Subregions Of Nucleus Accumbens Research Articles

Effects of selective dopamine D1 or D2 receptor blockade within nucleus accumbens subregions on ingestive behavior and associated motor activity

Two anatomically and neurochemically distinguishable regions of the nucleus accumbens (Acb), the core and the shell, have been shown to differentially regulate feeding behavior. Nevertheless, despite the well-known role of Acb dopamine in the modulation of motivated behaviors, there have been no studies directly comparing the effects of acute dopamine receptor blockade in the Acb core versus the Acb shell on feeding. In this study, D1- or D2-selective dopamine receptor antagonists were infused bilaterally into the Acb core or shell of hungry rats, whereupon feeding, drinking, and spontaneous motor activity were monitored. Both the D1 antagonist SCH 23390 (0, 1, and 2 μg/0.5 μl) and the D2 antagonist raclopride (0, 1, and 2 μg/0.5 μl) markedly suppressed ambulation and rearing when infused into either the Acb core or shell. Total food intake and latency to begin feeding were unaffected by either drug in either site. SCH 23390 in the Acb shell, and raclopride in the Acb core or shell, significantly decreased the total number of feeding bouts. In the Acb core, raclopride produced a small but statistically significant increase in overall feeding duration. Dopamine receptor blockade in either site tended to increase mean feeding bout duration. Measures of drinking behavior were generally unaffected. Hence, dopamine receptor blockade in either the Acb core or shell of hungry rats suppressed spontaneous motor activity and shifted the structure of feeding towards longer bout durations, but did not alter the total amount of food consumed. In the Acb shell, the effects of D1 receptor blockade tended to be of greater magnitude than the effects of D2 receptor blockade, although major differences between core and shell effects were not observed. These results are discussed with regard to current theories of dopaminergic control of feeding behavior, and with reference to the functional heterogeneity of Acb subregions.

Glutamate and Dopamine in Nucleus Accumbens Core and Shell: Sequence Learning Versus Performance

This study sought to determine whether neurochemical changes associated with chronic postweaning lead (Pb) exposure, namely, enhanced dopamine (DA) activity and/or blockade of NMDA function in nucleus accumbens (NAC), underlie the learning impairments also associated with this Pb regimen, and whether core or shell subregions of nucleus accumbens would be more important to such effects. If so, then mimicking these neurochemical changes in normal (control) rats should reproduce these Pb-induced learning impairments. For this purpose, the effects of DA (20–80 μg), the non-competitive NMDA antagonist MK-801 (1.0–2.5 μg) or DA+ MK-801 (40+1.0, 80+2.5 μg) were infused in core or shell of nucleus accumbens in normal rats and effects on a multiple schedule of repeated learning (RL) and performance (P) evaluated. In core, MK-801 mimicked the effects of Pb exposure, selectively reducing RL accuracy with no corresponding changes in P accuracy, an effect derived from an increased frequency of perseverative errors. DA produced non-specific changes, reducing accuracy levels in RL and P components. Accuracy and rate effects of DA could be reversed by concurrent administration of the higher MK-801 dose. In shell, MK-801, primarily the lower dose, reduced accuracy in both the RL and P components, while DA did not produce any systematic effects. Collectively, these results point to a greater importance of core as compared to shell in the mediation of learning of spatial sequences, and suggest that inhibition of glutamatergic NMDA function may play a critical role in the selective learning impairments associated with chronic low level Pb exposure.

Effects of serotonin (5-HT)(1B) receptor ligands, microinjected into accumbens subregions, on cocaine discrimination in rats.

