Effects of basolateral amygdala dopamine depletion on the nucleus accumbens and medial prefrontal cortical dopamine responses to stress

In vivo voltammetry was used to study the effects of basolateral amygdala dopamine depletion on stress-induced dopamine release in the nucleus accumbens and medial prefrontal cortex. Male Long-Evans rats received bilateral microinjections of 6-hydroxydopamine or vehicle into the basolateral amygdala. Changes in dopamine signal were monitored in the nucleus accumbens and in the right and left hemispheres of medial prefrontal cortex, in lesioned animals and shams. Animals were subjected to a physical stressor (tail pinch) and a species-typical threat (fox odour); each stressor was presented twice over four consecutive daily sessions. The results indicate that the nucleus accumbens dopamine responses to both stressors are significantly potentiated by dopamine-depleting lesions to basolateral amygdala. In contrast, while the dopamine stress response in the left medial prefrontal cortex did not differ between lesioned animals and shams, the right medial prefrontal cortical dopamine response to tail pinch, but not fox odour stress, was significantly attenuated in lesioned animals. Therefore, basolateral amygdala dopamine depletion had opposite effects on the nucleus accumbens and medial prefrontal cortical dopamine responses to stress, although the effect on the latter is lateralized to the right hemisphere in a stressor-specific manner. These data indicate that stress-induced activation of meso-amygdaloid dopamine exerts an inhibitory influence on the nucleus accumbens dopamine response to stress. They also suggest the possibility that meso-amygdaloid dopamine influences the nucleus accumbens dopamine response to stress indirectly by modulating stress-induced dopamine release in medial prefrontal cortex. These findings add to a growing body of evidence of a preferential involvement of right medial prefrontal cortical dopamine in a wide range of physiological responses to stress.     

Immunohistochemical assessment of mesotelencephalic dopamine activity during the acquisition and expression of Pavlovian versus instrumental behaviours

Dopaminergic activity during Pavlovian or instrumental learning in key target regions of the mesotelencephalic dopamine system was investigated immunohistochemically using antibodies raised against glutaraldehyde-conjugated dopamine. Experiment 1 examined dopamine immunoreactivity during acquisition of a Pavlovian conditioned-approach response. Observations were taken at three stages of learning: initial, intermediate and asymptotic; each with a conditioned stimulus+ (CS+) group for whom visual or auditory stimuli immediately preceded an unconditioned stimulus (sucrose), and a conditioned stimulus- (CS-) group for whom stimuli and the unconditioned stimulus were unpaired. Animals learned to approach the alcove during CS+ presentations, whilst approach behaviour of the CS- group remained low. In general, target regions exhibiting a dopaminergic reaction responded maximally during the intermediate stage of acquisition, and were less responsive initially, and not responsive at all at asymptote. Specifically, the pattern of dopaminergic response was: shell more than core of the nucleus accumbens; prefrontal cortex, central and basolateral nuclei of the amygdala also significantly responsive. Mediodorsal and laterodorsal striatal regions were reactive only very early in training. Experiment 2 examined dopaminergic reaction following acquisition of a novel conditioned instrumental response. The conditioned response+ (CR+) group responded at a much higher rate on the lever for which unconditioned stimulus-associated stimuli were presented, than on the control lever. The conditioned response- (CR-) group responded at a low rate on both levers. In contrast with experiment 1, the most responsive regions were the core of the nucleus accumbens, medial prefrontal cortex and basolateral area of the amygdala. Thus, the acquisition, but not expression of Pavlovian associations activated dopamine within several key target regions of the mesotelencephalic dopamine system, and preferentially within the shell rather than core of the nucleus accumbens. By contrast, acquisition of a novel instrumental response preferentially activated the core of the nucleus accumbens, and basolateral area of the amygdala. These data carry significant implications for the potential role of these regions in learning and memory.     

