Projections from the paraventricular nucleus of the thalamus to the rat prefrontal cortex and nucleus accumbens shell: ultrastructural characteristics and spatial relationships with dopamine afferents

The paraventricular nucleus of the thalamus (PVT) participates in the functional integration of limbic cortical and striatal circuitry. In the rat, the PVT projects to the deep layers of the medial prefrontal cortex (PFC) and to the shell of the nucleus accumbens (NAc). However, the synaptic organization of PVT afferents within these regions remains undescribed. Furthermore, although dopamine (DA) modulates excitatory glutamate transmission in both areas, possible anatomic substrates for specific DA modulation of PVT inputs have not yet been investigated. To address these issues, immunoperoxidase labeling for tyrosine hydroxylase (TH) in DA axons was combined with anterograde tract-tracing, either by biotinylated dextran amine (BDA) labeled with immunogold-silver or by degeneration after lesions of the PVT. In both regions, and with either tracing method, PVT terminals formed primarily asymmetric axospinous synapses; in the NAc, a proportion of PVT terminals also synapsed onto dendrites. PVT profiles in both regions were often seen in direct apposition to TH-immunoreactive axons; this association was more evident in the NAc where the DA innervation is denser. Within the PFC, PVT profiles and TH-labeled axons were occasionally apposed to the same dendrites, but synaptic specializations were not typically seen at these seeming points of convergence. Within the NAc, PVT profiles occasionally made synapses onto spines and distal dendrites that received convergent synapses from TH-immunoreactive varicosities. These findings represent the first demonstration of postsynaptic convergence between DA and thalamic afferents to a striatal region and are consistent with direct synaptic modulation of PVT transmission by DA in the NAc but not the PFC.     

Ventral mesopontine projections of the caudomedial shell of the nucleus accumbens and extended amygdala in the rat: double dissociation by organization and development.

The shell of the nucleus accumbens and central division of the extended amygdala are telencephalic structures that influence motor activity and lately have been regarded by some as components of a single functional-anatomic continuum. Each has a highly differentiated internal organization and output system and distinct pharmacologic responses however, and it is thus likely that each subserves distinct contributions to behavior. In this investigation, nucleus accumbens and extended amygdala outputs were compared by using retrograde tracing in adult and postnatal rats. Fluoro-Gold, when injected into the ventral tegmental area, produced substantial retrograde labeling in the adult nucleus accumbens shell, but only trivial amounts in the central division of the extended amygdala. Injection sites in the lateral mesopontine tegmentum produced robust labeling in the central extended amygdala but little in the nucleus accumbens. The projections of extended amygdala were substantially developed by postnatal day 1, whereas those of the caudomedial shell of the nucleus accumbens only reached the ventral tegmental area by approximately postnatal day 6. Few neurons projecting from the caudomedial shell of the accumbens to the ventral tegmental area were observed even at postnatal day 21. In consideration of the reported importance of the nucleus accumbens, particularly the caudomedial shell, in neural processing related to reward and motivation and the central nervous system response to antipsychotic drugs, it may be important to determine whether processes occurring during the protracted postnatal development of the caudomedial shell are vulnerable to destructive circumstances, such as drug intoxication, maternal separation, or social isolation.     

Axonal branching patterns of nucleus accumbens neurons in the rat

The patterns of axonal collateralization of nucleus accumbens (Acb) projection neurons were investigated in the rat by means of single-axon tracing techniques using the anterograde tracer biotinylated dextran amine. Seventy-three axons were fully traced, originating from either the core (AcbC) or shell (AcbSh) compartment, as assessed by differential calbindin D28k-immunoreactivity. Axons from AcbC and AcbSh showed a substantial segregation in their targets; target areas were either exclusively or preferentially innervated from AcbC or AcbSh. Axon collaterals in the subthalamic nucleus were found at higher than expected frequencies; moreover, these originated exclusively in the dorsal AcbC. Intercompartmental collaterals were observed from ventral AcbC axons into AcbSh, and likewise, interconnections at pallidal and mesencephalic levels were also observed, although mostly from AcbC axons toward AcbSh targets, possibly supporting crosstalk between the two subcircuits at several levels. Cell somata giving rise to short-range accumbal axons, projecting to the ventral pallidum (VP), were spatially intermingled with others, giving rise to long-range axons that innervated VP and more caudal targets. This anatomical organization parallels that of the dorsal striatum and provides the basis for possible dual direct and indirect actions from a single axon on either individual or small sets of neurons.     