Recent data indicate a significant input of serotonin (5-HT) on mesoaccumbens dopamine-dependent behavioral effects of cocaine in rats. The present study investigated the role of 5-HT(1B) receptors in nucleus accumbens subregions (the shell and the core) and the effect of stimulation of those receptors in the discriminative stimulus effects of cocaine in rats. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline (i.p.) in a two-choice, water-reinforced fixed-ratio 20 procedure. After reaching the cocaine-saline discrimination criterion, rats were stereotaxically implanted with bilateral cannulae in the accumbens shell or core, and then were microinjected with selective 5-HT(1B) receptor ligands. In substitution studies, microinjections of the 5-HT(1B) receptor antagonist GR 55562 (0.1-10 microg/side) or the 5-HT(1B) receptor agonist CP 93129 (0.1-10 microg/side) into accumbens subregions did not evoke cocaine-lever responding. Pretreatment with the 5-HT(1B) receptor antagonist GR 55562 (0.1-10 microg/side) in the accumbens shell or core failed to modulate the discriminative stimulus effects of cocaine (5 mg/kg). Combination tests using a fixed dose of CP 93129 (1-10 microg/side) into the accumbens shell prior to cocaine administration (0.6-5.0 mg/kg) did not affect cocaine discrimination. CP 93129 (1 microg/side, but not 0.1 microg/side) microinjected in the accumbens core, and low doses of systemic cocaine (0.6-2.5 mg/kg) produced a leftward shift in the cocaine dose-response curve and a decrease in its ED(50) value. GR 55562 (1 microg/side) significantly attenuated the enhancement of cocaine discrimination evoked by a combination of CP 93129 (1 microg/side) and cocaine (1.25 mg/kg or 2.5 mg/kg). These results seem to exclude a major role for the accumbens shell and core 5-HT(1B) receptors in controlling the discriminative stimulus effects of cocaine. However, they do suggest that the stimulation of 5-HT(1B) receptors in the accumbens core, but not in the shell, enhances cocaine discrimination in rats.

Dissociation in the involvement of dopaminergic neurons innervating the core and shell subregions of the nucleus accumbens in latent inhibition and affective perception

Mesencephalic dopaminergic neurons have been found to be involved in affective processes. Their implication in cognitive processes appears less well understood. The use of latent inhibition paradigms is a means of studying these kinds of processes. In this study, we investigated the involvement of dopaminergic projections in the core, the dorsomedial shell and the ventromedial shell of the nucleus accumbens, in latent inhibition in olfactory aversive learning. Variations in extracellular dopamine levels induced by an aversively conditioned olfactory stimulus were monitored in the three parts of the nucleus accumbens in the left hemisphere, after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. The parallel between dopamine changes and place preference or aversion toward the stimulus were analyzed in pre-exposed and non-pre-exposed animals. Results showed that dopaminergic neurons innervating the nucleus accumbens are differentially involved in the latent inhibition phenomenon. Dopaminergic neurons innervating the core and the dorsomedial shell subregions of the nucleus accumbens appeared to be involved in latent inhibition processes, unlike those reaching the ventromedial shell. Nonetheless dopamine in the ventromedial shell was found to be involved in affective perception of the stimulus. The present data suggest that dopaminergic neurons innervating the three nucleus accumbens subregions are functionally related to networks involved in parallel processing of the cognitive and affective values of environmental information, and that interaction between these systems, at some levels, may lead to a given behavioral output. These data may provide new insights into the pathophysiology of schizophrenic psychoses.

D1 or D2 antagonism in nucleus accumbens core or dorsomedial shell suppresses lever pressing for food but leads to compensatory increases in chow consumption

Although interference with dopamine (DA) systems can suppress lever pressing for food reinforcement, it is not clear whether this effect occurs because of a general disruption of food motivation. One way of assessing this has been a choice procedure in which a rat responds on an fixed ratio 5 (FR5) schedule for preferred Bioserve pellets while a less preferred lab chow is concurrently available in the operant chamber. Untreated rats consume little of the chow, preferring to respond for the Bioserve pellets. Previous studies have shown that depleting DA in the accumbens substantially decreased lever pressing while increasing chow consumption. In the present study, low doses (0.0625–1.0 μg) of the D1 antagonist SCH 23390 or the D2 antagonist raclopride were injected into the either the core or shell subregions of nucleus accumbens, and rats were tested on the concurrent lever pressing/feeding task. Analysis of the dose response curves showed that injections of SCH 23390 into the core were more potent than injections into the shell for suppressing lever pressing (i.e., the ED 50 was lower in the core). Nevertheless, injections of either drug into either site suppressed lever pressing and increased intake of the concurrently available chow. Across both drugs and at both sites, the amount of chow consumed was negatively correlated with the total number of responses. Neither drug significantly increased response duration, suggesting that accumbens DA antagonism did not produce the type of motor impairment that leads to severe alterations in the form of lever pressing. In summary, the blockade of D1 or D2 receptors in nucleus accumbens core or shell decreased lever pressing for food reinforcers, but rats remained directed toward the acquisition and consumption of food. These results indicate that accumbens D1 antagonism does not decrease lever pressing because of a general reduction in food motivation. Nevertheless, interference with accumbens DA does appear to set constraints upon which responses are selected for obtaining food, and may impair the ability of animals to overcome work-related response costs in order to obtain food.

