A light and electron microscopic study of NADPH-diaphorase-, calretinin- and parvalbumin-containing neurons in the rat nucleus accumbens

The rat nucleus accumbens contains medium-sized, spiny projection neurons and intrinsic, local circuit neurons, or interneurons. Sub-classes of interneurons, revealed by calretinin (CR) or parvalbumin (PV) immunoreactivity or reduced nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase histochemistry, were compared in the nucleus accumbens core, shell and rostral pole. CR, PV and NADPH-diaphorase-containing neurons are shown to form three non-co-localising populations in these three areas. No significant differences in neuronal population densities were found between the subterritories. NADPH-diaphorase-containing neurons could be further separated morphologically into three sub-groups, but CR- and PV-immunoreactive neurons form homogeneous populations. Ultrastructurally, NADPH-diaphorase-, CR- and PV-containing neurons in the nucleus accumbens all possess nuclear indentations. These are deeper and fewer in neurons immunoreactive for PV than in CR- and NADPH-diaphorase-containing neurons. CR-immunoreactive boutons form asymmetrical and symmetrical synaptic specialisations on spines, dendrites and somata, while PV-immunoreactive boutons make only symmetrical synaptic specialisations. Both CR- and PV-immunoreactive boutons form symmetrical synaptic specialisations with medium-sized spiny neurons and contact other CR- and PV-immunoreactive somata, respectively. A novel non-carcinogenic substrate for the peroxidase reaction (Vector Slate Grey, SG) was found to be characteristically electron-dense and may be distinguishable from the diaminobenzidine reaction product. We conclude that the three markers used in this study are localised in distinct populations of nucleus accumbens interneurons. Our studies of their synaptic connections contribute to an increased understanding of the intrinsic circuitry of this area.     

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.     

When administered into the nucleus accumbens core or shell,the NMDA receptor antagonist AP-5 reinstates cocaine-seeking behavior in the rat

Nucleus accumbens glutamate transmission plays a critical role in cocaine priming-induced reinstatement of drug seeking. Previous studies have demonstrated that systemic or intra-accumbens shell administration of an NMDA receptor antagonist reinstates cocaine-seeking behavior. However, it is unclear if antagonizing NMDA receptors in the nucleus accumbens core or shell subregions will differentially affect cocaine reinstatement. To investigate this possibility, we microinjected the competitive NMDA receptor antagonist AP-5 (0, 3 or 30 μg) into either the nucleus accumbens core or shell and assessed the reinstatement of cocaine-seeking behavior. When microinjected into the shell, both doses of AP-5 produced reinstatement of cocaine seeking. In contrast, when administered into the core, only the highest dose of AP-5 reinstated cocaine-seeking behavior; moreover, the magnitude of this effect was substantially less than when AP-5 was administered into the shell. This study provides evidence that pharmacological antagonism of NMDA receptors in the nucleus accumbens core or shell promotes the reinstatement of cocaine seeking.     

Neurotensin: revealing a novel neuromodulator circuit in the nucleus accumbens–parabrachial nucleus projection of the domestic chick

Lower brainstem projections from nucleus accumbens (Ac) subregions to the parabrachial complex (PB), the nucleus of the solitary tract and the vagal motor nuclei have been described previously in the domestic chick by our group. Such projections, particulary those from the core and rostral pole regions of Ac have not been found in mammals or pigeons. Here we report on the presence of neurotensin (NT) in the neurons projecting from different Ac subnuclei, and also from the bed nucleus of stria terminalis, to the PB in the domestic chicken. The study is based upon correlated retrograde tracing (using Fast Blue) and NT immunohistochemistry, supplemented with regional charting and quantitative analysis of double-labeled neurons. The number of retrogradely labeled cells in Ac subdivisions reflects the size of FB tracer deposit, and the degree to which it extends to the medial PB. Of all Ac subregions, the core contained the largest amount of double-labeled cells. The findings demonstrate that the anatomical pathway through which the Ac can directly modulate taste-responsive neurons of the PB employs mainly neurotensin as a neuromodulator. The observed anatomical difference between mammals and birds is either a general taxonomic feature or it reflects feeding strategies specific for the domestic chick. The results are also relevant to a better understanding of the role of NT in food intake and reward-related behaviors in birds.     

