Endogenous neurotensin down-regulates dopamine efflux in the nucleus accumbens as revealed by SR-142948A, a selective neurotensin receptor antagonist

SR-142948A belongs to the second generation of potent, selective, non-peptide antagonists of neurotensin receptors. It was used to investigate the role of endogenous neurotensin in the regulation of dopamine efflux in the nucleus accumbens and striatum of anaesthetized and pargyline-treated rats. All the data were obtained using in vivo electrochemistry. Electrically evoked (20 Hz, 10 s) dopamine efflux was monitored by differential pulse amperometry, whereas variations in basal (tonic) dopamine efflux were monitored by differential normal pulse voltammetry. Like the first-generation compound SR-48692, SR-142948A did not affect the tonic and evoked dopamine efflux, but dose-dependently enhanced haloperidol (50 microg/kg, i.p.) induced facilitation of the electrically evoked dopamine release in the nucleus accumbens. In contrast to SR-48692, SR-142948A dose-dependently potentiated haloperidol (50 microg/kg, i.p.) induced increase in the basal dopamine level in the nucleus accumbens. This potentiating effect did not appear in the striatum. When dopaminergic and/or neurotensinergic transmissions were modified by a higher dose of haloperidol (0.5 mg/kg, i.p.), apomorphine, amphetamine or nomifensine, SR-142948A pre-treatment affected only the effect of apomorphine on the basal dopamine level in the nucleus accumbens. These results strengthen the hypothesis that endogenous neurotensin could exert a negative control on mesolimbic dopamine efflux.     

Modification of dopamine neurotransmission in the nucleus accumbens of rats deficient in n-3 polyunsaturated fatty acids

We studied the effects of a diet chronically deficient in alpha-linolenic acid, the precursor of long-chain n-3 polyunsaturated fatty acids, on dopaminergic neurotransmission in the shell region of the nucleus accumbens of rats. In vivo microdialysis experiments showed increased basal levels of dopamine and decreased basal levels of metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in awake rats from the deficient group compared to controls. The release of dopamine under KCl stimulation was similar in both dietary groups. By contrast, the release of dopamine from the vesicular storage pool under tyramine stimulation was 90% lower in the deficient than in the control rats. Autoradiographic studies in the same cerebral region revealed a 60% reduction in the vesicular monoamine transporter sites in the deficient group. Dopamine D(2) receptors were 35% increased in these rats compared to controls, whereas no change occurred for D(1) receptors and membrane dopamine transporters. These results demonstrated that chronic n-3 polyunsaturated fatty acid deficiency modifies several factors of dopaminergic neurotransmission in the nucleus accumbens. These findings are in agreement with the changes in dopaminergic neurotransmission already observed in the frontal cortex, and with the behavioral disturbances described in these deficient rats.     

Role of dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo---hippocampal loop in response decrement

The mechanism of response decrement in hippocampal and dopaminergic neurons on repeating stimuli based on the dopamine-dependent negative feedback in the hippocampal--basal ganglia--thalamo--hippocampal loop is suggested. Activation of hippocampal neurons caused by new stimulus facilitates occurrence of reaction of dopaminergic cells due to their disinhibition through striatopallidal cells of nucleus accumbens and ventral pallidum. However, increase in dopamine level and activation accumbens and ventral pallidum. However, increase in dopamine level and activation of D2 receptors on the striatopallidal cell, while promoting depression of hippocampal inputs, prevents disinhibition of dopaminergic cells, and their reactions start their decrement. The subsequent decrease in D1 receptor activation leads to reduction of efficiency of neuron excitation in the hippocampal CA1 fields, as well as in striatonigral cells of nucleus accumbens. This leads to a decrease of disinhibition through a direct pathway via the basal ganglia of thalamic nucleus reunions which activates neurons of the CA1 field. This effect causes decrement of reactions of the hippocampal neurons, a subsequent reduction of dopaminergic cell disinhibition, and further decrement of their responses.     