In vivo characterization of basal amino acid levels in subregions of the rat nucleus accumbens: effect of a dopamine D 3/D 2 agonist

Recent evidence demonstrates that two subdivisions of the nucleus accumbens, the dorsolateral core and the ventromedial shell can be distinguished by morphological, immunohistochemical and chemoarchitectural differences. In the present study, we measured basal levels of amino acids in microdialysates from both the shell and core subterritories of the nucleus accumbens in freely moving rats using HPLC with fluorescence detection. The effect of the dopamine D 3/D 2 receptor agonist quinelorane (30 μg/kg s.c.) was then investigated in both subregions. With the exception of glutamate, histidine, and serine, which showed similar levels in both subterritories, alanine, arginine, aspartate, γ-aminobutyric acid, glutamine, and tyrosine were significantly higher in the shell compared with the core. In contrast, taurine levels were significantly lower in the shell than in the core. A particularly striking difference across subregions of the nucleus accumbens was observed for basal GABA levels with a shell/core ratio of 18.5. Among all the amino acids investigated in the present study, quinelorane selectively decreased dialysate GABA levels in the core subregion of the nucleus accumbens. The results of the present study point to specific profiles of both shell and core in terms of: (1) basal chemical neuroanatomical markers for amino acids; and (2) GABAergic response to the DA D 3/D 2 agonist quinelorane.

Neural integrative activities of nucleus accumbens subregions in relation to learning and motivation

In recent years, there has been much interest in the functional specializations of nucleus accumbens subregions. The two zones within the nucleus accumbens that have received considerable attention are the accumbens core, consisting of ventral striatal tissue surrounding the anterior commissure, and the accumbens shell, which envelops the core on its medial, ventral, and lateral borders. Differential connectivity and histochemical profiles suggest that these two subterritories may have distinctive behavioral roles with regard to the regulation of motivated behavior. Experiments focusing primarily on amino acid–coded neurotransmitter systems in these regions—that is, glutamate and gamma-amino butyric acid (GABA)—have revealed specific and contrasting functions of the core and the shell. It is proposed that the accumbens core, and specifically N-methyl-d-aspartate receptor-dependent plasticity within this area, is part of a network critical for appetitive instrumental learning, in which a motor response becomes “stamped in” when followed by a rewarding stimulus or event. The accumbens shell, particularly GABA and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors within the shell, is implicated in the executive control of brain feeding circuits and may also represent a key area at which appetitive and aversive stimuli interact to control behavioral selection. These functional specializations within the nucleus accumbens subregions may be integrated through the coordination of activity within striatal neuronal ensembles that communicate with complex networks of limbic, thalamic, and prefrontal circuitry.

In VivoElectrochemical Studies of Dopamine Clearance in Subregions of Rat Nucleus Accumbens: Differential Properties of the Core and Shell

The dopamine (DA) uptake/clearance properties of the DA transporter (DAT) in the core and shell of the nucleus accumbens were measured usingin vivoelectrochemical recordings. Calibrated amounts of a DA solution were pressure-ejected from a micropipette/electrode assembly placed in the core or shell of the nucleus accumbens in anesthetized male Fischer 344 rats. Initial studies in the two brain regions revealed that the core and shell have different DA clearance properties as measured by the extracellular DA signal amplitudes, clearance times, and clearance rates. Although the same number of picomoles of DA were applied, DA clearance signals recorded in shell had significantly greater amplitudes but faster clearance rates than those recorded in the core. Systemic administration of 20 mg/kg cocaine, a monoamine transporter inhibitor, greatly increased the signal amplitude from the locally applied DA in both the core and shell. Signal amplitudes were increased to a greater extent in the shell, compared with the core, after cocaine administration. However, cocaine affected the clearance time of DA only in the core and the DA clearance rate only in the shell. Taken together with previously reported data, these studies further support differential activity of the DAT in the core versus shell subregions of the nucleus accumbens. In addition, these data indicate that DATs are more sensitive to the effects of psychomotor stimulants, such as cocaine, in the shell of the nucleus accumbens.