Differential membrane properties and dopamine effects in the shell and core of the rat nucleus accumbens studied in vitro.

Electrophysiological differences between the shell and core of the rat nucleus accumbens were investigated by intracellular recordings from an in vitro slice preparation. The average input resistance of neurons recorded in the shell was larger than in the core. Neurons in the core were characterized by a more negative resting membrane potential than neurons in the shell. Furthermore, bath-applied dopamine attenuated synaptic responses recorded in the shell, but not in the core. Thus, the two main subregions of the nucleus accumbens differ both in basal membrane properties and in dopaminergic modulation of synaptic transmission.     

Three-dimensional organization of dendrites and local axon collaterals of shell and core medium-sized spiny projection neurons of the rat nucleus accumbens

Medium-sized spiny projection neurons (MSN) in the head of the primate caudate nucleus are thought to have preferred dendritic orientations that tend to parallel the orientations of the striosomes. Moreover, recurrent axon collaterals of MSN in the rat dorsal striatum have been categorized into two types, i.e., restricted and widespread. The nucleus accumbens (Acb) has a highly complex compartmental organization, and the spatial organization of dendritic and axonal arbors of MSN has not yet been systematically studied. In this study, using single-cell juxtacellular labeling with neurobiotin as well as anterograde neuroanatomical tracing with biotinylated dextran amine, we investigated the three-dimensional (3D) organization of dendrites and axons of MSN of the rat Acb in relation to subregional (shell-core) and compartmental (patch-matrix) boundaries. Our results show that dendritic arbors of MSN in both the Acb shell and core subregions are preferentially oriented, i.e., they are flattened in at least one of the 3D-planes. The preferred orientations are influenced by shell-core and patch-matrix boundaries, suggesting parallel and independent processing of information. Dendritic orientations of MSN of the Acb core are more heterogeneous than those of the shell and the dorsal striatum, suggesting a more complex distribution of striatal inputs within the core. Although dendrites respect the shell-core and patch-matrix boundaries, recurrent axon collaterals may cross these boundaries. Finally, different degrees of overlap between dendritic and axonal arborizations of individual MSN were identified, suggesting various possibilities of lateral inhibitory interactions within and between, functionally distinct territories of the Acb.     

On the significance of subterritories in the “accumbens” part of the rat ventral striatum

Although many workers have appreciated the striking cytologic and neurochemical similarities of neostriatum, accumbens and olfactory tubercle, a compelling case for regarding these areas as territories in a striatal complex awaited the arguments made by Heimer and his colleagues based on their investigations of connections. A number of recent papers support this viewpoint and extend it with the characterization of three accumbal subterritories: core, shell and rostral pole. The case for separate classifications of systems traversing the accumbens has become more compelling with each study that demonstrates connectional, cytoarchitectural and neurochemical specificity conforming to the boundaries separating the core and its downstream targets from the shell and its projection fields. Furthermore, its apparent composite of core-like and shell-like characteristics distinguishes the rostral pole as yet another unique subterritory. Differences in compartmental organization distinguish the accumbens and neostriatum. The available data are consistent with the periventricular and rostrolateral enkephalin-rich zones being ventralmost parts of the neostriatal patch and matrix compartments, respectively. The accumbal cell cluster compartment, on the other hand, appears to be a separate entity, with connectional and neurochemical features that are dissimilar to both patch and matrix of neostriatum. Boundaries between the accumbens and caudate-putamen remain elusive, and the point of view that such boundaries do not exist but, rather, are represented by "transition zones" must to a large degree reflect the reality. Likewise, it is important to acknowledge that the boundaries between accumbal subterritories are not necessarily distinct or observed faithfully by all of the afferent systems. "Transition zones" appear to be particularly significant organizational features in rostral and lateral parts of the accumbens. Interestingly, histochemically distinct cell clusters tend to be numerous in boundary regions between adjacent territories and subterritories. The predominant organizational pattern appears to be one in which the core, shell and rostral pole engage different forebrain systems that possibly subserve entirely different functions mediated by distantly related mechanisms. In this regard, it is of paramount interest that the processing of information conveyed to the accumbens by diverse cortical and subcortical inputs occurs within distinct and perhaps very different dopaminergic environments in the core, shell and rostral pole (e.g., see Refs 24, 34, 90, 110).     

