine A_2A receptor activation. As motor dysfunction also involves modifications of striatal glutamatergic innervation, we now tested if GDNF and its receptor system, Ret ( rearranged during transfection ) and GDNF family receptor α1 controlled the cortico-striatal glutamatergic pathway in an A_2A receptor-dependent manner. GDNF (10 ng/mL) enhanced (by ≈13%) glutamate release from rat striatal nerve endings, an effect potentiated (up to ≈30%) by the A_2A receptor agonist CGS 21680 (10 nM) and prevented by the A_2A receptor antagonist, SCH 58261 (50 nM). Triple immunocytochemical studies revealed that Ret and GDNF family receptor α1 were located in 50% of rat striatal glutamatergic terminals (immunopositive for vesicular glutamate transporters-1/2), where they were found to be co-located with A_2A receptors. Activation of the glutamatergic system upon in vivo electrical stimulation of the rat cortico-striatal input induced striatal Ret phosphorylation that was prevented by pre-treatment with the A_2A receptor antagonist, MSX-3 (3 mg/kg). The results provide the first functional and morphological evidence that GDNF controls cortico-striatal glutamatergic pathways in a manner largely dependent on the co-activation of adenosine A_2A receptors.     

Adenosine and dopamine receptor antagonist binding in the rat ventral and dorsal striatum: lack of changes after a neonatal bilateral lesion of the ventral hippocampus.

There is experimental evidence from radioligand binding experiments for the existence of strong antagonistic interactions between different subtypes of adenosine and dopamine receptors in the striatum, mainly between adenosine A1 and dopamine D1 and between adenosine A2A and dopamine D2 receptors. These interactions seem to be more powerful in the ventral compared to the dorsal striatum, which might have some implications for the treatment of schizophrenia. The binding characteristics of different dopamine and adenosine receptor subtypes were analysed in the different striatal compartments (dorsolateral striatum and shell and core of the nucleus accumbens), by performing saturation experiments with the dopamine D1 receptor antagonist [125I]SCH-23982, the dopamine D2-3 receptor antagonist [3H]raclopride, the adenosine A1 receptor antagonist [3H]DPCPX and the adenosine A2A receptor antagonist [3H]SCH 58261. The experiments were also performed in rats with a neonatal bilateral lesion of the ventral hippocampus (VH), a possible animal model of schizophrenia. Both dopamine D2-3 and adenosine A2A receptors follow a similar pattern, with a lower density of receptors (40%) in the shell of the nucleus accumbens compared with the dorsolateral caudate-putamen. A lower density of adenosine A1 receptors (20%) was also found in the shell of the nucleus accumbens compared with the caudate-putamen. On the other hand, dopamine D1 receptors showed a similar density in the different striatal compartments. Therefore, differences in receptor densities cannot explain the stronger interactions between adenosine and dopamine receptors found in the ventral, compared to the dorsal striatum. No statistical differences in the binding characteristics of any of the different adenosine and dopamine receptor antagonists used were found between sham-operated and VH-lesioned rats.     

Co-localization and functional interaction between adenosine A(2A) and metabotropic group 5 receptors in glutamatergic nerve terminals of the rat striatum

The anti-Parkinsonian effect of glutamate metabotropic group 5 (mGluR5) and adenosine A(2A) receptor antagonists is believed to result from their ability to postsynaptically control the responsiveness of the indirect pathway that is hyperfunctioning in Parkinson's disease. mGluR5 and A(2A) antagonists are also neuroprotective in brain injury models involving glutamate excitotoxicity. Thus, we hypothesized that the anti-Parkinsonian and neuroprotective effects of A(2A) and mGluR5 receptors might be related to their control of striatal glutamate release that actually triggers the indirect pathway. The A(2A) agonist, CGS21680 (1-30 nM) facilitated glutamate release from striatal nerve terminals up to 57%, an effect prevented by the A(2A) antagonist, SCH58261 (50 nM). The mGluR5 agonist, CHPG (300-600 mum) also facilitated glutamate release up to 29%, an effect prevented by the mGluR5 antagonist, MPEP (10 microm). Both mGluR5 and A(2A) receptors were located in the active zone and 57 +/- 6% of striatal glutamatergic nerve terminals possessed both A(2A) and mGluR5 receptors, suggesting a presynaptic functional interaction. Indeed, submaximal concentrations of CGS21680 (1 nM) and CHPG (100 microm) synergistically facilitated glutamate release and the facilitation of glutamate release by 10 nM CGS21680 was prevented by 10 microm MPEP, whereas facilitation by 300 microm CHPG was prevented by 10 nM SCH58261. These results provide the first direct evidence that A(2A) and mGluR5 receptors are co-located in more than half of the striatal glutamatergic terminals where they facilitate glutamate release in a synergistic manner. This emphasizes the role of the modulation of glutamate release as a likely mechanism of action of these receptors both in striatal neuroprotection and in Parkinson's disease.     