Distribution of natriuretic peptide precursor mRNAs in the rat brain

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) represent members of a recently discovered neuropeptide family involved in central regulation of endocrine and autonomic functions. The present study employed an in situ hybridization approach to provide the first detailed comparative mapping of ANP, BNP, and CNP mRNAs in brain. Results indicate that ANP mRNA is highly expressed in anterior olfactory nuclei, limbic cortices, dorsal endopiriform nucleus, hippocampal subfield CA1, cortical amygdaloid nuclei, medial habenula, anteroventral periventricular and arcuate nuclei, periventricular stratum, zona incerta, mammillary nuclei, inferior olive, nucleus ambiguus, and pontine paragigantocellular nuclei. CNP mRNA is expressed at highest levels in olfactory nuclei, limbic cortices, dorsal endopiriform nucleus, hippocampal subfields CA1–3, anteroventral periventricular and arcuate nuclei, and numerous brainstem regions (including the pontine, lateral reticular, solitary tract, prepositus hypoglossal, and spinal trigeminal nuclei). Positive labeling for BNP mRNA was not observed in brain. The presence of both ANP and CNP mRNA in the same regions of distinct nuclei (e.g., the anteroventral periventricular and arcuate nuclei) suggests the potential for coexpression. Overall, the present data are consistent with a prominent role for both ANP and CNP in neuroendocrine regulation and central cardiovascular integration. The extensive localization of ANP and/or CNP mRNA in olfactory nuclei, limbic cortex, hippocampus, amygdala and diencephalic limbic relays further indicate a putative role for ANP and CNP as neuromodulators of olfactory/limbic information processing. © 1995 Wiley-Liss, Inc.     

Increased volume of the nucleus accumbens in schizophrenia

Summary. The nucleus accumbens, an integral and important part of limbic and prefrontal cortico-striato-pallidal-thalamic circuits, is involved in several cognitive, emotional and psychomotor functions altered in schizophrenia. In animal models, developmental disturbances within the entorhinal cortex and the hippocampus induce a dysregulation of inputs to the nucleus accumbens resulting in behavioral abnormalities which point to psychotic psychopathology. Nonetheless, due to the complex neuroanatomy of the human ventral striatum hardly any morphometric data on the nucleus accumbens are available. A postmortem stereological investigation of the nucleus accumbens was performed in complete brains of 9 male schizophrenics and 9 male controls between the ages of 46 and 64. Complete serial coronal slices of both hemispheres were stained with a modified Nissl-technique. Tissue shrinkage after staining and embedding was corrected for both individual and regional shrinkage. Based on recent precise delimitations of the human ventral striatum, in vivo hemisphere-adjusted volumes of the nucleus accumbens (volume densities) and absolute accumbal volumes were calculated applying the Cavalieri-estimator. In schizophrenics, mean hemisphere-adjusted volumes of the nucleus accumbens were significantly increased on both sides (right accumbens: p = 0,005^**; left accumbens: p = 0,016^*). Hemispherical volumes and volumes of the nucleus accumbens were significantly correlated in both groups (p = 0,02^*). Most likely, this increase in volume of the ventral striatum reflects a decrease in naturally occuring cell death following prenatal cortical neurodevelopmental disturbances. Received May 23, 2000; accepted July 20, 2000     

Differentially altered mGluR1 and mGluR5 mRNA expression in rat caudate nucleus and nucleus accumbens in the development and expression of behavioral sensitization to repeated amphetamine administration.