Behavioral and neurophysiological evidence for a facilatory interaction between co-existing transmitters: cholecystokinin and dopamine

Cholecystokinin (CCK) and dopamine (DA) co-exist in ventral tegmental neurons which project via the mesencephalic pathway to the nucleus accumbens of the rat. CCK and DA are located in separate neurons in the substantia nigra which projects via the nigrostriatal pathway to the caudate nucleus in the rat. The functional significance of this peptide-amine co-localization was investigated using behavioral and neurophysiological techniques. CCK injected directly into the nucleus accumbens potentiated apomorphine-induced stereotypy and dopamine-induced hyperlocomotion. CCK injected directly into the caudate nucleus had no effect on apomorphine-induced stereotypy or dopamine-induced hyperlocomotion CCK injected alone into either site did not induce stereotypy or hyperlocomotion. The dose-response curve to apomorphine induction of stereotypy was shifted to the left by CCK, indicating increased sensitivity to the dopaminergic agonist. Neurophysiological analysis of the firing rate of ventral tegmental neurons demonstrated that CCK produced a left-shift in the dose-response curve of apomorphine on inhibition of neuronal firing. These data suggest that CCK acts as a modulator of dopamine, increasing neuronal responses to dopaminergic agonists. The potentiation of dopamine by CCK may be specific to the mesolimbic neurons, where CCK and DA co-exist in the rat.     

gamma-Endorphin and N alpha-acetyl-gamma-endorphin interfere with distinct dopaminergic systems in the nucleus accumbens via opioid and non-opioid mechanisms

Low doses (10 ng) of the dopamine agonist apomorphine induced hypolocomotion when injected into the nucleus accumbens of rats. This behavioral response was antagonized by local treatment with either the opioid peptide gamma-endorphin (gamma E) or the non-opioid peptide N alpha-acetyl-gamma-endorphin (Ac gamma E) in a dose of 100 pg. High doses of apomorphine (10 micrograms) r amphetamine (2 micrograms) injected into the nucleus accumbens resulted in hyperlocomotion. This response was blocked by pretreatment with gamma E but not with Ac gamma E. This effect of gamma E could be prevented by local treatment with naloxone. Neither peptides interfered with the apomorphine-induced stereotyped sniffing when the substances were injected into the nucleus caudatus. It is concluded that gamma E and Ac gamma E differentially interact with distinct dopaminergic systems in the nucleus accumbens of the rat brain via an opioid and a non-opioid mechanism, suggesting that the peptide fragments originating from pro-opiomelanocortin may be specifically implicated in the control of dopaminergic activity in this brain area.     

Differences in effects of sultopride and sulpiride on dopamine turnover in rat brain

Sultopride and sulpiride are both chemically similar benzamide derivatives and selective antagonists of dopamine D2 receptors. However, these drugs differ in clinical properties. We compared the effects of sultopride and sulpiride on dopamine turnover in rats following the administration of these drugs alone or in combination with apomorphine. The administration of sultopride or sulpiride markedly accelerated dopamine turnover in the rat brain. The increase in the level of dopamine metabolites in the striatum was more marked in the sultopride-treated rats. Sulpiride affected the limbic dopamine receptors preferentially, whereas sultopride affected the striatal and the limoic dopamine receptors equally. A low dose of apomorphine induced a reduction in the concentration of dopamine metabolites in the striatum and the nucleus accumbens by approximately 55%, but not in the medial prefrontal cortex. Sultopride was more effective in preventing an apomorphine-induced reduction in dopamine metabolite levels. These results from rat experiments would model the pharmacological differences observed between sultopride and sulpiride in clinical use.     

Prenatal Amphetamine-Induced Dopaminergic Alteration in a Gender- and Estrogen-Dependent Manner