Potential contributions of efferents from medial prefrontal cortex to neural activation following sexual behavior in the male rat

The limbic system plays an important role in the regulation of sexual motivation and reward. At the core of this system is an interconnected mesocorticolimbic circuit, comprised of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. Previously, our laboratory showed that sexual behavior causes neural activation in the ventral tegmental area of male rats. The main goal of this study is to identify afferent inputs to ventral tegmental area neurons that may contribute to their activation during sexual behavior. Hence, the anterograde tracer biotinylated dextran amine was injected into subregions of the rat medial prefrontal cortex, which is known to project to the ventral tegmental area. Visualization of biotinylated dextran amine-labeled axons was combined with immunostaining for sex-induced Fos expression. Quantitative analysis showed that the majority of sex-activated ventral tegmental area neurons receive putative contacts from the infralimbic and prelimbic--but not the anterior cingulate--subregions of the medial prefrontal cortex. Thus, inputs from infralimbic area and prelimbic are in an anatomical position to provide a major source of input during sexual behavior. A second goal of this study was to determine if the medial prefrontal cortex projects to sex-activated neurons in other brain regions important for sexual behavior and motivation. Infralimbic area and prelimbic area sent projections to nucleus accumbens, medial preoptic area, principal nucleus of the bed nucleus of the stria terminalis, basolateral amygdala, and parvocellular subparafasicular thalamic nucleus. Thus, the infralimbic and prelimbic subregions of the medial prefrontal cortex may also influence sexual behavior and motivation via brain regions other than the ventral tegmental area.     

N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning

The effect of microinfusion of the N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5) into the amygdala, medial prefrontal cortex, and dorsal and ventral subiculum on acquisition of a lever-pressing task for food in rats was examined. Serial transmission between the basolateral amygdala and nucleus accumbens core was also examined in an asymmetric infusion design. AP-5 administered bilaterally into either the amygdala or medial prefrontal cortex markedly impaired learning, whereas administration into the dorsal or ventral subiculum had no effect. Unilateral infusion of AP-5 into either the nucleus accumbens core or amygdala was also sufficient to impair learning. These data provide novel evidence for NMDA receptor-dependent plasticity within corticostriatal networks in the acquisition of appetitive instrumental learning.     

Neuroadaptive changes in mesocorticolimbic dopamine and acetylcholine neurons following cocaine or saline self-administration are dependent on pre-existing individual differences

Previously, we demonstrated that stress-induced self-grooming behaviour in rats predicted an enhanced motivation to self-administer cocaine as determined under a progressive ratio schedule of reinforcement. The enhanced motivation of high grooming (HG) rats was associated with a reduced reactivity of dopaminergic neurons in the medial prefrontal cortex and amygdala, but not nucleus accumbens. In the present study, we studied the effect of cocaine and saline self-administration on these pre-existing differences in neurochemical profile by determining the electrically evoked release of [3H]dopamine and [14C]acetylcholine from superfused slices of the nucleus accumbens shell and core, medial prefrontal cortex and amygdala of HG and low grooming (LG) rats. Although HG and LG rats did not differ in acquisition of cocaine and saline self-administration, both conditions induced substantially different neuroadaptations in these rats. Differences in depolarisation-induced dopamine and acetylcholine release were maintained in the medial prefrontal cortex, emerged in the nucleus accumbens and dissipated in the amygdala. These results indicate that altered reactivity of mesocorticolimbic dopaminergic and cholinergic neurons due to exposure to cocaine and environmental stimuli (saline) is dependent on pre-existing neurochemical differences and displays region-specificity. These pre-existing differences and the cocaine- and environmental-induced neuroadaptations seem to act in concert to produce an enhanced motivational state to self-administer cocaine.     

An immunohistochemical examination of the effects of sensitisation on the mesotelencephalic dopaminergic response to d-amphetamine