Altered glutamatergic transmission in the striatum may be implicated in behavioral sensitization to repeated amphetamine (AMPH) administration. Quantitative in situ hybridization histochemistry was performed to define the effects of acute and chronic AMPH exposures on mRNA expression of Group I metabotropic glutamate receptors (mGluRs) in the striatum. Behavioral ratings indicated that the motor activity of rats was significantly higher after the final of five daily AMPH injections (4 mg/kg, i.p.) than that after the first of five daily AMPH, indicative of the development of behavioral sensitization. Moreover, the motor activity of rats treated with five daily AMPH was significantly greater than that of rats treated with five daily saline in response to a 2 mg/kg challenge dose of AMPH 7, 14, 28, and 60 days after the discontinuation of drug treatments, indicative of the persistent expression of behavioral sensitization. Three hours after acute administration of AMPH to naive rats, mGluR1 and mGluR5 mRNA expression in the dorsal (caudatoputamen) and ventral (nucleus accumbens) striatum showed no change as compared to acute saline injection. In rats that developed behavioral sensitization to repeated AMPH, mGluR1 levels in the dorsal and ventral striatum were increased by 53% and 43%, respectively, 3 h after the final AMPH treatment. However, this change did not persist during withdrawal since it was not observed 7, 14, and 28 days after the discontinuation of AMPH treatment. Conversely, mGluR5 levels were markedly reduced 3 h after the final of five daily AMPH treatments in the entire striatum of sensitized rats (34% and 77% of controls in the dorsal and ventral striatum, respectively). The reduction persisted at 7, 14, and 28 days of withdrawal. These results reveal a close linkage between striatal Group I mGluR gene expression and behavioral sensitization to AMPH. This may indicate functional implications of the two subtypes of Group I mGluRs in the regulation of behavioral sensitization to the dopamine stimulant.     

Prefrontal cortical efferents in the rat synapse on unlabeled neuronal targets of catecholamine terminals in the nucleus accumbens septi and on dopamine neurons in the ventral tegmental area.

Physiological and pharmacological studies indicate that descending projections from the prefrontal cortex modulate dopaminergic transmission in the nucleus accumbens septi and ventral tegmental area. We investigated the ultrastructural bases for these interactions in rat by examining the synaptic associations between prefrontal cortical terminals labeled with anterograde markers (lesion-induced degeneration or transport of Phaseolus vulgaris leucoagglutinin; PHA-L) and neuronal processes containing immunoreactivity for the catecholamine synthesizing enzyme, tyrosine hydroxylase. Prefrontal cortical terminals in the nucleus accumbens and ventral tegmental area contained clear, round vesicles and formed primarily asymmetric synapses on spines or small dendrites. In the ventral tegmental area, these terminals also formed asymmetric synapses on large dendrites and a few symmetric axodendritic synapses. In the nucleus accumbens septi, degenerating prefrontal cortical terminals synapsed on spiny dendrites which received convergent input from terminals containing peroxidase immunoreactivity for tyrosine hydroxylase, or from unlabeled terminals. In single sections, some tyrosine hydroxylase-labeled terminals formed thin and punctate symmetric synapses with dendritic shafts, or the heads and necks of spines. Close appositions, but not axo-axonic synapses, were frequently observed between degenerating prefrontal cortical afferents and tyrosine hydroxylase-labeled or unlabeled terminals. In the ventral tegmental area, prefrontal cortical terminals labeled with immunoperoxidase for PHA-L were in synaptic contact with dendrites containing immunogold reaction product for tyrosine hydroxylase, or with unlabeled dendrites. These results suggest that: (1) catecholaminergic (mainly dopaminergic) and prefrontal cortical terminals in the nucleus accumbens septi dually synapse on common spiny neurons; and (2) dopaminergic neurons in the ventral tegmental area receive monosynaptic input from prefrontal cortical afferents. This study provides the first ultrastructural basis for multiple sites of cellular interaction between prefrontal cortical efferents and mesolimbic dopaminergic neurons.     