Cholecystokinergic Innervation of Nucleus Accumbens Subregions

Behavioral and pharmacological evidence has shown a different and opposite role of the neuropeptide cholecystokinin (CCK) on the dopamine (DA) function in the caudal versus rostral part of the nucleus accumbens. Previous reports have speculated that the caudal region of the nucleus accumbens would receive CCKergic innervation from dopaminergic neurons of the mesencephalic ventral tegmental area, whereas the CCKergic input to the rostral accumbens would originate in non-dopaminergic neurons from extra-mesencephalic areas of the brain. In the present study, this issue was addressed using retrograde tracing techniques in conjunction with immunocytochemistry. Retrograde tracers were injected in the three compartments of the accumbens (i.e., rostral pole, core and septal shell). In summary, our results demonstrate that 1) the main CCKergic input of the accumbens originates in the ventral mesencephalon; 2) the rostral pole is equally innervated by CCK neurons projecting from both substantia nigra pars compacta and ventral tegmental area; 3) the primary source of CCK innervation of the accumbal core is the substantia nigra pars compacta; and 4) whereas the CCKergic input to the septal shell originates primarily in the ventral tegmental area. Additionally, our results also showed that most of the CCKergic neurons projecting to any of the accumbal compartments also produce dopamine. These data constitute the first neuroanatomical evidence for the differential effects of CCK on dopamine actions in the different regions of the nucleus accumbens.

Differential Behavioral Responses to Dopaminergic Stimulation of Nucleus Accumbens Subregions in the Rat

The following experiments investigated the behavioral response to local microinfusion of dopamine (DA) and selective DA agonists into the core and shell subregions of the nucleus accumbens. Rats were implanted with chronic indwelling cannulae aimed at these subregions. Two experiments were conducted. In experiment 1, the response to DA (0, 2, 5, 10 μg/0.5 μl/side), the D-1 agonist SKF-82598 (0, 0.1, 1.0 μg), the D-2/3 agonist quinpirole (0, 1, 5, 15 μg) and the D-3 preferring agonist pramipexole (0.1, 1.0, 10.0 μg) was examined in photocell activity cages. Locomotor (horizontal) and rearing (vertical) activities were measured. DA and SKF-82958 induced relatively greater increases in activity following stimulation of the shell as compared with the core. Quinpirole induced a dose-dependent suppression of activity after infusion into both sites, although the core was more sensitive to the suppressive effect than the shell. Pramipexole induced time-dependent, biphasic effects that were small in magnitude and did not differentiate between site. In experiment 2, an observation procedure was used to record behaviors (locomotion, rearing, feeding, drinking). Dopamine (0, 2, 10 μg) elicited greater increases in rearing and feeding behavior in the shell than in the core. SKF-82958 (0, 0.75 μg) enhanced locomotion and rearing to a similar extent in both subregions in this test, whereas a mixture of a low dose (0.25 μg) of the D-1 and D-2 agonists selectively induced behavioral activation in the shell. In contrast to the results in the activity cage test, quinpirole (0, 1, 5 μg) increased motor activity at the lower dose when infused into the shell but not into the core. No alterations in feeding were observed following infusion of selective agonists, and no changes in drinking were found with any of the treatments. In summary, the shell appears to be relatively more sensitive to the motor activating effects of DA agonists than the core. Moreover, circuits associated with shell may be preferentially involved in feeding.