Prenatal exposure to amphetamine induces changes in dopamine receptors in mesolimbic areas and alters locomotor response to amphetamine during adulthood. Sex differences have been reported in amphetamine-induced brain activity and stress sensitivity. We evaluated the effects of prenatal amphetamine exposure on locomotor activity, dopamine receptors and tyrosine hydroxylase mRNA expression in nucleus accumbens and caudate-putamen in response to amphetamine challenge in adult female and male rats. The role of estrogen in the response to restraint stress was analyzed in ovariectomized, prenatally amphetamine-exposed rats. Pregnant rats were treated with d-amphetamine during days 15–21 of gestation. Nucleus accumbens and caudate-putamen were processed for mRNA determination by real-time PCR. In nucleus accumbens, higher mRNA dopamine (D3) receptor expression was found in basal and d-amphetamine-challenge conditions in female than male, and prenatal amphetamine increased the difference. No sex differences were observed in caudate-putamen. Basal saline-treated females showed higher locomotor activity than males. Amphetamine challenge in prenatally amphetamine-exposed rats increased locomotor activity in males and reduced it in females. In nucleus accumbens, estrogen diminished mRNA D1, D2 and D3 receptor expression in basal, and D1 and D3 in ovariectomized stressed rats. Estrogen prevented the increase in tyrosine hydroxylase expression induced by stress in ovariectomized prenatally exposed rats. In conclusion, estrogen modulates mRNA levels of D1, D2 and D3 receptors and tyrosine hydroxylase expression in nucleus accumbens; prenatal amphetamine-exposure effects on D3 receptors and behavioral responses were gender dependent.

     

Cortical Regulation of Subcortical Dopamine Release: Mediation via the Ventral Tegmental Area

Abstract: In vivo microdialysis was used to determine the extent to which ionotropic glutamate receptors in the ventral tegmental area (VTA) regulate dopamine release in the nucleus accumbens. Coapplication of 2-amino-5-phosphonopentanoic acid (AP5; 200 µ M ) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 µ M ) to the VTA via reverse dialysis decreased extracellular concentrations of dopamine in the nucleus accumbens by ∼30%. In accordance with previous results, electrical stimulation of the prefrontal cortex increased dopamine release by 60%. Application of AP5 and CNQX to the VTA during cortical stimulation blocked the effect of stimulation on dopamine release. These results indicate that ionotropic glutamate receptors in the VTA are critically involved in basal and evoked dopamine release in the nucleus accumbens and suggest that a glutamatergic projection from the prefrontal cortex regulates the activity of dopaminergic neurons in the VTA.     

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.     

Iron Deficiency Alters Discrete Proteins in Rat Caudate Nucleus and Nucleus Accumbens

Young rats (21 days old) made nutritionally iron deficient, by feeding them a semisynthetic diet containing skimmed milk for 5 weeks, had significantly lowered hemoglobin levels (5.2 +/- 4 g/100 ml). The nonheme iron content in caudate nucleus was decreased by 47%. The behavioral response of iron-deficient rats to apomorphine (2 mg/kg) and the density of 3,4-dihydroxyphenylethylamine (dopamine) D2 receptors, as measured by [3H]spiperone binding in caudate nucleus, were significantly reduced by 70 and 53%, respectively. The possibility that nutritional iron deficiency may affect protein content in brain was investigated by measuring the apparent concentration of proteins in caudate nucleus and nucleus accumbens from iron-deficient and control animals using two-dimensional gel electrophoresis. The data indicate that iron deficiency can affect content in these two brain regions. Significant changes in the content of 10 proteins were noted in the caudate nucleus and nucleus accumbens in iron-deficient rats. The albumin level was significantly increased in both regions studied, whereas the neuron-specific enolase level was increased in the nucleus accumbens and the glial fibrillary acidic protein level was reduced in the caudate nucleus. The significance of these protein content changes, as well as a reduction in content of a 94-kilodalton protein (a molecular size similar to that of the D2 dopamine receptor), remains to be established.     

Characterization of [3H]LS‐3‐134, a novel arylamide phenylpiperazine D3 dopamine receptor selective radioligand