Effects of risperidone and haloperidol on tachykinin and opioid precursor peptide mRNA levels in the caudate-putamen and nucleus accumbens of the rat

We investigated whether the two output pathways of the striatum are differently affected by the novel atypical drug risperidone and the conventional typical antipsychotic drug haloperidol. To this end, changes in mRNA levels of preproenkephalin-A, preproenkephalin-B, and preprotachykinin were determined in the rat striatum following chronic drug treatment for 14 days, using quantitative in situ hybridization. Furthermore, we studied the contribution of the dopamine D₂ and serotonin 5-HT_2A antagonist components of risperidone in establishing its effects on neuropeptide mRNA levels in the striatum. The results showed that both risperidone and haloperidol had major effects on the preproenkephalin-A mRNA and thus on the indirect striatal output route, whereas they had minor effects on preproenkephalin-B and preprotachykinin mRNA, contained by the direct output route. When both drugs were administered in the same dose, preproenkephalin-A mRNA was much more elevated by haloperidol than by risperidone. However, when doses of risperidone and haloperidol were modified to attain comparable dopamine D₂ receptor occupancy, the drugs had comparable effects on preproenkephalin-A mRNA levels. It was further found that 5-HT_2A/C receptor blockade with ritanserin had only modest effects on preproenkephalin-B and preprotachykinin mRNA levels and did not affect preproenkephalin-A mRNA levels. We conclude that risperidone and haloperidol, administered in the same dose, differently affect the striatal output routes. Furthermore, the results suggest that the effects of risperidone on neuropeptide mRNA levels are fully accounted for by its D₂ antagonism and that no indication exists for a role of 5-HT_2A receptor blockade in this action. Synapse 28:302–312, 1998. © 1998 Wiley-Liss, Inc.     

Ultrastructural characteristics of enkephalin-immunoreactive boutons and their postsynaptic targets in the shell and core of the nucleus accumbens of the rat

The present study compared the ultrastructural morphology of enkephalin-immunoreactive boutons and their postsynaptic targets in different territories of the nucleus accumbens in the rat. The synaptic bouton profiles were identified by antibodies directed against [leu⁵]enkephalin. Ninety-five percent of the synaptic contacts were symmetric in configuration and the remaining 5% were asymmetric. Axosomatic contacts comprised 6% of all enkephalin-immunoreactive junctions and were distributed equally in all parts of the nucleus. Most (76%) synaptic terminals contacted dendrites but they contacted proportionally fewer dendrites in the shell (71%) than in the core (78%). Moreover, enkephalin-immunoreactive synaptic boutons in the shell (19%) and caudal enkephalin-rich areas (17%) of the core contacted twice as many spines than in the remaining parts of the core (8.5%). In the core, long pallidum-like dendrites were occasionally found ensheathed in enkephalin-immunoreactive terminal boutons. We conclude that the differential arrangement of enkephalinergic contacts in the shell and core could have important functional consequences, especially when considered in relation to other known morphological and neurochemical differences between these regions. © 1993 Wiley-Liss, Inc.     

Electrophysiological evidence of mediolateral functional dichotomy in the rat nucleus accumbens during cocaine self‐administration II: phasic firing patterns

In the cocaine self‐administering rat, individual nucleus accumbens (NAcc) neurons exhibit phasic changes in firing rate within minutes and/or seconds of lever presses (i.e. slow phasic and rapid phasic changes, respectively). To determine whether neurons that demonstrate these changes during self‐administration sessions are differentially distributed in the NAcc, rats were implanted with jugular catheters and microwire arrays in different NAcc subregions (core, dorsal shell, ventromedial shell, ventrolateral shell, or rostral pole). Neural recording sessions were typically conducted on days 13–17 of cocaine self‐administration (0.77 mg/kg per 0.2‐mL infusion; fixed‐ratio 1 schedule of reinforcement; 6‐h daily sessions). Pre‐press rapid phasic firing rate changes were greater in lateral accumbal (core and ventrolateral shell) than in medial accumbal (dorsal shell and rostral pole shell) subregions. Slow phasic pattern analysis revealed that reversal latencies of neurons that exhibited change + reversal patterns differed mediolaterally: medial NAcc neurons exhibited more early reversals and fewer progressive/late reversals than lateral NAcc neurons. Comparisons of firing patterns within individual neurons across time bases indicated that lateral NAcc pre‐press rapid phasic increases were correlated with tonic increases. Tonic decreases were correlated with slow phasic patterns in individual medial NAcc neurons, indicative of greater pharmacological sensitivity of neurons in this region. On the other hand, the bias of the lateral NAcc towards increased pre‐press rapid phasic activity, coupled with a greater prevalence of tonic increase firing, may reflect particular sensitivity of these neurons to excitatory afferent signaling and perhaps differential pharmacological influences on firing rates between regions.     