The dopaminergic response to d-amphetamine with or without prior repeated experience with the drug was investigated immunohistochemically in key target regions of the mesotelencephalic dopamine system using antibodies raised against glutaraldehyde-conjugated dopamine. This methodology permitted the unambiguous determination of dopaminergic activity within specific subregions of structures implicated in the behavioural effects of psychomotor stimulants drugs, and in the expression of behavioural sensitisation. Experiment 1 examined dopamine immunoreactivity in central or basolateral amygdala, shell or core of the nucleus accumbens, medial and lateral caudate-putamen and medial prefrontal cortex following the administration of various doses of d-amphetamine to drug-na?ve rats. Whilst dose-related increases in dopaminergic activity were detected in all regions examined, a regional heterogeneity was clearly evident. For example, d-amphetamine enhanced dopaminergic activity preferentially within the shell subregion of the nucleus accumbens both with respect to the core subregion and to other striatal and non-striatal areas. Experiment 2 examined changes in dopaminergic activity following the administration of a low dose of d-amphetamine to d-amphetamine-sensitised rats and saline-pretreated control animals. Regional heterogeneity both between and within terminal areas was again detected. Thus, there was evidence of a preferential increase in dopaminergic activity within the shell of the nucleus accumbens of sensitised rats. Moreover, sensitisation to d-amphetamine increased the dopaminergic response to acute administration of d-amphetamine within all striatal and non-striatal areas examined. Comparison of this effect across subterritories of the areas under investigation revealed that in sensitised rats, acute administration of d-amphetamine elevated dopaminergic activity within the shell of the nucleus accumbens to a greater extent than within the core. These data therefore indicate that systemic administration of d-amphetamine is associated with regionally heterogeneous changes in dopaminergic activity within terminal regions of the mesotelencephalic dopamine system in both sensitised and unsensitised rats. Moreover, the present methodology permitted resolution of these changes at an anatomical level beyond that of conventional approaches.     

Differential neuronal changes in medial prefrontal cortex,basolateral amygdala and nucleus accumbens after postweaning social isolation

The mesocorticolimbic system contains dopamine (DA)-producing neurons in the ventral tegmental area (VTA) and their projection targets, including the medial prefrontal cortex (mPFC), amygdala (AMY) and nucleus accumbens (NAc). Disruption of this system might attribute to mental illnesses. In the present study, we adopted the postweaning social isolation paradigm to model neuropsychiatric disorders and studied the functional and structural changes of the mesocorticolimbic system. After 8–9 weeks of isolation, rats exhibited hyperlocomotor activity and impaired sensorimotor gating compared to group-reared controls. However, the number of tyrosine hydroxylase-positive VTA neurons and the volume of VTA were not affected. Comparing with group-reared controls, the DA levels in the isolation-reared were not altered in the VTA, mPFC and NAc but decreased in the AMY. In the structural aspect, dendritic features of layer II/III pyramidal mPFC neurons; pyramidal neurons in the basolateral nucleus of amygdala (BLA) and medium spiny neurons in the core region of the NAc (NAcc) were examined. Interestingly, the neuronal changes were region-specific. The mPFC neurons had reduced dendritic complexity, spine density and elongated terminal branches. The BLA neurons had extensive dendritic arbors with short branches but unchanged spine density. The NAcc neurons had reduced total dendritic length but the segment length and spine density remained the same. Together, the results demonstrated the structural and functional changes in the mesocorticolimbic DA system of socially isolated rats. These changes may account for the behavioral impairments in these rats and attribute to the susceptibility to mental disorders related to schizophrenia and depression.     