Reduced prepulse inhibition after electrolytic lesions of nucleus accumbens subregions in the rat

A variety of neurochemical and anatomical studies have shown that the ventral striatal nucleus accumbens (NAcc) can be divided into a predominantly medial `shell' and a predominantly lateral `core'. These accumbens subdivisions are innervated by different cortical regions and project to different anatomical targets. Additionally, recent behavioral observations suggest functional differences between the accumbens shell and core. In order to further examine core and shell function, we measured prepulse inhibition (PPI) of the acoustic startle reflex after electrolytic lesions aimed at the central NAcc, the NAcc shell, the NAcc core, and the adjacent anteroventrolateral striatum. Acoustic startle is the contraction of whole-body musculature in response to a sudden, loud auditory stimulus, and PPI is the inhibition of acoustic startle by a weak auditory `prepulse' administered 30–500 ms prior to the startling stimulus. Previous work has shown that PPI is regulated by the NAcc, and recent observations suggest that PPI is regulated by different neurochemical interactions in the core and shell. PPI was significantly reduced by electrolytic lesions of the central NAcc, as well as by lesions that predominantly damaged either the NAcc shell or the core. Lesions of the anteroventrolateral striatum and lateral edge of the NAcc core did not significantly alter PPI. These findings suggest that, despite neurochemical differences between the two subregions, PPI is regulated by both the NAcc shell and core.

Sensorimotor gating in rats is regulated by different dopamine-glutamate interactions in the nucleus accumbens core and shell subregions

The amplitude of the acoustic startle reflex is normally reduced when the startling stimulus is preceded by a weak click or ‘prepulse’. Prepulse inhibition (PPI) of acoustic startle has been used as an operational measure of sensorimotor gating or inhibition, and is reduced in schizophrenia patients and in rats with central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus offer a useful animal model to study impaired sensorimotor gating in schizophrenia. We have previously reported that DA-glutamate interactions in the nucleus accumbens (NAC) regulate PPI. The NAC has at least two major subregions — the core and shell — that have distinct anatomical and neurochemical properties. In this study, we compared changes in PPI after manipulations of DA-glutamate activity in these two NAC subregions. Consistent with previous findings, infusion of the non-NMDA agonist AMPA into the NAC core subregion significantly reduced PPI, and this effect was opposed by systemic administration of the D 2 antagonist haloperidol. Also consistent with previous reports, infusion of the non-NMDA antagonist CNQX into the NAC core subregion did not alter PPI, but its co-infusion with D-amphetamine (AMPH) attenuated the AMPH-disruption of PPI. In contrast, while PPI was reduced after AMPA infusion into the NAC shell subregion, this effect of AMPA could not be blocked by pretreatment with haloperidol. Infusion of either AMPH or CNQX into the NAC shell subregion reduced PPI independently. The PPI-disruptive effects of intra-shell CNQX infusion were not blocked by haloperidol. The present results suggest striking differences between the NAC core and shell subregions in their neurochemical modulation of sensorimotor gating of acoustic startle in the rat.

Repeated treatment with haloperidol and clozapine exerts differential effects on dye coupling between neurons in subregions of striatum and nucleus accumbens

The delayed onset of action of antipsychotic drugs (APDs) during the treatment of schizophrenia has been hypothesized to temporally correlate with the induction of depolarization block in rat mesencephalic dopamine (DA) cell groups. Nevertheless, it is unknown whether these drugs also exert a delayed action on the dopaminoceptive postsynaptic target cells in the striatal complex. Using in vivo intracellular recording and dye labeling techniques, the effects of APDs on dye coupling were examined in subregions of the striatal complex defined by double staining for calbindin immunoreactivity. Rats treated repeatedly with APDs were found to exhibit a 66-71% higher incidence of coupling that occurred in a drug- and a region-specific manner, that is, both drug treatments increased dye coupling in the limbic-associated accumbens shell region whereas only haloperidol increased dye coupling in the motor-related striatal matrix and accumbens core regions. In addition, cells located in regions in which dye coupling was altered also showed significantly higher input resistance. These changes were not observed in response to DA receptor blockade by acute drug administration or when haloperidol was administered for a period sufficient to induce DA receptor supersensitivity but not DA cell depolarization block (i.e., 2 weeks). Therefore, alteration in dye coupling appears to be correlated temporally with the induction of DA cell depolarization block. The finding that both APDs exert a common action on neurons in the accumbens shell region is consistent with its identification as the site of therapeutic drug actions, whereas the capacity of haloperidol to also affect cells in the motor-related matrix and core regions correlates with its high propensity to induce extrapyramidal side effects.