Distribution of mRNAs for Chromogranins A and B and Secretogranin II in Rat Brain

The mRNA distribution of chromogranins A and B and secretogranin II was determined in rat brain. In Northern blots the oligonucleotide probes used hybridized with single mRNA species of the expected sizes. With tissue hybridization the mRNA signals for these three proteins were found throughout the brain. However, each of the three messages had a distinct distribution, which was exemplified by the fact that in the various regions either all three proteins, a combination of two or only one of them were apparently synthesized. Significant levels of all three mRNAs were found in several regions of the hippocampus and of the amygdala, in some thalamic nuclei and in the pyriform cortex. On the other hand the subiculum contained only the message for chromogranin A, the granule cell layer of the cerebellum only that for chromogranin B, and in posterior intralaminar thalamic and medial geniculate nuclei and in the nucleus of the solitary tract only secretogranin II mRNA was found. The distinct distributions of mRNAs for the chromogranins in various brain regions support the concept that these proteins are propeptides giving rise to functionally active components.     

The role of the nucleus accumbens in learned approach behavior diminishes with training

Nucleus accumbens dopamine plays a key role in reward‐directed approach. Past findings suggest that dopamine's role in the expression of learned behavior diminishes with extended training. However, little is known about the central substrates that mediate the shift to dopamine‐independent reward approach. In the present study, rats approached and inserted the head into a reward compartment in response to a cue signaling food delivery. On days 4 and 5 of 28‐trial‐per‐day sessions, D1 receptor antagonist R(+)‐7‐chloro‐8‐hydroxy‐3‐methyl‐1‐phenyl‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine hydrochloride (SCH23390) infused to the NAc core reduced the probability and speed of cued approach. The disruptive effect of D1 receptor blockade was specific to the nucleus accumbens core and not seen with drug infusions to nearby dopamine target regions. In rats that received drug infusions after extended training (days 10 or 11), accumbens core D1 receptor blockade produced little effect on the expression of the same behavior. These results could have been due to a continued accumbens mediation of cued approach even after the behavior had become independent of accumbens D1 receptors. However, accumbens core ionotropic glutamate receptor blockade disrupted cued approach during early but not late stages of training, similar to the effects of D1 antagonist infusions. The results suggest that with extended training, a nucleus accumbens D1‐dependent behavior becomes less dependent not only on nucleus accumbens D1 transmission but also on excitatory transmission in the nucleus accumbens. These findings fill an important gap in a growing literature on reorganization of striatal function over the course of training.     

Distribution of the mineralocorticoid and the glucocorticoid receptor mRNAs in the rat hippocampus