The topographic order of inputs to nucleus accumbens in the rat

Afferents to the nucleus accumbens have been studied with the retrograde transport of unconjugated wheatgerm agglutinin as detected by immunohistochemistry using the peroxidase-antiperoxidase method, in order to define precisely afferent topography from the cortex, thalamus, midbrain and amygdala. Cortical afferent topography was extremely precise. The largest number of cells was found following injections to the anterior accumbens. Anteromedial injections labelled a very large extent of the subiculum and part of the entorhinal cortex. Anterolateral injections produced less subicular and entorhinal label but also labelled the posterior perirhinal cortex. Posteromedial injections labelled only the ventral subiculum and a few cells in the adjacent medial entorhinal cortex. Posterolateral injections labelled few lateral entorhinal neurones but did label a long anteroposterior strip of perirhinal cortex. Prefrontal cortex label was found only after anterior accumbens injections. In the amygdala labelled neurones were found in cortical, central, lateral posterior, anteromedial and basolateral nuclei. Basolateral amygdala projected chiefly to the anteromedial accumbens and central nucleus to anterolateral accumbens. Only a weak amygdala label was found after posterior accumbens injections. In the ventral tegmental area, the midline interfascicular nucleus projected only to medial accumbens. The paranigral ventral tegmentum projected chiefly to the medial accumbens and the parabrachial area chiefly to the lateral accumbens. In the thalamus, heaviest label was found after anterior accumbens injections. Most cells were found in the paraventricular, reuniens and rhomboid nuclei and at posterior thalamic levels lying medial to the fasciculus retroflexus. There was only restricted topography found from thalamic sites. Retrograde label was also found in the ventral pallidum and lateral hypothalamus. Single small injection sites within accumbens received input from the whole anteroposterior extent of the thalamus and ventral tegmentum. The medial accumbens was found to have a close relationship to habenula, globus pallidus and interfascicular nucleus. It appeared that the heaviest volume of inputs projected to anteromedial accumbens, where output from hippocampus (CAI), subiculum, entorhinal and prefrontal cortices converged with output from amygdala, midline thalamus and ventral tegmentum.     

Activation of dopaminergic neurotransmission in the medial prefrontal cortex by N-methyl-d-aspartate stimulation of the ventral hippocampus in rats

Many behavioral functions-including sensorimotor, attentional, memory, and emotional processes-have been associated with hippocampal processes and with dopamine transmission in the medial prefrontal cortex (mPFC). This suggests a functional interaction between hippocampus and prefrontal dopamine. The anatomical substrate for such an interaction is the intimate interconnection between the ventral hippocampus and the dopamine innervation of the mPFC. The present study yielded direct neurochemical evidence for an interaction between ventral hippocampus and prefrontal dopamine transmission in rats by demonstrating that subconvulsive stimulation of the ventral hippocampus with N-methyl-d-aspartate (NMDA; 0.5 mug/side) activates dopamine transmission in the mPFC. Postmortem measurements revealed that bilateral NMDA stimulation of the ventral hippocampus, resulting in locomotor hyperactivity, increased the homovanillic acid/dopamine ratio, an index of dopamine transmission, in the mPFC; indices of dopamine transmission in any of five additionally examined forebrain regions (amygdala, nucleus accumbens shell/core, lateral prefrontal cortex, caudate putamen) were unaltered. In vivo microdialysis measurements in freely moving rats corroborated the suggested activation of prefrontal dopamine transmission by demonstrating that unilateral NMDA stimulation of the ventral hippocampus increased extracellular dopamine in the ipsilateral mPFC. The suggested influence of the ventral hippocampus on prefrontal dopamine may be an important mechanism for hippocampo-prefrontal interactions in normal behavioral processes. Moreover, it indicates that aberrant hippocampal activity, as found in neuropsychiatric diseases, such as schizophrenia and mood disorders, may contribute to disruption of certain cognitive and emotional functions which are extremely sensitive to imbalanced prefrontal dopamine transmission.     

The distribution of the projection from the parataenial nucleus of the thalamus to the nucleus accumbens in the rat: An autoradiographic study

Summary In this study the intrastriatal distribution of afferents arising from the parataenial nucleus of the thalamus was investigated. Tritiated leucine and proline injected into the parataenial nucleus was found to densely label the entire anterior-posterior extent of the medial nucleus accumbens. The projection was for the most part limited to this striatal subregion, although some moderate labelling was found along the medial wall of the anterior caudateputamen. The terminal labelling within accumbens was characterized by a distinct patchiness. Other efferent connections of the parataenial nucleus observed in this study include the thalamic reticular nucleus, the basolateral and central nuclei of the amygdala, the septum, the medial frontal cortex, the entorhinal cortex and subiculum.This projection is distributed to the limbic afferented sector of striatum, and there is a nearly complete overlap between the parataenial afferents and those coming from hippocampus. The present findings suggest that the parataenial nucleus is an important thalamic link between limbic and striatal processing.Abbreviations A nucleus accumbens - AC anterior commissure - abl basolateral nucleus of amygdala - abm basomedial nucleus of amygdala - ac central nucleus of amygdala - am medial nucleus of amygdala - al lateral nucleus of amygdala - bst bed nucleus of Stria terminalis - CAI internal capsule - CC crus cerebri - CP caudate-putamen - F fornix - FCX frontal cortex - FH fimbria hippocampi - fr fasciculus retroflexus - GP globus pallidus - IL infralimbic cortex - lh lateral habenula - MD mediodorsal nucleus - MFH medial forebrain bundle - MO medial orbital cortex - nb nucleus basalis - ot olfactory tubercle - Pt parataenial nucleus - PV paraventricular nucleus - sl lateral septum - SM Stria medullaris - ST Stria terminalis - tam anterior medial nucleus - tav anterior ventral nucleus - tol nucleus of lateral olfactory tract - tr reticular nucleus - tv ventral nucleus - VL lateral ventricle - V_III third ventricle Presented in part at the Sixth European Neuroscience Congress, Malaga, Spain, 1982New address: Psychobiologie des Comportements Adaptatifs, INSERM U. 259, Rue Camille Saint Saens, Domaine de Carreire, F-33077 Bordeaux Cedex, France     