LS‐3‐134 is a substituted N‐phenylpiperazine derivative that has been reported to exhibit: (i) high‐affinity binding (K_i value 0.2 nM) at human D3 dopamine receptors, (ii) > 100‐fold D3 versus D2 dopamine receptor subtype binding selectivity, and (iii) low‐affinity binding (K_i > 5000 nM) at sigma 1 and sigma 2 receptors. Based upon a forskolin‐dependent activation of the adenylyl cyclase inhibition assay, LS‐3‐134 is a weak partial agonist at both D2 and D3 dopamine receptor subtypes (29% and 35% of full agonist activity, respectively). In this study, [³H]‐labeled LS‐3‐134 was prepared and evaluated to further characterize its use as a D3 dopamine receptor selective radioligand. Kinetic and equilibrium radioligand binding studies were performed. This radioligand rapidly reaches equilibrium (10–15 min at 37°C) and binds with high affinity to both human (K_d = 0.06 ± 0.01 nM) and rat (K_d = 0.2 ± 0.02 nM) D3 receptors expressed in HEK293 cells. Direct and competitive radioligand binding studies using rat caudate and nucleus accumbens tissue indicate that [³H]LS‐3‐134 selectively binds a homogeneous population of binding sites with a dopamine D3 receptor pharmacological profile. Based upon these studies, we propose that [³H]LS‐3‐134 represents a novel D3 dopamine receptor selective radioligand that can be used for studying the expression and regulation of the D3 dopamine receptor subtype.     

Repeated exposure to methamphetamine, cocaine or morphine induces augmentation of dopamine release in rat mesocorticolimbic slice co-cultures

Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1-1000 μM), cocaine (0.1-300 μM) or morphine (0.1-100 μM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1-1000 μM) had little effect. Following repeated exposure to methamphetamine (10 μM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1-300 μM) or morphine (10 and 100 μM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 μM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA receptors and the medial prefrontal cortex play an essential role in the dopaminergic sensitization. This in vitro sensitization model provides a unique approach for studying mechanisms underlying behavioral sensitization to drugs of abuse.     

Different Effects of Opiate Withdrawal on Dopamine Turnover,Uptake, and Release in the Striatum and Nucleus Accumbens

The purpose of these experiments was to further characterize changes in dopaminergic function that follow withdrawal from chronic opiate treatment. Withdrawal after treatment to a maximum dose of 120 mg/kg of morphine did not alter dopamine concentrations in the substantia nigra, ventral tegmental area, striatum, or nucleus accumbens; but did decrease concentrations of DOPAC and the ratio of DOPAC to dopamine in the lateral striatum and nucleus accumbens. Uptake of tritiated dopamine was diminished for withdrawn slices obtained from the striatum with no effect observed for tissue from the nucleus accumbens. Deficits of in vitro release of tritiated dopamine also occurred following withdrawal, with the nucleus accumbens being sensitive to dependence produced by a lower dose of morphine. In conclusion, opiate withdrawal produces a complex pattern of effects on dopaminergic function that is specific for the striatum and nucleus accumbens.     

Transient and rapid activation of Akt/GSK‐3β and mTORC1 signaling by D3 dopamine receptor stimulation in dorsal striatum and nucleus accumbens

D2/D3 dopamine receptors (D2R/D3R) agonists regulate Akt, but their effects display a complex time‐course. In addition, the respective roles of D2R and D3R are not defined and downstream targets remain poorly characterized, especially in vivo. These issues were addressed here for D3R. Systemic administration of quinelorane, a D2R/D3R agonist, transiently increased phosphorylation of Akt and GSK‐3β in rat nucleus accumbens and dorsal striatum with maximal effects 10 min after injection. Akt activation was associated with phosphorylation of several effectors of the mammalian target of rapamycin complex 1 (mTORC1): p70S6 kinase, ribosomal protein‐S6 (Ser240/244), and eukaryotic initiation factor‐4E binding protein‐1. The action of quinelorane was antagonized by a D2/D3R antagonist, raclopride, and the selective D3R antagonist S33084, inactive by themselves. Furthermore, no effect of quinerolane was seen in knock‐out mice lacking D3R. In drd1a‐EGFP transgenic mice, quinelorane activated Akt/GSK‐3β in both neurons expressing and lacking D1 receptor. Thus, the stimulation of D3R transiently activates the Akt/GSK‐3β pathway in the two populations of medium‐size spiny neurons of the nucleus accumbens and dorsal striatum. This effect may contribute to the influence of D3R ligands on reward, cognition, and processes disrupted in schizophrenia, drug abuse, and Parkinson's disease.     