Specificity in the projection patterns of accumbal core and shell in the rat

The efferent projections of the core and shell areas of the nucleus accumbens were studied with a combination of anterograde and retrograde tract-tracing methods, including Phaseolus vulgaris-leucoagglutinin, horseradish peroxidase and fluorescent tracers. Both the core and shell regions project to pallidal areas, i.e. ventral pallidum and entopeduncular nucleus, with a distinct topography in the sense that the core projection is located in the dorsolateral part of ventral pallidum, whereas the shell projects to the medial part of the subcommissural ventral pallidum. Both regions of the accumbens also project to mesencephalon with a bias for the core projection to innervate the substantia nigra-lateral mesencephalic tegmentum, and for the shell projection to reach primarily the ventral tegmental-paramedian tegmentum area. The most pronounced differences between core and shell projections exist in regard to the hypothalamus and extended amygdala. Whereas the core projects primarily to the entopeduncular nucleus including a part that invades the lateral hypothalamus, the shell, in addition, projects diffusely throughout the rostrocaudal extent of the lateral hypothalamus as well as to the extended amygdala, especially its sublenticular part. Both the core and shell of the accumbens have unmistakable striatal characteristics both histologically and in their connectional patterns. The shell, however, has additional features that are reminiscent of the recently described extended amygdala [Alheid G.F. and Heimer L. (1988) Neuroscience 27, 1-39; de Olmos J.S. et al. (1985) In The Rat Nervous System, pp. 223-334]; in fact, the possibility exists that the shell represents a transitional zone that seems to characterize most of the fringes of the striatal complex, where it adjoins the extended amygdala.     

Cocaine reward and hyperactivity in the rat: sites of mu opioid receptor modulation

Opioid receptor agonists and antagonists have profound effects on cocaine-induced hyperactivity and conditioned reward. Recently, the role specifically of the mu opioid receptor has been demonstrated based on the finding that i.c.v. administration of the selective mu opioid receptor antagonist, d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), can attenuate cocaine-induced behaviors. The purpose of the present study was to determine the location of mu opioid receptors that are critical for cocaine-induced reward and hyperactivity. Adult male Sprague-Dawley rats received injections of CTAP into the caudate putamen, the rostral or caudal ventral tegmental area (VTA) or the medial shell or core of the nucleus accumbens prior to cocaine to determine the role of mu opioid receptors in cocaine-induced reward and hyperactivity. Cocaine-induced reward was assessed using an unbiased conditioned place preference procedure. Results demonstrate that animals pre-treated with CTAP into the nucleus accumbens core or rostral VTA, but not the caudal VTA, caudate putamen or medial nucleus accumbens shell, during conditioning with cocaine showed an attenuation of the development of cocaine-induced place preference. In contrast, CTAP injected into the nucleus accumbens shell but not the core attenuated the expression of cocaine place preference. Intra-nucleus accumbens core, caudate putamen or caudal VTA CTAP significantly attenuated cocaine-induced hyperactivity. In addition, the number of cFos positive cells was increased in the motor cortex, medial and ventromedial aspects of the nucleus accumbens shell, basolateral amygdala and caudal VTA during the expression of cocaine place preference, and this increase was attenuated in the animals that received intra-accumbens core CTAP during daily cocaine conditioning. These results demonstrate the importance of mu opioid receptors in the nucleus accumbens and VTA in cocaine-induced reward and hyperactivity and suggest that some aspects of the behavioral effects of cocaine are mediated by endogenous activation of mu opioid receptors in these brain regions.     

Topographical organization of amygdaloid projections to the caudatoputamen, nucleus accumbens, and related striatal-like areas of the rat brain.