In vivo modulation of α7 nicotinic receptors on striatal glutamate release induced by anatoxin-A

In vitro studies suggest that α7 nicotinic receptors located on striatal glutamatergic terminals stimulate the release of glutamate which in turn acts at ionotropic glutamate receptors on dopaminergic terminals to increase dopamine release. However, this mechanism has never been observed in in vivo studies. In the present work, the effect of the nicotinic receptors agonist, anatoxin-a, on striatal glutamate and dopamine release has been studied. Using in vivo microdialysis technique, our results have shown that anatoxin-a evokes glutamate release in a dependent way of activation α7 nicotinic receptors. The increase of glutamate is followed by an increase on dopamine levels. These results represent a clear in vivo evidence of the striatal modulation of dopamine by means of glutamate release through α7 nicotinic receptors.     

A single in vivo cocaine administration impairs 5‐HT1B receptor‐induced long‐term depression in the nucleus accumbens

The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward‐based decision‐making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5‐hydroxytryptamine (5‐HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5‐HT or 5‐HT_1B receptor agonist CP 93129 induced a long‐term depression (LTD) of glutamatergic transmission in NAc neurons. This LTD was presynaptically mediated and inducible by endogenous 5‐HT. Remarkably, a single cocaine exposure impaired the induction of LTD by 5‐HT or CP 93129. The inhibition was blocked when a selective dopamine D₁ receptor antagonist SCH23390 was coadministered with cocaine. Cocaine treatment resulted in increased phosphorylation of presynaptic proteins, rabphilin 3A and synapsin 1, and significantly attenuated CP 93129‐induced decrease in rabphilin 3A and synapsin 1 phosphorylation. Application of cAMP‐dependent protein kinase inhibitor KT5720 caused a prominent synaptic depression in NAc neurons of mice with a history of cocaine exposure. Our results reveal a novel 5‐HT_1B receptor‐mediated LTD in the NAc and suggest that cocaine exposure may result in elevated phosphorylation of presynaptic proteins involved in regulating glutamate release, which counteracts the presynaptic depressant effects of 5‐HT_1B receptors and thereby impairs the induction of LTD by 5‐HT.     

Glucose increases synaptic transmission from vagal afferent central nerve terminals via modulation of 5-HT3 receptors

Acute hyperglycemia has profound effects on vagally mediated gastrointestinal functions. We have reported recently that the release of glutamate from the central terminals of vagal afferent neurons is correlated directly with the extracellular glucose concentration. The present study was designed to test the hypothesis that 5-HT(3) receptors present on vagal afferent nerve terminals are involved in this glucose-dependent modulation of glutamatergic synaptic transmission. Whole-cell patch-clamp recordings were made from neurons of the nucleus tractus solitarius (NTS) in thin rat brainstem slices. Spontaneous and evoked glutamate release was decreased in a concentration-dependent manner by the 5-HT(3) receptor selective antagonist, ondansetron. Alterations in the extracellular glucose concentration induced parallel shifts in the ondansetron-mediated inhibition of glutamate release. The changes in excitatory synaptic transmission induced by extracellular glucose concentration were mimicked by the serotonin uptake inhibitor, fenfluramine. These data suggest that glucose alters excitatory synaptic transmission within the rat brainstem via actions on tonically active 5-HT(3) receptors, and the number of 5-HT(3) receptors on vagal afferent nerve terminals is positively correlated with the extracellular glucose concentration. These data indicate that the 5-HT(3) receptors present on synaptic connections between vagal afferent nerve terminals and NTS neurons are a strong candidate for consideration as one of the sites where glucose acts to modulate vagovagal reflexes.     

