N-methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens

Systemic nicotine enhances burst firing of dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens, mainly via stimulation of nicotinic acetylcholine receptors in the ventral tegmental area. Given that both the neuronal activity of mesolimbic dopamine neurons and terminal dopamine release are regulated by excitatory amino acid inputs to the ventral tegmental area and that nicotine facilitates glutamatergic transmission in brain, we investigated the putative role of ionotropic glutamate receptors within the ventral tegmental area for the effects of nicotine on dopamine release in the nucleus accumbens using microdialysis, with one probe implanted in the ventral tegmental area for drug application and another in the ipsilateral nucleus accumbens for measuring dopamine, in awake rats. Systemic nicotine (0.5 mg/kg, s.c.) and infusion of nicotine (1.0 mM) into the ventral tegmental area increased dopamine output in the nucleus accumbens. Intrategmental infusion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (0.1 mM) or N-methyl-D-aspartate (0.3 mM) increased accumbal dopamine release; these effects were antagonized by concomitant infusion of a selective antagonist at N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid (0.3 mM), and non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (0.3 mM), respectively. Infusion of either antagonist (0.3 or 1.0 mM) into the ventral tegmental area did not affect basal dopamine levels, whereas infusion of 2-amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2,3-dione, starting 40 min before nicotine injection dose-dependently attenuated the nicotine-induced increase in accumbal dopamine release. Concurrent intrategmental infusion of 2-amino-5-phosphonopentanoic acid and nicotine decreased nicotine-induced dopamine release in the nucleus accumbens. These results indicate that the stimulatory action of nicotine on the mesolimbic dopamine system is to a considerable extent mediated via stimulation of N-methyl-D-aspartate receptors within the ventral tegmental area.     

Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: anatomical and electrophysiological studies

The goal of this study was to investigate the functional organization of the subpallidal-->accumbens direct and indirect feedback loops by both anatomical and electrophysiological methods. The results of the dextran-conjugated rhodamine injections into the subpallidal area has shown three distinct projections: (1) a substantial pathway from the subpallidal area to the ventral tegmental area, (2) a more diffuse rostral projection from the subpallidal area to the core area of the nucleus accumbens, and (3) a sparse pathway projecting rostrodorsally from the subpallidal area toward the thalamic regions. Electrical or chemical stimulation of the subpallidal region, which was studied by the axonal tracer, evoked inhibitory responses in the majority (60 and 80%, respectively) of the accumbens and ventral tegmental area neurons in a standard extracellular recording study. Less than 1/3 of the accumbens or ventral tegmental area cells showed an increase in the mean firing rate. The majority (77.5%) of all responded neurons had a latency of less than 10 ms. Furthermore, injection of glutamate into the subpallidal area not only altered the firing pattern of the accumbens neurons, but also attenuated their excitatory responses elicited by the electrical stimulation of the ventral subiculum. Our results indicate that the subpallidal area plays a predominantly inhibitory role in the ventral tegmental area-accumbens-subpallidal circuitry, presumably by its GABAergic projections, and may also modulate subicular input into the nucleus accumbens.     

Systemic morphine-induced Fos protein in the rat striatum and nucleus accumbens is regulated by mu opioid receptors in the substantia nigra and ventral tegmental area