The topographical organization of amygdaloid projections to the caudatoputamen, nucleus accumbens, and lateral portions of the bed nucleus of the stria terminalis and central amygdaloid nucleus was investigated, in the rat, using the retrograde transport of wheat germ agglutinin-conjugated horseradish peroxidase. Although the caudatoputamen and nucleus accumbens are the principal components of the striatum, there is evidence that lateral portions of the bed nucleus of the stria terminalis and central amygdaloid nucleus may be striatal-like structures. The basolateral nucleus was the main source of amygdaloid fibers to all of these structures. In many instances labeled areas of the basolateral nucleus were continuous with labeled areas in the adjacent lateral and basomedial nuclei. Amygdaloid neurons projecting to the striatum and striatal-like areas exhibited an overlapping topographical organization. In general, the medial-to-lateral coordinate in the striatum corresponds to the medial-to-lateral coordinate in the basolateral nucleus. There was also a partial reversed sagittal topography in that the caudal caudatoputamen receives its principal projection from the rostral basolateral nucleus. However, the rostral basolateral nucleus had a stronger projection to the rostral caudatoputamen and lateral nucleus accumbens than the caudal basolateral nucleus. The principal striatal projection of the caudal basolateral nucleus was to the medial nucleus accumbens. Amygdaloid labeling produced by injections into the medial nucleus accumbens was very similar to that seen with injections into the lateral portions of the bed nucleus of the stria terminalis and central amygdaloid nucleus. The retrograde amygdaloid labeling seen in this investigation, when compared to labeling seen with cortical injections in previous studies, suggests that specific amygdaloid domains project to particular cortical areas as well as to the principal striatal targets of the same areas.     

The distribution and compartmental organization of the cholinergic neurons in nucleus accumbens of the rat

In this study the distribution of the cholinergic neurons was examined in relation to the compartmental organization of nucleus accumbens. This was accomplished by charting the location of the choline acetyltransferase-immunoreactive neurons and mapping their distribution in relation to cytoarchitectural features and the patterns of acetylcholinesterase activity and enkephalin immunoreactivity. Choline acetyltransferase-containing perikarya are inhomogeneously distributed in nucleus accumbens. Their density is lowest at the rostral pole and highest, caudomedially, at the septal pole. The cells form a compact, medial column and a diffuse, lateral zone and, moreover, there are distinct gradients in their distribution. The highest numbers of immunoreactive perikarya occur within the intensely immunostained zones of choline acetyltransferase-immunoreactive neuropil in ventral and ventromedial parts of the nucleus, whereas lower numbers coincide with choline acetyltransferase-poor zones in the central part of the nucleus. Zones of intensely choline acetyltransferase-immunoreactive neuropil are largely in register with regions of high acetylcholinesterase activity in middle and caudal parts of the nucleus but do not coincide rostrally. Choline acetyltransferase-rich zones correspond to moderate enkephalin immunoreactivity in the outer shell of the nucleus, but a moderately choline acetyltransferase-immunostained matrix surrounds "patches" of intense enkephalin immunoreactivity in the core. Small aggregates of cells, which feature commonly in nucleus accumbens, seem to be avoided by both choline acetyltransferase- and enkephalin-immunoreactive zones. Choline acetyltransferase-immunoreactive processes are mostly confined by the boundaries of their respective immunoreactive zones. Few choline acetyltransferase-immunoreactive neurons lie in the enkephalin-rich patches and those that lie close to the patches show little preference in the directionality of their processes such that some cross the borders, whereas others do not. Thus, our findings show that the cholinergic elements are differentially distributed within nucleus accumbens; that these elements are compartmentally ordered; and that, in light of their limited access to other compartments, they possibly play only a minor role in intercompartmental communication.     

Reciprocal connections between the claustrum and the gyrus sigmoideus posterior in the cat. An experimental study using the antegrade degeneration methods and the HRP retrograde axonal transport

Following coagulation lesions affecting the gyrus sigmoideus posterior we investigated the termination field of the cortico-claustral projection using impregnation techniques (NAUTA, GYGAX 1954; FINK, HEIMER 1967). Preterminal and terminal fragments of the degenerating axons were identified ipsilaterally on the dorsal and lateral margins of the claustrum dorsale in the rostral half of the nucleus. Labeled neurons were found ipsilaterally within the claustrum dorsale, in the termination field of the cortico-claustral projection rising from the gyrus sigmoideus posterior following injections of HRP (Sigma VI) into the gyrus sigmoideus posterior. There are reciprocal connections between the dorsolateral region of the claustrum dorsale and the cortex of the gyrus sigmoideus posterior. A prevailing number of the HRP-positive neurons of the claustrum are located in the termination field of the particular cortico-claustral projection. The discussion deals with some problems concerning the cortico-claustral and claustro-cortical projections and presents opinions as to the functional significance of the claustrum.     