Excitatory amino acid receptors within nucleus accumbens subregions differentially mediate spatial learning in the rat

The present experiments investigated the effects of excitatory amino acid antagonists, infused into core and shell subregions of the nucleus accumbens, on spatial behavior in the rat. A food-search task was used, in which animals learn a specific pattern of food gathering; duration of each trial (time taken to gather all four pellets) and number of errors (visits to empty holes) were measured. In experiment 1, animals first underwent training, and subsequently were given microinfusions of either D-2-amino-5 phosphonopentanoic acid (AP-5), an N-methyl-d-aspartate (NMDA) antagonist (0, 0.2, 1.0µg/0.5µl), or 6,7-dinitroquinoxaline-2,3-dione (DNQX), an antagonist of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors (0, 0.075, 0.75µg/0.5µl). AP-5-significantly increased trial duration in both core and shell groups, but increased errors only in the core group. DNQX treatment also impaired performance in both groups, but the effect was greater in the core group compared with the shell group. In experiment 2, animals were treated during acquisition. Rats infused with AP-5 (1µg/0.5µl) took significantly longer to finish trials, made more errors and showed a marked learning impairment across days. AP-5 impaired learning in both core and shell groups, but the disruption was significantly greater in the core group. DNQX (0.75µg/0.5µl) also impaired learning when infused into the core during acquisition; however, the pattern of disruption contrasted markedly with that of AP-5. DNQX in the shell had no effect on trial duration during learning. It is hypothesized that both NMDA and non-NMDA receptors in the nucleus accumbens mediate spatial learning and performance, and that NMDA receptors may have a relatively more important role in memory or retrieval mechanisms. Moreover, the core subregion may be preferentially involved in the control of spatial behavior.

Differential behavioral effects following microinjection of an NMDA antagonist into nucleus accumbens subregions.

Recent studies have demonstrated the existence of two distinct regions within the nucleus accumbens (N.Acc) known as "core" and "shell". In order to investigate whether the behavioral functions of excitatory amino acid receptors differed between these two subregions, rats were administered microinjections of 2-amino-5-phosphonovaleric acid (AP-5), a competitive NMDA antagonist (0, 0.05, 0.2, 0.5, 1.0 microgram/0.5 microliter) into selected central and medial regions of the accumbens. The central and medial sites were assumed to correspond approximately to core and shell subregions, respectively. The animals were tested in two exploratory tasks: the open field and a novel object test. In the open field test, AP-5 significantly decreased peripheral locomotion and center rearing frequency in the central but not the medial group. Locomotion and rearing were not affected by AP5 infusion into a control site, the anterior dorsal striatum (ADS). In the novel object test, animals were tested in the same open field, with prior habituation, and with several novel objects placed within it. In this test, infusions of AP-5 (0, 1.0 microgram/0.5 microliter) decreased the number and duration of contacts with the novel objects in the central but not the medial group. In addition, peripheral and center locomotion were decreased by AP-5 infusions into the central site, whether objects were present or not. In contrast, AP-5 infusions into the medial site elicited an increase in peripheral locomotion in both stimulus conditions. These findings provide behavioral-pharmacological evidence that the central and medial subregions of the nucleus accumbens can be differentiated.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of dopamine, homovanillic acid and 3,4-dihydroxyphenylacetic acid in rat brain striatum by high-performance liquid chromatography with electrochemical detection

Two procedures using liquid chromatography with electrochemical detection are described for the determination of dopamine (DA) and its two acidic metabolites, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC), in subregions of rat striatum and nucleus accumbens. A strong cation-exchange column was used for DA analysis and a C 1 reversed-phase column was used for the analysis of the metabolites. Effects of pH, temperature and percentage of methanol on the retention time of HVA and DOPAC were studied. Levels of these compounds in the subregions of rat striatum and nucleus accumbens are reported.