Reduction of zif268 messenger RNA expression during prolonged withdrawal following "binge" cocaine self-administration in rats

Cocaine self-administration increases dopamine efflux and neuronal activity in the mesocorticolimbic dopamine system compared with experimenter-administered cocaine. Following a prolonged cocaine self-administration binge, dopamine efflux in the nucleus accumbens is attenuated and behaviors emerge that are indicative of anhedonia and anxiety. The neuronal correlates of these behavioral and neurochemical effects of a cocaine binge were assessed using in situ hybridization histochemistry to detect changes in zif268 messenger RNA expression. Rats were fitted with intravenous catheters; one group was trained to self-administer cocaine (0.5mg/injection), then allowed continuous access to cocaine during a 16h binge, while yoked animals received either saline or cocaine according to the same schedule. Measurement of tactile startle responses and ultrasonic distress calls either immediately after termination of cocaine access or one or 14 days later confirmed peak withdrawal at 24h after the binge. The level of zif268 messenger RNA was lower upon termination of cocaine self-administration than in both yoked treatment groups in the ventral tegmental area and hippocampus. In contrast, zif268 messenger RNA expression increased in the periaqueductal gray matter one day after termination of passive cocaine treatment, coincident with enhanced expression of ultrasonic vocalizations. Zif268 messenger RNA expression decreased over time in the nucleus accumbens core and infralimbic cortex, with reduced expression observed in the nucleus accumbens core, caudatoputamen, hippocampus and amygdala 14 days after termination of cocaine self-administration.The results suggest that withdrawal following a cocaine self-administration binge produces a long-lasting reduction of constitutive zif268 messenger RNA expression in mesocorticolimbic brain regions related to the nucleus accumbens. The relatively greater effect in animals that self-administered cocaine implies a relationship of certain regional responses to behavioral conditioning.     

Neuronal and behavioral correlations in the medial prefrontal cortex and nucleus accumbens during cocaine self-administration by rats

Up to 31 neurons per animal were simultaneously recorded from the medial prefrontal cortex and nucleus accumbens in 15 rats during i.v. cocaine self-administration sessions, using a multi-channel, single-unit recording technique. Alterations of neuronal activity (both excitatory and inhibitory) were found a few seconds before each lever press for cocaine infusion; we have called these pre-lever press neuronal activations "anticipatory responses". A detailed video analysis revealed that these neuronal firing alterations were associated with specific portions of the behavioral sequence performed before each lever press in both recording areas. Some of the simultaneously recorded neurons displayed similar firing patterns in relation to a given behavioral episode within the behavioral sequence (turning, raising head, etc.), while others fired at different times relative to each behavioral event. Cross-correlational analyses revealed inter-regional and intra-regional correlated firing patterns between pairs of simultaneously recorded medial prefrontal cortex and nucleus accumbens neurons. This correlated firing occurred in the neurons with and without anticipatory responses, although the incidence of correlations between anticipatory neuron pairs was much higher than that between non-anticipatory neuron pairs (18.4% vs 3.6%). Many correlated neuron pairs displayed a time lag in the peak of correlational activity that indicated a temporal sequence in correlated activity. In contradiction to our hypothesis, the temporal pattern of correlation reveals that there are more cases in which nucleus accumbens neurons fired ahead of medial prefrontal cortex neurons.The results suggest that multiple mesocorticolimbic neuronal circuits may code sequential steps during the behavioral sequence performed to obtain an infusion of cocaine. The observed correlated firing between the medial prefrontal cortex and the nucleus accumbens indicates that dynamic, coherent activity occurs within the mesocorticolimbic circuit. Because this circuit is hypothesized to drive drug-seeking behavior, we suggest that this correlated firing between the nucleus accumbens and the medial prefrontal cortex may participate in the control of cocaine self-administration. In addition, the finding that correlated activity within the nucleus accumbens more often precedes that of the medial prefrontal cortex suggests that the nucleus accumbens may play a prime role in the initiation of cocaine self-administration.     