Morphological differences between projection neurons of the core and shell in the nucleus accumbens of the rat.

The somatodendritic morphology of projection neurons in the shell and core of the rat nucleus accumbens was studied. These cells were retrogradely labelled with Fast Blue from the ventral mesencephalon (substantia nigra/ventral tegmental area) and subsequently injected intracellularly with Lucifer Yellow and processed immunocytochemically. Digitized reconstructions revealed that the cell bodies of neurons located throughout the nucleus are small-to-medium in size. Neurons in the shell have significantly fewer dendritic arbours with fewer branch segments, fewer terminal segments, and lower spine densities than those in the core. Values for the same parameters are significantly greater for cells in lateral than in medial parts of the shell but the same for neurons located within and without enkephalin enriched parts of the core, with an exception of spine density being significantly greater in the enkephalin-rich compartment. Calculations based on these data reveal that neurons in the core have as much as 50% more surface area than those in the shell, which suggests that core neurons have a greater potential for collecting synaptic information than have shell cells. Furthermore, the differential distribution and action of various neurochemicals such as dopamine in the shell and core, supports the idea that different morphologies reflect the presence of distinct neuronal circuits in these two territories.     

Organization of the projections from the subiculum to the ventral striatum in the rat. A study using anterograde transport of Phaseolus vulgaris leucoagglutinin

The projections of the subiculum, as the main output structure of the hippocampal formation, to the striatum were studied in the rat using the anterograde tracer Phaseolus vulgaris leucoagglutinin. It appears that not only the entire nucleus accumbens, part of the so-called ventral striatum, receives fibres from the subiculum, but that the hippocampal projection area in the striatum includes also the most medial, ventral, rostral and caudal parts of the caudate-putamen complex. Moreover, a relatively small number of fibres and terminals are present in the striatal elements of the medial part of the olfactory tubercle. The projections to the ventral and caudal parts of the caudate-putamen are predominantly derived from the ventral subiculum, whereas the projections to the rostral part of the caudate-putamen are derived from the dorsal subiculum. Furthermore, with respect to the subiculum-accumbens pathway a topographical organization could be established. Thus, the ventral or temporal part of the subiculum projects predominantly to the caudomedial part of the nucleus accumbens, and to a lesser degree to its rostromedial portion, whereas progressively more dorsal or septal parts of the subiculum send fibres to successively more lateral and rostral portions of the nucleus accumbens. Very sparse projections are found to the contralateral nucleus accumbens, arranged in a topographical manner similar to the ipsilateral projections. An important observation with respect to the structure of the nucleus accumbens is that the subicular terminations are inhomogeneously distributed, although a relation with earlier described mosaic patterns in the connectivity and neurochemical composition of the nucleus is not yet clear. Subicular fibres have their densest terminations in relatively cell-poor regions of the nucleus accumbens, and in particular tend to avoid small cell clusters.     

Subcellular and subsynaptic localization of group I metabotropic glutamate receptors in the nucleus accumbens of cocaine-treated rats