To characterize how systemic morphine induces Fos protein in dorsomedial striatum and nucleus accumbens (NAc), we examined the role of receptors in striatum, substantia nigra (SN), and ventral tegmental area (VTA). Morphine injected into medial SN or into VTA of awake rats induced Fos in neurons in ipsilateral dorsomedial striatum and NAc. Morphine injected into lateral SN induced Fos in dorsolateral striatum and globus pallidus. The morphine infusions produced contralateral turning that was most prominent after lateral SN injections. Intranigral injections of [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a mu opioid receptor agonist, and of bicuculline, a GABAA receptor antagonist, induced Fos in ipsilateral striatum. Fos induction in dorsomedial striatum produced by systemic administration of morphine was blocked by (1) SN and VTA injections of the mu1 opioid antagonist naloxonazine and (2) striatal injections of either MK 801, an NMDA glutamate receptor antagonist, or SCH 23390, a D1 dopamine receptor antagonist. Fos induction in dorsomedial striatum and NAc after systemic administration of morphine seems to be mediated by dopamine neurons in medial SN and VTA that project to medial striatum and NAc, respectively. Systemic morphine is proposed to act on mu opioid receptors located on GABAergic interneurons in medial SN and VTA. Inhibition of these GABA interneurons disinhibits medial SN and VTA dopamine neurons, producing dopamine release in medial striatum and NAc. This activates D1 dopamine receptors and coupled with the coactivation of NMDA receptors possibly from cortical glutamate input induces Fos in striatal and NAc neurons. The modulation of target gene expression by Fos could influence addictive behavioral responses to opiates.     

Dopamine release in the nucleus accumbens by hypothalamic stimulation-escape behavior

It is known that lateral hypothalamic stimulation or self-stimulation can release dopamine in the nucleus accumbens (NAc). The present experiment illustrates that an aversively motivated behavior can also do this. Rats were prepared with microdialysis probes in the NAc and electrodes in the lateral hypothalamus (LH) or medial hypothalamus (MH). Automatic stimulation of the LH increased extracellular dopamine in the NAc 30% as reported earlier. The animals would perform both self-stimulation to turn the current on and stimulation-escape to turn it off, suggesting a combination of reward and aversion. Escape responding increased extracellular dopamine (DA) 100%, even though there was less total stimulation. Automatic stimulation of the MH did the opposite of the LH by decreasing accumbens dopamine (-20%), and the animals would only perform stimulation-escape, indicative of pure aversion. But again, extracellular DA in the NAc increased 100% during escape responding. Thus DA can be released during negative reinforcement when an animal's behavior is reinforced by escape from lateral or medial hypothalamic stimulation. This suggests that DA release was correlated with stimulation-escape behavior, rather than the aversiveness of automatic stimulation.     

Dopamine D? receptor stimulation of the nucleus accumbens or the medial preoptic area promotes the onset of maternal behavior in pregnancy-terminated rats.

There is good evidence that interference with the mesolimbic dopamine (DA) system results in impaired maternal responding in postpartum female rats. However, whether activation of the mesolimbic DA system is capable of promoting maternal behavior has not been investigated. This study examined whether increasing DA activity in various brain regions of pregnancy-terminated, naive female rats would stimulate the onset of maternal behavior. Experiments 1 and 2 examined the effects of microinjection of various doses (0, 0.2, or 0.5 μg/0.5 μl/side) of a D? DA receptor agonist, SKF 38393, or a D? DA receptor agonist, quinpirole, into the nucleus accumbens (NA) on latency to show full maternal behavior, and Experiment 3 determined the effects of SKF 38393 injection into a control site. Finally, because the medial preoptic area (MPOA) is also important for maternal behavior, receives DA input, and expresses DA receptors, the authors examined whether microinjection of SKF 38393 into MPOA was capable of stimulating the onset of maternal behavior. Results indicated that microinjection of SKF 38393 into either the NA or the MPOA facilitates maternal responding in pregnancy-terminated rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine depletion reorganizes projections from the nucleus accumbens and ventral pallidum that mediate opioid-induced motor activity