In Human Brain Two Subtypes of D1 Dopamine Receptors Can Be Distinguished on the Basis of Differences in Guanine Nucleotide Effect on Agonist Binding

D1 dopamine receptors were identified in membranes of human nucleus caudatus, nucleus accumbens, amygdala, and globus pallidus, by the specific binding of [3H](+)-R-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-benzazepine-7 -ol [( 3H]SCH 23390). In these four brain regions, dopamine/[3H]SCH 23390 competition binding curves were computer-analyzed to a two-site model, distinguishing a high- (RH) and low- (RL) affinity site for dopamine. The ability of guanine nucleotides (0.4 mM GTP or 0.1 mM 5'-guanylylimidodiphosphate) to provoke a conversion of RH into RL was different between these brain regions. In amygdala, a complete conversion was seen, whereas there was no guanine nucleotide-effect on RH in globus pallidus. In nucleus caudatus and nucleus accumbens, guanine nucleotides provoked only a partial conversion of RH into RL, suggesting that these brain regions may contain guanine nucleotide-sensitive and -insensitive receptors. Heating of the membranes at 60 degrees C for 5 min had the same effect as guanine nucleotides. The pharmacological profiles of the guanine nucleotide-sensitive and -insensitive D1 receptors were similar, suggesting that D1 receptors in human brain are heterogeneous only with respect to their effector-coupling mechanism: guanine nucleotide-sensitive receptors, which are capable of undergoing functional coupling with Gs, and guanine nucleotide-insensitive receptors, which are not.(ABSTRACT TRUNCATED AT 250 WORDS)     

Receptors in the Ventral Tegmental Area Mediating Nicotine-Induced Dopamine Release in the Nucleus Accumbens

Nicotine or cocaine, when administered intravenously, induces an increase of extracellular dopamine in the nucleus accumbens. The nicotine-mediated increase was shown to occur at least in part through increase of the activity of dopamine neurons in the ventral tegmental area. As part of our continuing studies of the mechanisms of nicotine effects in the brain, in particular, effects on reward and cognitive mechanisms, in the present study we examined the role of various receptors in the ventral tegmental area in nicotine and cocaine reward. We assayed inhibition of the increase of dopamine in the nucleus accumbens induced by intravenous nicotine or cocaine administration by antagonists administered into the ventral tegmental area. Nicotine-induced increase of accumbal dopamine release was inhibited by intrategmental nicotinic (mecamylamine), muscarinic (atropine), dopaminergic (D₁: SCH 23390, D₂: eticlopride), and NMDA glutamatergic (MK 801) and GABA_B (saclofen) antagonists, but not by AMPA-kainate (CNQX, GYKI-52466) antagonists under our experimental circumstances. The intravenous cocaine-induced increase of dopamine in the nucleus accumbens was inhibited by muscarinic (atropine), dopamine 2 (eticlopride), and GABA_B (saclofen) antagonists but not by antagonists to nicotinic (mecamylamine), dopamine D₁ (SCH 23390), glutamate (MK 801), or AMPA-kainate (CNQX, GYKI-52466) receptors. Antagonists administered in the ventral tegmental area in the present study had somewhat different effects when they were previously administered intravenously. When administered intravenously atropine did not inhibit cocaine effects. The inhibition by atropine may be indirect, since this compound, when administered intrategmentally, decreased basal dopamine levels in the accumbens. The findings indicate that a number of receptors in the ventral tegmental area mediate nicotine-induced dopamine changes in the nucleus accumbens, a major component of the nicotine reward mechanism. Some, but not all, of these receptors in the ventral tegmental area also seem to participate in the reward mechanism of cocaine. The importance of local receptors in the ventral tegmental area was further indicated by the increase in accumbal dopamine levels after intrategmental administration of nicotine or also cocaine.     

Differential Effects of Forced Locomotion, Tail-Pinch, Immobilization, and Methyl-β-Carboline Carboxylate on Extracellular 3,4-Dihydroxyphenylacetic Acid Levels in the Rat Striatum, Nucleus Accumbens, and Prefrontal Cortex: An In Vivo Voltammetric Study