The cellular localization of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) gene expression in the rat hippocampus was studied by in situ hybridization using 35S-labeled RNA-probes, complementary to either 513 bases of the rat brain mineralocorticoid receptor (MR)-mRNA or 500 bases of the rat liver glucocorticoid receptor (GR)-mRNA. Neurons in CA1, CA2, and the dentate gyrus expressed both receptor genes at high levels. The MR-mRNA was demonstrated in all pyramidal cell fields (CA1-4) of the hippocampal formation and the granular neurons of the dentate gyrus. In contrast, GR-mRNA was mainly restricted to CA1 and CA2 pyramidal cell fields and the dentate gyrus. This pattern of hybridization was found to agree with the cellular distribution of the two types of corticosteroid receptors detected previously in the hippocampus by autoradiography of the radio-labeled receptors and by immunocytochemistry of the receptor protein. These observations suggest that the corticosteroid receptors described previously as type 1 and type 2 are encoded by MR- and GR-mRNA, respectively. Although both the MR and GR genes are co-expressed in some hippocampal neurons, the unique patterns of distribution of the two receptor mRNAs in the hippocampal formation suggest that the genes for these receptors are differentially regulated. Moreover, the microanatomy of MR and GR expression provides insight into molecular mechanisms underlying the characteristic action of various steroids on behaviors involved in stress and circadian regulation.     

Withdrawal from repeated amphetamine administration reduces NMDAR1 expression in the rat substantia nigra, nucleus accumbens and medial prefrontal cortex

Glutamate plays a critical role in neuroadaptations induced by drugs of abuse. This study determined whether expression of the NMDAR1 subunit of the NMDA receptor is altered by repeated amphetamine administration. We quantified NMDAR1 mRNA (using in situ hybridization with 35S-labelled oligonucleotide probes) and immunolabelling (using immunocytochemistry with 35S-labelled secondary antibodies) in rat ventral midbrain, nucleus accumbens and prefrontal cortex after 3 or 14 days of withdrawal from five daily injections of saline or amphetamine sulphate (5 mg/kg/day). No changes in NMDAR1 expression were observed after 3 days of withdrawal, whereas significant decreases were observed in all regions after 14 days. NMDAR1 mRNA levels in midbrain were too low for reliable quantification, but immunolabelling was decreased significantly in intermediate and caudal portions of the substantia nigra. This may indicate a reduction in excitatory drive to substantia nigra dopaminergic neurons. In the nucleus accumbens, there were significant decreases in NMDAR1 mRNA levels (74.8 +/- 7. 7% of control, P < 0.05) and immunolabelling (76.7 +/- 4.4%, P < 0. 05). This may account for previously-reported decreases in the electrophysiological responsiveness of nucleus accumbens neurons to NMDA after chronic amphetamine treatment, and contribute to dysregulation of goal-directed behaviour. In prefrontal cortex, there was a significant decrease in NMDAR1 mRNA levels (76.1 +/- 7. 1%, P < 0.05) and a trend towards decreased immunolabelling (89.5 +/- 7.0%). This may indicate decreased neuronal excitability within prefrontal cortex. A resultant decrease in activity of excitatory prefrontal cortical projections to nucleus accumbens or midbrain could synergize with local decreases in NMDAR1 to further reduce neuronal excitability in these latter regions.     

Specificity in the efferent projections of the nucleus accumbens in the rat: Comparison of the rostral pole projection patterns with those of the core and shell

The efferent connections of the rostral pole of the rat accumbens, where distinct core and shell subterritories can not be identified, were examined with the aid of the anterogradely transported plant lectin, Phaseolus vulgaris-leucoagglutinin (PHA-L), for comparison with the previously reported projection patterns of the accumbal core and shell. Injection sites and transported PHA-L were evaluated with the aid of reference to adjacent sections processed to display substance P or calbindin 28 kD immunoreactivities, i.e., markers that demonstrate the core and shell. Lateral parts of the rostral pole gave rise to a “core-like” projection system that involved the rostroventral globus pallidus, subcommissural ventral pallidum, entopeduncular nucleus and an adjacent part of the lateral hypothalamus, lateral ventral tegmental area, dorsal pars compacta, and structures in the lateral mesencephalic tegmentum and central grey. The medial part of the rostral pole gave rise to a “shell-like” innervation of the subcommissural ventral pallidum, lateral preoptic region, lateral hypothalamus, ventral tegmental area, dorsalmost pars compacta, retrorubral field, lateral midbrain tegmentum, and central grey. In contrast to the large numbers of axon varicosities observed through the entire length of lateral hypothalamus following shell injections, dense accumulations of axon collaterals and varicosities in hypothalamus were limited to the levels of origin of the stria medullaris bundle and entopeduncular nucleus and to the posterlateral region following medial injections. The medial part of the rostral pole contributed some projections to preoptic and sublenticular regions, but not to the bed nucleus of the stria terminalis. Noteworthy concentrations of calbindin immunoreactive cells observed in the lateral rostral pole correlate with the origin of the “basal ganglia-like” projection system, provoking the speculation that ventral striatal calbindin immunoreactive cells contribute principally to basal ganglia-like projections while cells lacking calbindin immunoreactivity contribute to the innervation of hypothalamus and midbrain tegmentum. © 1993 Wiley-Liss, Inc.     