Reverse microdialysis of a dopamine D2 receptor antagonist alters extracellular adenosine levels in the rat nucleus accumbens

Recent evidence suggests that modulation of dopaminergic transmission alters striatal levels of extracellular adenosine. The present study used reverse microdialysis of the selective dopamine D₂ receptor antagonist raclopride to investigate whether a blockade of dopamine D₂ receptors modifies extracellular adenosine concentrations in the nucleus accumbens. Results reveal that perfusion of raclopride produced an increase of dialysate adenosine which was significant with a high (10 mM) and intermediate (1 mM) drug concentration, but not with lower drug concentrations (10 and 100 μM). Thus, the present study demonstrates that a selective blockade of dopamine D₂ receptors in the nucleus accumbens produced a pronounced increase of extracellular adenosine. The cellular mechanisms underlying this effect are yet unknown. It is suggested that the increase of extracellular adenosine might be related to a homeostatic modulatory mechanism proposed to be a key function of adenosine in response to neuronal metabolic challenges.     

Activation of post-synaptic dopamine D₁ receptors promotes the release of tissue plasminogen activator in the nucleus accumbens via PKA signaling

We have previously demonstrated that tissue plasminogen activator (tPA) plays an important role through the conversion of plasminogen to plasmin in the release of dopamine in the nucleus accumbens (NAc) evoked by depolarization or the systemic administration of drugs of abuse such as morphine and nicotine. In the present study, we examined the mechanisms by which drugs of abuse increase extracellular tPA activity in the NAc in vivo using in situ zymography. The dopamine D₁ receptor (D₁R) agonist SKF38393, but not D₂ receptor agonist quinpirole, significantly increased extracellular tPA activity in the NAc. The effect of SKF38393 was blocked by pre-treatment with the dopamine D₁R antagonist SCH23390. Microinjection of Rp-cAMPs, a protein kinase A inhibitor, into the NAc completely blocked the effect of SKF38393. Systemic administration of morphine and methamphetamine increased extracellular tPA activity in the NAc, and these effects were completely blocked by pre-treatment with SCH23390 and raclopride. The results suggest that activation of post-synaptic dopamine D₁Rs in the NAc leads to an increase in extracellular tPA activity via protein kinase A signaling. Furthermore, dopamine D₂ receptors are also involved in the release of tPA induced by morphine and methamphetamine.     

Autocrine activation of adenosine A1 receptors blocks D1A but not D1B dopamine receptor desensitization

Adenosine is known to modulate dopamine responses in several brain areas. Here, we show that tonic activation of adenosine receptors is able to impede desensitization of D1 dopamine receptors. As measured by cAMP accumulation in transfected COS-7 cells, long-term exposure to dopamine agonists promoted desensitization of D1B receptor but not that of D1A receptor. The inability of D1A receptor to desensitize was a result of the adenosine present in culture medium acting through activation of adenosine A1 receptors. Cell incubation with either adenosine deaminase, CGS-15943, a generic adenosine receptor antagonist, or the A1 antagonist DPCPX restored the long-term desensitization time-course of D1A receptors. In Ltk cells stably expressing A1 adenosine receptors and D1A dopamine receptors, pre-treatment of cells with R(-)-PIA, a full A1 receptor agonist, did not significantly inhibit the acute increase in cAMP levels induced by D1 receptor agonists, but blocked desensitization of D1A receptors. However, simultaneous activation of A1 and D1A receptors promoted a delayed D1A receptor desensitization. This suggests that functional interaction between A1 and D1A receptors may depend on the activation kinetics of components regulating D1 receptor responses, acting differentially on D1A and D1B receptors.     

Somatostatin stimulates striatal acetylcholine release by glutamatergic receptors: an in vivo microdialysis study