Motor activity elicited pharmacologically from the nucleus accumbens by the mu-opioid receptor agonist D-Ala-Tyr-Gly-NMePhe-Gly-OH (DAMGO) is augmented in rats sustaining dopamine depletions. GABAergic projections from the nucleus accumbens to ventral pallidum and ventral tegmental area (VTA) are involved because stimulation of GABAB receptors in the VTA (by baclofen) or GABAA receptors in the ventral pallidum (by muscimol) inhibit the motor response induced by the microinjection of DAMGO into the nucleus accumbens. The present study was done to determine which of these projections is mediating the augmented DAMGO-induced motor activity that follows 6-hydroxydopamine lesions of the nucleus accumbens. The inhibition of DAMGO-induced activation by pallidal injections of muscimol was markedly attenuated in lesioned animals, whereas the inhibition by VTA injections with baclofen was greatly enhanced. A similar switch in emphasis from pallidal to mesencephalic efferents was not observed for dopamine-induced motor activity, because muscimol microinjections inhibited the response elicited by dopamine microinjection into the nucleus accumbens in all subjects. The stimulation of mu-opioid receptors in the ventral pallidum also elicits motor activation, and this is blocked by baclofen microinjection into the VTA. However, after dopamine depletion in the nucleus accumbens, baclofen in the VTA was ineffective in blocking the motor response by DAMGO in the ventral pallidum. These data reveal that dopamine depletion in the nucleus accumbens produces a lesion-induced plasticity that alters the effect of mu-opioid receptor stimulation on efferent projections from the nucleus accumbens and ventral pallidum.     

A comparative study of self-administration of morphine into the amygdala and the ventral tegmental area in mice

The concentrations of zinc, cadmium and copper were determined in different benthic algal species from some sites located in Guanabara Bay, Sepetiba Bay and Ribeira Bay (State of Rio de Janeiro). The aim is to verify the possibility of using algae as indicators of metallic contamination in these areas. According to our results, the highest concentrations of Zn and Cd in algae were observed in Sepetiba Bay. In this region, the differences among the concentrations of the metals were analysed in three sampling sites. Padina gymnospora was the species recommended to monitor the contamination of Zn and Cd in Sepetiba Bay, for the following reasons: 1) its great abundance and distribution in the areas, and 2) its high ability to accumulate metals. More studies are suggested to evaluate the levels of metals in Guanabara Bay.     

Pyruvate infusions into the septal area attenuate spontaneous alternation impairments induced by intraseptal morphine injections.

Glucose infusions into the medial septal area attenuate memory impairments produced by concurrent intraseptal morphine injections. One possible explanation for these effects of glucose on memory is that the treatment modulates regional energy metabolism. As a test of this hypothesis, the present experiment determined whether intraseptal pyruvate injections could attenuate a spontaneous alternation impairment seen after intraseptal morphine injections. Intraseptal injections of morphine (4.0 nmol) 30 min prior to testing produced spontaneous alternation scores significantly lower than those in control groups. Morphine injections near, but outside, the septal region did not impair spontaneous alternation performance. The morphine induced impairment was similarly reversed by coadministration of either glucose (18 nmol) or pyruvate (18 nmol) into the septum. These findings suggest that glucose may act through the tricarboxylic acid cycle by increasing the availability of ATP, augmenting the synthesis of certain neurotransmitters, or both. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Insulin receptor substrate-2 in the ventral tegmental area regulates behavioral responses to cocaine.

Neurotrophic factor signaling modulates cellular and behavioral responses to drugs of abuse. Among other biochemical adaptations, chronic exposure to abused drugs decreases the expression of insulin receptor substrate-2 (IRS-2; a protein involved in neurotrophic signaling) in the ventral tegmental area (VTA), a neural substrate for many drugs of abuse. Using viral-mediated gene transfer to locally alter the activity of IRS-2, the authors show that overexpression of IRS-2 in the VTA results in an enhanced preference for environments previously paired with cocaine, as measured by the place conditioning paradigm, whereas blockade of IRS-2 activity results in avoidance of cocaine-paired compartments. In addition, IRS-2 overexpression leads to enhanced cocaine-induced locomotor activity, and blockade of IRS-2 expression significantly blunts behavioral responses to cocaine. These results demonstrate that levels of IRS-2 in the VTA regulate responsiveness to the behavioral effects of cocaine. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Locomotor activation induced by infusion of endorphins into the ventral tegmental area: evidence for opiate-dopamine interactions

beta-Endorphin in nanomole quantities produced a stimulation of locomotor activity when infused into the region of the dopamine cell bodies of the ventral tegmental area (VTA) in rats. alpha-, gamma-, and des-Tyr-gamma-endorphin produced similar effects, but the D-alanine analogues of alpha and gamma-endorphin produced a larger and longer-lasting activation, presumably reflecting their resistance to degradation. This locomotor activation was reversible by pretreatment with naloxone and by destruction of the terminal projections of the mesocorticolimbic dopamine system originating in the VTA. These results demonstrate that locally infused endorphin can interact with the opioid receptors in the VTA, and they suggest a means by which endorphins activate limbic excitability.     