There is significant pharmacological and behavioral evidence that group I metabotropic glutamate receptors (mGluR1a and mGluR5) in the nucleus accumbens play an important role in the neurochemical and pathophysiological mechanisms that underlie addiction to psychostimulants. To further address this issue, we undertook a detailed ultrastructural analysis to characterize changes in the subcellular and subsynaptic localization of mGluR1a and mGluR5 in the core and shell of nucleus accumbens following acute or chronic cocaine administration in rats. After a single cocaine injection (30 mg/kg) and 45 min withdrawal, there was a significant decrease in the proportion of plasma membrane-bound mGluR1a in accumbens shell dendrites. Similarly, the proportion of plasma membrane-bound mGluR1a was decreased in large dendrites of accumbens core neurons following chronic cocaine exposure (i.e. 1-week treatment followed by 3-week withdrawal). However, neither acute nor chronic cocaine treatments induced significant change in the localization of mGluR5 in accumbens core and shell, which is in contrast with the significant reduction of plasma membrane-bound mGluR1a and mGluR5 induced by local intra-accumbens administration of the group I mGluR agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG). In conclusion, these findings demonstrate that cocaine-induced glutamate imbalance has modest effects on the trafficking of group I mGluRs in the nucleus accumbens. These results provide valuable information on the neuroadaptive mechanisms of accumbens group I mGluRs in response to cocaine administration.     

Observations on the projection from the perihypoglossal nuclei to the cerebellar cortex and nuclei in the cat

Summary The origin and distribution of cerebellar cortical and nuclear afferents from the perihypoglossal nuclei have been studied by means of retrograde transport after implants and injections of the wheat germ agglutinin-horse-radish peroxidase complex in the cat. The projection reaches all the cerebellar nuclei as well as vermal, intermediate and lateral parts of the cerebellar cortex. It is bilateral with an ipsilateral predominance and originates from all the perihypoglossal nuclei. The majority of the projecting neurons are situated caudally in the nucleus prepositus, while smaller numbers of projecting neurons are located in the rostral part of this nucleus, in the rostral nucleus intercalatus and in the nucleus of Roller. Small and medium-sized spindle-shaped to round cells located throughout the nucleus prepositus and in the rostral nucleus intercalatus have widespread projections, reaching all parts of the cerebellar cortex and nuclei, whereas large multipolar cells located in the caudal ventromedial part of the nucleus prepositus and in the nucleus of Roller have projections only to the flocculus and nodulus and the lateral and intermediate cortices.Retrograde fluorescent double-labelling experiments were made to investigate possible axonal branching of the perihypoglosso-cerebellar fibres. In experiments with injections of rhodamine-B-isothiocyanate (RITC) in the left cerebellar hemisphere and implants of crystalline Fluoro-Gold in the right hemisphere, single- and double-labelled cells were found intermingled throughout the perihypoglossal nuclei. Experiments with cerebellar cortical injections of RITC and implants of crystalline Fluoro-Gold in the underlying nucleus, demonstrated single- and double-labelled cells in the nucleus prepositus and the rostral nucleus intercalatus, while only single-labelled RITC neurons were seen in the group of large neurons in the ventromedial part of the nucleus prepositus and the nucleus of Roller. After injections of RITC in the cerebellar cortex and implants of crystalline Fluoro-Gold in the abducent nucleus on the same side, double-labelled neurons were found only in the rostral nucleus prepositus.     

The orbital cortex in rats topographically projects to central parts of the caudate-putamen complex

Disturbances of the orbitofrontal-striatal pathways in humans have been associated with several psychopathologies including obsessive-compulsive disorder and drug addiction. In nonhuman primates, different subareas of the orbitofrontal cortex project topographically to central and ventromedial parts of the striatum. Relatively little is known about the anatomical organization of the rat orbital cortex while there is a growing interest in this cortical area from a functional and behavioral point of view. The aim of the present neuroanatomical tracing study was to determine in rats the striatal target area of the projections of the orbital cortex as well as the topographical organization within these projections. To this end, anterograde tracers were injected in the different cytoarchitectonically distinct subareas of the orbital cortex. The results show that the individual orbital areas, i.e. medial orbital area, ventral orbital area, ventrolateral orbital area and lateral orbital area, project to central parts of the caudate-putamen, exhibiting a mediolateral and, to a lesser degree, rostrocaudal topographical arrangement. Orbital projections avoid the most dorsal, as well as rostral and caudal parts of the caudate-putamen. Terminal fields from cytoarchitectonically different areas show a considerable overlap. Superficial cortical layers project preferentially to the striatal matrix, deep layers to the patch compartment. The projections from the ventrolateral orbital area are strongest and occupy the most extensive striatal area. In addition to projections to the caudate-putamen, the ventrolateral, lateral and dorsolateral orbital areas have a scarce projection to the most lateral part of the nucleus accumbens shell in the ventral striatum. In contrast to nonhuman primates, the remainder of the rat nucleus accumbens is virtually free of orbital projections.     