Dopaminergic involvement in medial prefrontal cortex and core of the nucleus accumbens in the regulation of ethanol self-administration: a dual-site microinjection study in the rat

The complex mesolimbic-mesocortical system involved with behavioral selection has been implicated in the control of ethanol self-administration. However, the nature of the interactions within this multiple-structured system in ethanol intake regulation remains unclear. Although the role of dopamine (DA) in the prefrontal cortex and the nucleus accumbens has been examined individually, the interaction of DA activity in both structures at the same time remains to be examined. Male, Long-Evans rats were initiated to self-administer ethanol in an operant situation using the sucrose-substitution procedure. Following initiation, bilateral cannula guides were located to allow microinjection in the medial prefrontal cortex (mPFC) and the core of the nucleus accumbens. The DA D2/D3 agonist quinpirole (10.0-microg dose in the prefrontal cortex; 4.0-microg dose in n. accumbens) and the D2 antagonist raclopride (0.05-microg dose in prefrontal cortex; 1.0-microg dose in the nucleus accumbens) were then tested in each site alone and in combination in both sites in each rat. Changes in total responding, ethanol intake, and the pattern of responding were analyzed. Single-site injections replicated most of our previous findings for these doses. Changes in single-site effects were found when dual-site injections were performed, with altered input from the prefrontal areas impacting the effects of accumbens injections. Based on these interactions, our hypothesis that the prefrontal area is involved with the onset and offset of drinking, while the nucleus accumbens is involved with maintaining the ongoing behavior, remains viable.     

Limited collateralization of neurons in the rat prefrontal cortex that project to the nucleus accumbens

The specificity and selectiveness of a neuronal message depends in part on the number of recipient neurons that simultaneously receive this message. Hence, projections involved in higher order cognitive processes might be expected to exhibit a lower degree of collateralization than projections that mediate more basic brain functions. This study sought to determine the degree to which neurons projecting from the prefrontal cortex to the nucleus accumbens collateralize to major cortical and subcortical regions: the contralateral prefrontal cortex, the basolateral amygdala or the ventral tegmental area. Fluoro-Gold and cholera toxin-b were used to label prefrontal cortex neurons that project to these targets, and the proportion of neurons singly and dually labeled by immunofluorescence for these tracers was determined. The prefrontal cortex neurons projecting to these regions exhibited a partially complementary laminar distribution. Furthermore, of the neurons projecting to the nucleus accumbens, 13% sent a collateralized projection to the contralateral prefrontal cortex, 7% collateralized to the basolateral amygdala, and 3% sent a branched projection to the ventral tegmental area. No differences were observed in the degree of collateralization of neurons in superficial versus deep layers.Thus, the degree of collateralization of corticoaccumbens neurons was overall limited, but significantly greater to a cortical target than to subcortical regions. These branching patterns provide anatomical substrates for temporal and spatial coordination of activity in limbic circuits.     

Organization of amygdaloid projections to the prefrontal cortex and associated striatum in the rat.