Expression of D1 receptor mRNA in projections from the forebrain to the ventral tegmental area

The presence of subunit proteins, 1H9 for the alpha-subunit and 2B6 for the beta-subunit, of H(+)-K+ ATPase and its activity in tubulovesicles and intracellular canaliculi of gastric parietal cells were immunocytochemically and enzyme cytochemically examined. Specimens were taken from healthy human volunteers by endoscopic biopsy in resting, tetragastrin-stimulated and omeprazole-inhibited conditions. H(+)-K+ ATPase was present in both intracellular canaliculi and tubulovesicles in these three conditions. Gold particles of the alpha-subunit decreased in number, and those showing the beta-subunit increased under both gastrin-stimulating and omeprazole-inhibiting conditions compared with parietal cells in the resting state. We suggest that the administration of tetragastrin and omeprazole alter the turnover rate of each subunit of H(+)-K+ ATPase, resulting in the difference of the proportions of alpha- and beta-subunits. Moreover, the activity of H(+)-K+ ATPase was detected strongly beneath the membrane of microvilli and weakly in that of tubulovesicles under these three conditions. After 7 days of daily oral omeprazole intake, H(+)-K+ ATPase in parietal cells were detected in intracellular canaliculi and tubulovesicles. However, the H(+)-K+ ATPase activity in tubulovesicles was diminished 1 h after omeprazole intake, and the activity in intracellular canaliculi was completely inhibited even 3 h after omeprazole administration. These results show that omeprazole inhibited the H(+)-K+ ATPase activity in both intracellular canaliculi and tubulovesicles.     

Altered nociception, analgesia and aggression in mice lacking the receptor for substance P

The peptide neurotransmitter substance P modulates sensitivity to pain by activating the neurokinin-1 (NK-1) receptor, which is expressed by discrete populations of neurons throughout the central nervous system. Substance P is synthesized by small-diameter sensory 'pain' fibres, and release of the peptide into the dorsal horn of the spinal cord following intense peripheral stimulation promotes central hyperexcitability and increased sensitivity to pain. However, despite the availability of specific NK-1 antagonists, the function of substance P in the perception of pain remains unclear. Here we investigate the effect of disrupting the gene encoding the NK-1 receptor in mice. We found that the mutant mice were healthy and fertile, but the characteristic amplification ('wind up') and intensity coding of nociceptive reflexes was absent. Although substance P did not mediate the signalling of acute pain or hyperalgesia, it was essential for the full development of stress-induced analgesia and for an aggressive response to territorial challenge, demonstrating that the peptide plays an unexpected role in the adaptive response to stress.     

Differential effects on effort discounting induced by inactivations of the nucleus accumbens core or shell.

The authors investigated the contribution of the nucleus accumbens (NAc) core and shell to effort-based decision making using a discounting procedure. Selection of 1 lever delivered a smaller, 2-pellet reward immediately, whereas the other lever delivered a 4-pellet reward after a fixed ratio of presses (2, 5, 10, or 20) that increased over 4 blocks of 10 discrete choice trials. Subsequent testing employed an equivalent delays procedure, whereby the relative delay to reward delivery after selection of either option was equalized. In well-trained rats, inactivation of the core, but not the shell, via infusion of GABA A/B agonists muscimol/baclofen reduced preference for the high-effort option under standard conditions and also when rats were tested using an equivalent delays procedure. However, inactivation of the core did not alter preference for 4-pellet versus 2-pellet rewards when the relative costs of each option were the same (1 press). Thus, the NAc core, but not the shell, appears to be part of a neural circuit that biases choice toward larger rewards associated with a greater effort cost. Furthermore, the contributions by the NAc core to this form of decision making can be dissociated from its role in delay discounting. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Self-infusion of GABAA antagonists directly into the ventral tegmental area and adjacent regions.