The modulation of striatal cholinergic neurons by somatostatin (SOM) was studied by measuring the release of acetylcholine (ACh) in the striatum of freely moving rats. The samples were collected via a transversal microdialysis probe. ACh level in the dialysate was measured by the high performance liquid chromatography method with an electrochemical detector. Local administration of SOM (0.1, 0.5 and 1 microM) produced a long-lasting and concentration-dependent increase in the basal striatal ACh output. The stimulant effect of SOM was antagonized by the SOM receptor antagonist cyclo(7-aminopentanoyl-Phe-D-Trp-Lys-Thr[BZL]) (1 microM). In a series of experiments, we studied the effect of 6,7-dinitroquinoxaline-2, 3-dione (DNQX), a selective non-NMDA (N-methyl-D-aspartate) glutamatergic antagonist, on the basal and SOM-induced ACh release from the striatum. DNQX, 2 microM, perfused through the striatum had no effect on the basal ACh output but inhibited the SOM (1 microM)-induced ACh release. The non-NMDA glutamatergic receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylendioxy-5H-2,3- benzodiazepine (GYKI-52466), 10 microM, antagonized the SOM (1 microM)-induced release of ACh in the striatum. Local administration of the NMDA glutamatergic receptor antagonist, 2-amino-5-phosphonopentanoic acid (APV), 100 microM, blocked SOM (1 microM)-evoked ACh release. Local infusion of tetrodotoxin (1 microM) decreased the basal release of ACh and abolished the 1 microM SOM-induced increase in ACh output suggesting that the stimulated release of ACh depends on neuronal firing. The present results are the first to demonstrate a neuromodulatory role of SOM in the regulation of cholinergic neuronal activity of the striatum of freely moving rats. The potentiating effect of SOM on ACh release in the striatum is mediated (i) by SOM receptor located on glutamatergic nerve terminals, and (ii) by NMDA and non-NMDA glutamatergic receptors located on dendrites of cholinergic interneurones of the striatum.     

Effects of Cannabinoids on Dopamine Release in the Corpus Striatum and the Nucleus Accumbens In Vitro

Cannabinoid receptors are widely distributed in the nuclei of the extrapyramidal motor and mesolimbic reward systems; their exact functions are, however, not known. The aim of the present study was to characterize the effects of cannabinoids on the electrically evoked release of endogenous dopamine in the corpus striatum and the nucleus accumbens. In rat brain slices dopamine release elicited by single electrical pulses was determined by fast cyclic voltammetry. Dopamine release was markedly inhibited by the OP2 opioid receptor agonist U-50488 and the D2/D3 dopamine receptor agonist quinpirole, indicating that our method is suitable for studying presynaptic modulation of dopamine release. In contrast, the CB1/CB2 cannabinoid receptor agonists WIN55212-2 (10(-6) M) and CP55940 (10(-6)-10(-5) M) and the CB1 cannabinoid receptor antagonist SR141716A (10(-6) M) had no effect on the electrically evoked dopamine release in the corpus striatum and the nucleus accumbens. The lack of a presynaptic effect on terminals of nigrostriatal and mesolimbic dopaminergic neurons is in accord with the anatomical distribution of cannabinoid receptors: The perikarya of these neurons in the substantia nigra and the ventral tegmental area do not synthesize mRNA, and hence protein, for CB1 and CB2 cannabinoid receptors. It is therefore unlikely that presynaptic modulation of dopamine release in the corpus striatum and the nucleus accumbens plays a role in the extrapyramidal motor and rewarding effects of cannabinoids.     

Extracellular Striatal Dopamine and Glutamate After Decortication and Kainate Receptor Stimulation, as Measured by Microdialysis

Abstract: Disruption of corticostriatal glutamate input in the striatum decreased significantly extracellular striatal glutamate and dopamine levels. Local administration of 300 µ M concentration of excitatory receptor agonist kainic acid increased significantly extracellular striatal dopamine in intact freely moving rats. These findings support the hypothesis that glutamate exerts a tonic facilitatory effect on striatal dopamine release. The effect of kainic acid on extracellular striatal glutamate concentration in intact rats was a biphasic increase. The first glutamate increase can be explained by stimulation of presynaptic kainate receptors present on corticostriatal glutamatergic nerve terminals; the second increase is probably the result of a continuous interaction of the different striatal neurotransmitters after disturbance of their balance. Release of dopamine and glutamate was modulated differently in the intact striatum and in the striatum deprived of corticostriatal input. Dopamine release in the denervated striatum after kainate receptor stimulation was significantly lower than in intact striatum, confirming the so-called cooperativity between glutamate and kainic acid. Loss of presynaptic kainate receptors on the glutamatergic nerve terminals after decortication resulted in a loss of effect of kainic acid on glutamate release in denervated striatum. Aspartate showed no significant changes in this study.     