In vivo voltammetry with carbon fiber electrodes was used to assess extracellular 3,4-dihydroxyphenylacetic acid (DOPAC) levels in striatum, nucleus accumbens, and anteromedial prefrontal cortex of freely moving rats subjected to altered motor activity or anxiogenic stimuli. Forced locomotion on a rotarod for 40 min caused an increase in extracellular DOPAC levels in the striatum and to a lesser extent in the nucleus accumbens but not in the prefrontal cortex. Subcutaneous injection of the anxiogenic agent methyl-beta-carboline carboxylate (10 mg/kg) increased extracellular DOPAC levels to a similar extent in prefrontal cortex and nucleus accumbens. Immobilization for 4 min augmented dopamine (DA) metabolism preferentially in the nucleus accumbens and to a lesser extent in the prefrontal cortex. Tail-pinch caused a selective activation of DA metabolism in the nucleus accumbens. None of these stimuli altered extracellular striatal DOPAC levels. These results confirm the involvement of dopaminergic systems projecting to the striatum and nucleus accumbens in motor function and suggest that mesolimbic and mesocortical dopaminergic systems can be specifically activated by certain kinds of anxiogenic stimuli; the relative activation of either of these latter systems could depend primarily on the nature (sensory modality, intensity) of the acute stressor.     

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.     

Differential Effects of δ- and μ-Opioid Receptor Antagonists on the Amphetamine-Induced Increase in Extracellular Dopamine in Striatum and Nucleus Accumbens

Abstract: The specific opioid receptor antagonist naloxone attenuates the behavioral and neurochemical effects of amphetamine. Furthermore, the amphetamine-induced increase in locomotor activity is attenuated by intracisternally administered naltrindole, a selective δ-opioid receptor antagonist, but not by the irreversible μ-opioid receptor antagonist β-funaltrexamine. Therefore, this research was designed to determine if naltrindole would attenuate the neurochemical response to amphetamine as it did the behavioral response. In vivo microdialysis was used to monitor the change in extracellular concentrations of dopamine in awake rats. Naltrindole (3.0, 10, or 30 µg) or vehicle was given 15 min before and β-funaltrexamine (10 µg) or vehicle 24 h before the start of cumulative dosing, intracisternally in a 10-µl volume, while the rats were lightly anesthetized with methoxyflurane. Cumulative doses of subcutaneous d-amphetamine (0.0, 0.1, 0.4, 1.6, and 6.4 mg/kg) followed pretreatment injections at 30-min intervals. Dialysate samples were collected every 10 min from either the striatum or nucleus accumbens and analyzed for dopamine content by HPLC. Amphetamine dose-dependently increased dopamine content in both the striatum and nucleus accumbens, as reported previously. Naltrindole (3.0, 10, and 30 µg) significantly reduced the dopamine response to amphetamine in the striatum. In contrast, 30 µg of naltrindole did not modify the dopamine response to amphetamine in the nucleus accumbens. On the other hand, β-funaltrexamine (10 µg) had no effect in the striatum but significantly attenuated the amphetamine-induced increase in extracellular dopamine content in the nucleus accumbens. These data suggest that δ-opioid receptors play a relatively larger role than μ-opioid receptors in mediating the amphetamine-induced increase in extracellular dopamine content in the striatum, whereas μ-opioid receptors play a larger role in mediating these effects in the nucleus accumbens.     

Presynaptic control of dopamine metabolism in the nucleus accumbens. Lack of effect of buspirone as demonstrated using in vivo voltammetry

Buspirone is a non-benzodiazepine drug with anxiolytic properties. It has been reported to induce a marked increase in the metabolism of dopamine in the striatum and the nucleus accumbens which is similar to that induced by neuroleptics. It has been suggested that the effect observed in the striatum reflects an action of buspirone on dopaminergic autoreceptors in both terminals and cell bodies. In the present study, presynaptic effects of buspirone on dopaminergic metabolism in the nucleus accumbens were investigated, and they were compared to the effects of the classical neuroleptic, haloperidol. Dopaminergic terminals were isolated by infusion of tetrodotoxin into the median forebrain bundle in order to evaluate the effects of buspirone and haloperidol on presynaptic receptors. Changes in dopamine metabolism were determined by in vivo voltammetry. Buspirone administered after interruption of the impulse flow did not affect dopamine metabolism. In contrast haloperidol treatment led to an increase in metabolism of dopamine. It is concluded that buspirone did not act at the presynaptic level and furthermore on dopaminergic autoreceptors.