This study used an intracerebral self-administration paradigm in rats to determine if blockade of GABAA receptors in the ventral tegmental area (VTA) has a reinforcing effect. Rats quickly learned to self-infuse a picrotoxin solution into the anterior VTA; rats discriminated the lever that produced picrotoxin infusions from the lever without consequences; and when the response requirement was increased, rats increased response levels for picrotoxin infusion. The reinforcing effect of picrotoxin was site-specific: Anterior VTA regions supported vigorous self-infusions, but not the posterior VTA, substantia nigra, or lateral hypothalamus. Muscimol, a GABAA agonist, disrupted picrotoxin self-infusion, but bicuculline, a GABAA antagonist, was self-infused into the VTA. The results suggest that blockade of GABAA receptors in the anterior VTA is reinforcing and that functional organization of the GABA systems within the VTA is heterogeneous. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of D1 or D2 dopamine receptor antagonism in the medial preoptic area, ventral pallidum, or nucleus accumbens on the maternal retrieval response and other aspects of maternal behavior in rats.

The medial preoptic area (MPOA), ventral pallidum (VP), and nucleus accumbens (NA) receive dopaminergic afferents and are involved in maternal behavior. Experiments investigated whether dopamine (DA) receptor antagonism in NA disrupts maternal behavior, determined the type of DA receptor involved, and investigated the involvement of drug spread to VP or MPOA. Injection of SCH 23390 (D1 DA receptor antagonist) into NA of postpartum rats disrupted retrieving at dosage levels that were ineffective when injected into MPOA or VP. Motor impairment was not the cause of the deficit. Injection of eticlopride (D2 DA receptor antagonist) into NA or VP was without effect. Results emphasize the importance of DA action on D1 receptors in NA for retrieval behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effect of morphine applied by intrapallidal microdialysis on the release of dopamine in the nucleus accumbens

The effect of morphine, administered intrapallidally, on extracellular concentrations of DA, DOPAC, and HVA in the nucleus accumbens and striatum was studied in the behaving rat using the in vivo microdialysis technique. Unilateral application of morphine hydrochloride was performed through microdialysis probes into the rat ventral pallidum (10 microliters of 0, 2.6, 4.0, 13.0, and 26.0 mM) or globus pallidus (10 microliters of 0 and 26.0 mM). The levels of DA, DOPAC, and HVA were measured using the HPLC with EC detection in dialysates collected from the nucleus accumbens, anteromedial, and anterolateral striatum. Samples were taken every 45 min over 3 h before and over 5 h after morphine or vehicle administration. Administration of morphine into the ventral pallidum resulted in increased DOPAC and HVA concentrations in the nucleus accumbens. Pretreatment with naloxone (1 mg/kg, SC) abolished this effect of morphine. Administration of morphine into the globus pallidus resulted in increased DA, DOPAC, and HVA concentrations in the nucleus accumbens and DA in the anteromedial striatum. The levels of DA and metabolites in anterolateral striatum remained rather unchanged following morphine administered into the ventral pallidum or the globus pallidus. The changes in DA neurotransmission into the nucleus accumbens induced by morphine application into the ventral pallidum and globus pallidus are reminiscent of a phasic and tonic release of DA respectively. The results show that intrapallidal morphine increases DA neurotransmission in nucleus accumbens and suggest that the effect of morphine is mediated by ventral pallidum/mesolimbic and globus pallidus/thalamocortical pathways, depending on the site of injection.     

Conjunctive encoding of movement and reward by ventral tegmental area neurons in the freely navigating rodent.