A topographically organized gamma-aminobutyric acid projection from the ventral pallidum to the nucleus accumbens in the rat

Anatomical and electrophysiological studies have indicated that a reciprocal projection from the ventral pallidum back to the nucleus accumbens exists and has functional relevance. In this study, the topographical projection from the ventral pallidum to the nucleus accumbens was examined by using retrograde tracing with fluoro-gold iontophoresed in subcompartments of the nucleus accumbens in rats combined with either in situ hybridization for glutamic acid decarboxylase and preproenkephalin mRNA or substance P immunoreactivity. Deposits made into the medial nucleus accumbens preferentially labeled neurons in the medial ventral pallidum, while deposits into the dorsolateral nucleus accumbens, at or lateral to the anterior commissure, labeled primarily cells in the dorsal and lateral ventral pallidum. A mediolateral to rostrocaudal topography was also observed, with the medial deposits preferentially labeling cells in rostral ventral pallidum and the lateral deposits resulting in retrogradely labeled cells in the ventral pallidum below the crossing of the posterior anterior commissure (subcommissural) as well as below the globus pallidus (sublenticular). The majority of cells retrogradely labeled with fluoro-gold were double-labeled for glutamic acid decarboxylase mRNA. In contrast, very few retrogradely labeled neurons in the ventral pallidurn were double labeled for mRNA for preproenkephalin. These data demonstrate a topographically organized projection from the ventral pallidum, to the nucleus accumbens that is primarily γ-aminobutyric acid (GABA)-ergic and reciprocal to the GABAergic projection from the nucleus accumbens to the ventral pallidum. © 1994 Wiley-Liss, Inc.     

Dynorphin-immunoreactive neurons in the rat nucleus accumbens: Ultrastructure and synaptic input from terminals containing substance P and/or dynorphin

The endogenous opioid peptide dynorphin is enriched in neurons in the nucleus accumbens, for which coexistence and synaptic interactions with substance P have been postulated. We examined the immunogold-silver localization of dynorphin and immunoperoxidase labeling for substance P in single coronal sections through the core subregion of the nucleus accumbens of acrolein-fixed rat brain tissue. Dynorphin-immunoreactive somata were more prevalent than substance P-containing neurons throughout the region sampled for ultrastructural analysis. Dynorphin-labeled cells were spherical, contained unindented nuclei, and were closely apposed to other somata and dendrites, some of which also contained dynorphin immunoreactivity. The appositions were characterized by the absence of glial processes and contiguous contacts between the plasma membranes. Smooth endoplasmic reticulum and coated vesicles could also be identified in the cytoplasms on either side of the somatic or dendritic appositions. The dynorphin somata and dendrites received synaptic input from numerous unlabeled as well as dynorphin-and/or substance P-labeled axon terminals. Both types of terminals were morphologically similar in their content of small and large dense core vesicles and their formation of mainly symmetric synaptic specializations. In addition to dynorphin-immunoreactive targets, numerous dynorphin-and substance P-labeled terminals also formed synapses with unlabeled somata and dendrites. In some cases, terminals separately labeled for dynorphin and substance P converged on common targets with or without detectable dynorphin immunoreactivity. Terminals colocalizing both peptides were also found to synapse on unlabeled or dynorphin-labeled somata and dendrites. Additionally, presynaptic interactions were suggested by close appositions between dynorphin-and/or substance P-labeled terminals and other terminals that were unlabeled, dynorphin labeled, or substance P labeled. These results provide morphological data suggesting nonsynaptic communication between dynorphin-immunoreactive neurons and other neurons possibly mediated through receptive sites or second messengers associated with smooth endoplasmic reticulum in the nucleus accumbens. They also indicate that, in this region, 1) the activity of dynorphin neurons may be dependent on activation of autoreceptors for dynorphin as well as substance P and 2) additional neurons lacking dynorphin immunoreactivity are most likely inhibited (symmetric junctions) by terminals containing either one or both peptides. The findings may have implications for motor and analgesic responses to aversive tonic pain transmitted through dynorphin and substance P pathways within the nucleus accumbens. © 1995 Willy-Liss, Inc.     