Adenosine A2A Receptors in Striatal Glutamatergic Terminals and GABAergic Neurons Oppositely Modulate Psychostimulant Action and DARPP-32 Phosphorylation

Adenosine A_2A receptors (A_2AR) are located postsynaptically in striatopallidal GABAergic neurons, antagonizing dopamine D₂ receptor functions, and are also located presynaptically at corticostriatal terminals, facilitating glutamate release. To address the hypothesis that these two A_2AR populations differently control the action of psychostimulants, we characterized A_2AR modulation of cocaine-induced effects at the level of DARPP-32 phosphorylation at Thr-34 and Thr-75, c-Fos expression, and psychomotor activity using two lines of cell-type selective A_2AR knockout (KO) mice with selective A_2AR deletion in GABAergic neurons (striatum-A_2AR-KO mice), or with A_2AR deletion in both striatal GABAergic neurons and projecting cortical glutamatergic neurons (forebrain-A_2AR-KO mice). We demonstrated that striatum-A_2AR KO mice lacked A_2ARs exclusively in striatal GABAergic terminals whereas forebrain-A_2AR KO mice lacked A_2ARs in both striatal GABAergic and glutamatergic terminals leading to a blunted A_2AR-mediated facilitation of synaptosomal glutamate release. The inactivation of A_2ARs in GABAergic neurons reduced striatal DARPP-32 phosphorylation at Thr-34 and increased its phosphorylation at Thr-75. Conversely, the additional deletion of corticostriatal glutamatergic A_2ARs produced opposite effects on DARPP-32 phosphorylation at Thr-34 and Thr-75. This distinct modulation of DARPP-32 phosphorylation was associated with opposite responses to cocaine-induced striatal c-Fos expression and psychomotor activity in striatum-A_2AR KO (enhanced) and forebrain-A_2AR KO mice (reduced). Thus, A_2ARs in glutamatergic corticostriatal terminals and in GABAergic striatal neurons modulate the action of psychostimulants and DARPP-32 phosphorylation in opposite ways. We conclude that A_2ARs in glutamatergic terminals prominently control the action of psychostimulants and define a novel mechanism by which A_2ARs fine-tune striatal activity by integrating GABAergic, dopaminergic and glutamatergic signaling.     

Orexin A in the ventral tegmental area induces conditioned place preference in a dose-dependent manner: Involvement of D1/D2 receptors in the nucleus accumbens

It has been shown that orexin A in the ventral tegmental area (VTA) is necessary for development of morphine place preference. Additionally, D1 and D2 dopamine receptors in the nucleus accumbens (NAc) have critical roles in motivation and reward. However, little is known about the function of orexin in conditioned place preference (CPP) in rats and involvement of D1/D2 receptors in the NAc. In the present study, we investigated the effect of direct administration of orexin A into the VTA, and examined the role of intra-accumbal dopamine receptors in development (acquisition) of reward-related behaviors in the rats. Adult male Wistar rats were unilaterally implanted by two separate cannulae into the VTA and NAc. The CPP paradigm was used, and, conditioning score and locomotor activity were recorded by Ethovision software. The results showed that unilateral intra-VTA administration of orexin A (27, 53 and 107ng/0.3μl saline) during conditioning phase induced CPP in a dose-dependent manner. The most effective dose of intra-VTA orexin-A in eliciting CPP was 107ng. However, intra-NAc administration of SCH 23390 (0.25, 1 and 4μg/0.5μl saline), a D1 receptor antagonist, and sulpiride (0.25, 1 and 4μg/0.5μl DMSO), a D2 receptor antagonist, inhibited the development of orexin-induced CPP. The inhibitory effect of D2 but not D1 receptor antagonist was exerted in a dose-dependent manner. It is supposed that the activation of VTA dopaminergic neuron by orexin impresses the D2 receptors more than D1 receptors in the NAc.     

Possible involvement of protease-activated receptor-1 in the regulation of morphine-induced dopamine release and hyperlocomotion by the tissue plasminogen activator-plasmin system

We have previously demonstrated that tissue plasminogen activator (tPA)-plasmin system participates in the rewarding effect of morphine, by regulating dopamine release in the nucleus accumbens (NAc). However, it is unclear how plasmin increases the morphine-induced release of dopamine and hyperlocomotion. In the present study we investigated whether protease activated receptor-1 (PAR-1) is involved in the regulation of acute morphine-induced dopamine release by the tPA-plasmin system. Morphine significantly but transiently increased extracellular tPA activity in the NAc, which was completely blocked by naloxone. Microinjection of a PAR-1 antagonist, (tyr(-1))-thrombin receptor activating peptide 7, into the NAc significantly reduced morphine-induced dopamine release in the NAc and hyperlocomotion although the treatment had no effect on basal dopamine release and spontaneous locomotor activity. Furthermore, the PAR-1 antagonist blocked the ameliorating effect of plasmin on the defect of morphine-induced dopamine release in the NAc of tPA-deficient mice. In contrast, intracerebroventricular injection of the PAR-1 antagonist had no effect on the antinociceptive effects of morphine in mice. These results suggest that PAR-1 is a target for the tPA-plasmin system in the regulation of acute morphine-induced dopamine release in the NAc.     