[Correction Notice: An erratum for this article was reported in Vol 124(3) of Behavioral Neuroscience (see record 2010-10681-004). There was one error in the text on p. 237 and several errors in the captions to Figures 1 (p. 238), 3 (p. 240), and 5 (p. 242). The corrected text and captions are provided in the erratum.] As one of the two main sources of brain dopamine, the ventral tegmental area (VTA) is important for several complex functions, including motivation, reward prediction, and contextual learning. Although many studies have identified the potential neural substrate of VTA dopaminergic activity in reward prediction functions during Pavlovian and operant conditioning tasks, less is understood about the role of VTA neuronal activity in motivated behaviors and more naturalistic forms of context-dependent learning. Therefore, VTA neural activity was recorded as rats performed a spatial memory task under varying contextual conditions. In addition to reward- and reward predicting cue-related firing commonly observed during conditioning tasks, the activity of a large proportion of VTA neurons was also related to the velocity and/or acceleration of the animal’s movement. It is important to note that movement-related activity was strongest when rats displayed more motivation to obtain reward. Furthermore, many cells displayed a dual code of movement- and reward-related activity. These two modes of firing, however, were differentially regulated by context information, suggesting that movement- and reward-related firing are two independently regulated modes of VTA neuronal activity and may serve separate functions. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Dopamine D2-receptors regulate neurotensin release from nucleus accumbens and striatum as measured by in vivo microdialysis

The present study was undertaken to examine the role of dopamine D2-receptors in the regulation of neurotensin release. Through a modification of the methods described by Maidment et al. (Neuroscience, 45 (1991) 81-93), we have developed a highly reproducible method of measuring changes in extracellular NT in the striatum and nucleus accumbens by in vivo microdialysis in awake animals. It was observed that calcium-dependent release of NT was evoked in both structures by infusing a high concentration of potassium. In addition, systemic administration of the D2 agonist quinpirole (5 mg/kg) induced a rapid increase of approximately 200% in extracellular NT levels in the lateral caudate and 30-40% in the nucleus accumbens. Conversely, treatment with the D2 antagonist eticlopride (0.5 mg/kg) reduced extracellular NT in the medial anterior caudate and nucleus accumbens 20-30%, but had no effect in the lateral anterior caudate. These data demonstrate for the first time that D2-receptors are important in the dopaminergic regulation of extrapyramidal and limbic NT release in conscious animals.     

Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P

1. Piroximone was administered orally (p.o.) and intravenously (i.v.) to male Beagle dog. In vitro, piroximone was incubated with dog liver microsomes. 2. Piroximone was metabolized in vivo to five metabolites (1-5) representing approximately 20% of the total administered dose. 3. The parent drug and its metabolites were totally eliminated in urine. 4. Reduced piroximone (piroximole), representing approximately 10% of the administered dose, was identified as the major metabolic product in vivo. 5. In vitro, piroximone was metabolized by dog liver microsomes to isonicotinic acid (1) and piroximole (4), with the same ratio as in vivo (1:4 = 0.2). The Michaelis-Menten parameters were determined for piroximole formation and were: Kmapp = 733 microM and Vmax app = 232 pmol/mg protein/min. 6. Comparison of the pharmacokinetics of piroximone and piroximole revealed that both compounds were very well absorbed (F = 93 +/- 7 and 89 +/- 8% respectively), slightly distributed (Vd app = 0.78 +/- 0.04 and 1.02 +/- 0.09 l/kg p.o., and 0.95 +/- 0.05 and 0.76 +/- 0.13 1/kg i.v. respectively) and excreted into urine to the same extent (UEx = 54.7 +/- 1.2 and 53.2 +/- 12.6% p.o., and 59.1 +/- 5.3 and 51.2 +/- 5.7% i.v. respectively), except that the clearance of piroximone was two-fold higher than that observed for piroximole (ClT = 7.77 +/- 1.35 and 4.12 +/- 0.44 ml/min/kg p.o., and 7.68 +/- 1.25 and 4.06 +/- 0.51 ml/min/kg i.v. respectively).