Pre- and postsynaptic sites for serotonin modulation of GABA-containing neurons in the shell region of the rat nucleus accumbens

The shell of the nucleus accumbens receives a dense serotonergic innervation and contains abundant gamma-aminobutyric acid (GABA)-immunoreactive neurons. Moreover, serotonin (5-hydroxytryptamine: 5-HT) and GABA have been implicated in a variety of common motivational and motor-related functions partially ascribed to this brain area. We used immunoelectron microscopy of antisera directed against 5-HT and GABA in the same section of tissue to examine whether there were cellular substrates that might indicate more specific sites for functional interactions involving these transmitters in the shell region of the rat nucleus accumbens. Immunogold-silver labeling for GABA was localized to perikarya, dendrites, axons and axon terminals, whereas immunoperoxidase labeling for 5-HT was restricted to axons and axon terminals. Approximately half (187/366) of the 5-HT-immunoreactive axon terminals apposed or formed synaptic junctions with postsynaptic neurons. These junctions were mainly of the symmetric-type (83/187) characteristic of inhibitory transmitters, and were equally prevalent on dendrites with and without detectable gold-silver labeling for GABA. Of the 187 5-HT-labeled axon terminals with recognized synaptic contacts, 36% also showed convergence on a common dendrite with a GABA-labeled axon terminal. In addition, 5-HT- and GABA-immunoreactive axon terminals were commonly (83/366) identified in direct apposition to one another. Within a single plane of section, 41% of the apposed GABA-immunoreactive axon terminals formed symmetric-type junctions with dendrites or somata, whereas, the apposed 5-HT-labeled axon terminals rarely showed postsynaptic contacts. These results indicate that 5-HT-containing axon terminals may postsynaptically inhibit GABAergic neurons and their targets within the shell of the rat nucleus accumbens. Additionally, our results strongly suggest that, in this brain region, appositions between 5-HT and GABA axons and axon terminals may facilitate presynaptic interactions between these transmitter systems. © 1996 Wiley-Liss, Inc.     

Rewarding and aversive effects of nicotine are segregated within the nucleus accumbens

Forebrain dopamine plays a critical role in motivated behavior. According to the classic view, mesolimbic dopamine selectively guides behavior motivated by positive reinforcers. However, this has been challenged in favor of a wider role encompassing aversively motivated behavior. This controversy is particularly striking in the case of nicotine, with opposing claims that either the rewarding or the aversive effect of nicotine is critically dependent on mesolimbic dopamine transmission. In the present study, the effects of 6-hydroxydopamine lesions of nucleus accumbens core vs. medial shell on intravenous nicotine conditioned place preference and conditioned taste aversion were examined in male adult rats. Dopaminergic denervation in accumbens medial shell was associated with decreased nicotine conditioned place preference. Conversely, denervation in accumbens core was associated with an increase in conditioned place preference. In addition, dopaminergic denervation of accumbens core but not medial shell abolished conditioned taste aversion for nicotine. We conclude that nucleus accumbens core and medial shell dopaminergic innervation exert segregated effects on rewarding and aversive effects of nicotine. More generally, our findings indicate that dopaminergic transmission may mediate or enable opposing motivational processes within functionally distinct domains of the accumbens.