Met-enkephalin and preproenkephalin mRNA changes in the striatum of the nicotine abstinence mouse

We studied the changes of met-enkephalin (Met-Enk) content and preproenkephalin (PPE) mRNA in the striatum in a mouse model of nicotine abstinence. Nicotine, 2 mg/kg, s.c., was administered four times daily for 14 days and Met-Enk and PPE mRNA evaluated at various times (4-96 h) following drug discontinuation. Met-Enk, assayed by radioimmunoassay, was increased in the ventral (nucleus accumbens) but not dorsal (putamen/caudate) striatum, while PPE mRNA, assayed in whole striatum by Northern blotting was elevated. Both changes were seen early during withdrawal and lasted over 72 h. In situ hybridization revealed enhanced signal in the dorsal striatum, mostly laterally, and smaller increases in the rostral pole, core and shell of the nucleus accumbens. These observations indicate that during nicotine withdrawal, striatal enkephalinergic neurons undergo adaptative responses, which might contribute to the abstinence behavioral syndrome.     

Response of ventral pallidal neurons to amygdala stimulation and its modulation by dopamine projections to nucleus accumbens

It has been shown that the nucleus accumbens receives input from the amygdala and that mesolimbic dopaminergic projection from the ventral tegmental area (VTA) modulates the response of accumbens neurons to amygdala input. Since the nucleus accumbens projects to the ventral pallidum, the purpose of this study was to investigate, using electrophysiological techniques, whether or not the nucleus accumbens relays the projection from the amygdala to the ventral pallidum and whether or not the mesolimbic dopamine projection interacts with this pathway. Extracellular single-unit recordings were obtained from the ventral pallidum of urethan-anesthetized rats, and the responses of these neurons to electrical stimulation of the amygdala were investigated. Of 392 neurons tested, 36% were inhibited and 11% were excited following amygdala stimulation. Latency of onset of inhibitory responses showed a bimodal distribution with peaks in the ranges of 4-6 ms and 16-18 ms, respectively. Fifty-four percent of inhibitory responses with latencies greater than 12 ms were attenuated by 1) injection of procaine hydrochloride into the nucleus accumbens, or 2) injection of d-amphetamine into the nucleus accumbens, or 3) stimulation of VTA with a train of 10 pulses (10 Hz) prior to stimulation of amygdala. Acute administration of haloperidol intraperitoneally or injection of 6-hydroxydopamine into the ipsilateral VTA, 2 days prior to the recording experiment, reduced the attenuating effects of intra-accumbens injection of d-amphetamine and VTA conditioning stimulations on the inhibitory response of ventral pallidal neurons to amygdala stimulation. These results support the hypothesis that the nucleus accumbens provides a link between the amygdala and the ventral pallidum. Since the amygdala is a limbic structure and the ventral pallidum has possible connections with the extrapyramidal motor system, it is suggested that the amygdala to nucleus accumbens to ventral pallidum projection may be a bridge between the limbic and motor systems. We also suggest that this relay of output from the amygdala to the ventral pallidum via the nucleus accumbens is under the modulating influence of the mesolimbic dopamine projection from the ventral tegmental area.     

Facilitated extinction of appetitive instrumental conditioning following excitotoxic lesions of the core or the medial shell subregion of the nucleus accumbens in rats

The nucleus accumbens has been implicated in the control of goal-directed behaviour, including instrumental conditioning. Here, we evaluated the effect of N-methyl-d-aspartate (NMDA)-induced excitotoxic lesions restricted to either the core or the medial shell subregions of the nucleus accumbens (NAC) on extinction in rats using a trial discrete fixed ratio-5 (FR-5) appetitive operant procedure. Neither core nor shell lesions of the NAC affected the acquisition of instrumental responding. Both lesions facilitated the cessation of responding when the instrumental act no longer yielded reinforcement. Our results suggest that both the NAC core and medial shell contribute to the control of extinction learning of appetitively motivated instrumental behaviour.