An update on the mechanisms of the psychostimulant effects of caffeine

There has been a long debate about the predominant involvement of the different adenosine receptor subtypes and the preferential role of pre- versus post-synaptic mechanisms in the psychostimulant effects of the adenosine receptor antagonist caffeine. Both striatal A₁ and A_2A receptors are involved in the motor-activating and probably reinforcing effects of caffeine, although they play a different role under conditions of acute or chronic caffeine administration. The present review emphasizes the key integrative role of adenosine and adenosine receptor heteromers in the computation of information at the level of the striatal spine module (SSM). This local module is mostly represented by the dendritic spine of the medium spiny neuron with its glutamatergic and dopaminergic synapses and astroglial processes that wrap the glutamatergic synapse. In the SSM, adenosine acts both pre- and post-synaptically through multiple mechanisms, which depend on heteromerization of A₁ and A_2A receptors among themselves and with D₁ and D₂ receptors, respectively. A critical aspect of the mechanisms of the psychostimulant effects of caffeine is its ability to release the pre- and post-synaptic brakes that adenosine imposes on dopaminergic neurotransmission by acting on different adenosine receptor heteromers localized in different elements of the SSM.     

Dopaminergic Modulation of Glutamate Release in Striatum as Measured by Microdialysis

Glutamate and aspartate are the primary neurotransmitters of projections from motor and premotor cortices to the striatum. Release of glutamate may be modulated by dopamine receptors located on corticostriatal terminals. The present study used microdialysis to investigate the dopaminergic modulation of in vivo striatal glutamate and aspartate release in the striatum of awake-behaving rats. Local perfusion with a depolarizing concentration of K+ through a dialysis probe into the rat striatum produced a significant increase in the release of glutamate, aspartate, and taurine. The D2 agonist LY171555 blocked the K(+)-induced release of glutamate and aspartate, but not taurine, in a concentration-dependent manner. The D1 agonist SKF 38393 did not alter K(+)-induced release of glutamate and taurine, but did significantly decrease aspartate release. Neither agonist had any effect on basal amino acid release. The D2 antagonist (-)-sulpiride reversed the inhibitory effects of LY 171555 on K(+)-induced glutamate release. These results provide in vivo evidence for a functional interaction between dopamine, the D2 receptor, and striatal glutamate release.     

Striatal glutamate release evoked in vivo by NMDA is dependent upon ongoing neuronal activity in the substantia nigra, endogenous striatal substance P and dopamine

The aim of the present microdialysis study was to investigate whether the increase in striatal glutamate levels induced by intrastriatal perfusion with NMDA was dependent on the activation of extrastriatal loops and/or endogenous striatal substance P and dopamine. The NMDA-evoked striatal glutamate release was mediated by selective activation of the NMDA receptor-channel complex and action potential propagation, as it was prevented by local perfusion with dizocilpine and tetrodotoxin, respectively. Tetrodotoxin and bicuculline, perfused distally in the substantia nigra reticulata, prevented the NMDA-evoked striatal glutamate release, suggesting its dependence on ongoing neuronal activity and GABA(A) receptor activation, respectively, in the substantia nigra. The NMDA-evoked glutamate release was also dependent on striatal substance P and dopamine, as it was antagonized by intrastriatal perfusion with selective NK(1) (SR140333), D(1)-like (SCH23390) and D(2)-like (raclopride) receptor antagonists, as well as by striatal dopamine depletion. Furthermore, impairment of dopaminergic transmission unmasked a glutamatergic stimulation by submicromolar NMDA concentrations. We conclude that in vivo the NMDA-evoked striatal glutamate release is mediated by activation of striatofugal GABAergic neurons and requires activation of striatal NK(1) and dopamine receptors. Endogenous striatal dopamine inhibits or potentiates the NMDA action depending on the strength of the excitatory stimulus (i.e. the NMDA concentration).