The organization of connections between the amygdala, prefrontal cortex and striatum was studied using anterograde and retrograde tract tracing techniques in the rat. The anterograde transport of Phaseolus vulgaris leucoagglutinin and wheat germ agglutinin conjugated to horseradish peroxidase was used to examine the striatal projections of the prefrontal cortex. These studies revealed that the prelimbic area of the medial prefrontal cortex projects mainly to the medial part of the striatum, whereas the dorsal agranular insular area of the lateral prefrontal cortex projects mainly to the ventrolateral part of the striatum. The organization of amygdaloid projections to the prefrontal cortex and its associated portions of the striatum was investigated using the fluorescence retrograde tract tracing technique. Different color fluorescent dyes, True Blue and Diamidino Yellow, were injected into the prefrontal cortex and striatum. These studies demonstrated that medial portions of the basolateral nucleus, and adjacent portions of the lateral, basomedial and amygdalo-hippocampal nuclei, project to both the medial prefrontal cortex and its associated medial striatal region. The rostral pole and lateral portions of the basolateral nucleus project to both the lateral prefrontal cortex and its associated lateral striatal region. Many neurons in the basolateral amygdaloid nucleus, and to a lesser extent other amygdaloid nuclei, were double-labeled in these experiments, indicating that these cells send collaterals to both the prefrontal cortex and striatum. These findings indicate that discrete areas of the amygdala, and in some cases individual amygdaloid neurons, can modulate information processing in the first two links of distinct cortico-striato-pallidal systems arising in the medial and lateral prefrontal cortex.     

Specificity of amygdalostriatal interactions in the involvement of mesencephalic dopaminergic neurons in affective perception

We have recently shown that dopaminergic responses to an attractive or an aversive stimulus were respectively increased and decreased in the core part of the nucleus accumbens and the ventromedial dorsal striatum. By contrast, increases in dopaminergic responses were obtained in the shell part of the nucleus accumbens with stimuli of both affective values. In addition, the involvement of the basolateral amygdala in affective processes has been reported by several authors. Anatomo-functional relationships between the basolateral amygdala and striatal structures have also been described. Thus, in the present work we studied the regulation by the basolateral amygdala of affective dopaminergic responses in the two parts of the nucleus accumbens (core and shell) and the ventromedial dorsal striatum. More precisely, variations in extracellular levels of dopamine induced by an attractive or an aversive olfactory stimulus were studied using in vivo voltammetry in freely moving rats. Changes in dopamine levels in the three left striatal regions were measured after functional blockade of the ipsilateral basolateral amygdala with tetrodotoxin. Changes in place attraction or aversion toward the stimulus were studied in parallel to dopamine variations.The results obtained suggest a specific regulation of affective dopaminergic responses in the two parts of the nucleus accumbens by the basolateral amygdala and a lack of influence of the basolateral amygdala on the ventromedial dorsal striatum. The results suggest that attraction or aversion toward a stimulus are correlated with dopamine variations in the core of the nucleus accumbens and that the basolateral amygdala controls affective behavioural responses. These data may provide new insights into the pathophysiology of schizophrenic psychoses.     

Withdrawal duration differentially affects c-fos expression in the medial prefrontal cortex and discrete subregions of the nucleus accumbens in cocaine-sensitized rats

Intermittent administration of cocaine can result in behavioral sensitization, which is indicated by an augmented behavioral response to a subsequent administration of cocaine. This increase in behavior can be seen after various periods of abstinence from the drug, and is believed to model the cravings of drug users and the onset of drug addiction. It is believed that behavioral sensitization is mediated by activity of the mesocorticolimbic dopamine system. In particular, the nucleus accumbens and prefrontal cortex have been shown to play integral roles in this phenomenon. Recently, it has been demonstrated that the shell portion of the nucleus accumbens can no longer be considered a homogeneous structure, and can be subdivided into five separate regions. The present study was designed to assess the activation of key neuronal populations in subdivisions of the accumbens and subdivisions of the medial prefrontal cortex in cocaine-sensitized rats, using the expression of the immediate early gene, c-fos, as a marker of neuronal activation. Repeated cocaine administration resulted in robust sensitization that correlated with a significant decrease in the density of c-fos nuclei in all three subdivisions of the medial prefrontal cortex, and two subdivisions of the nucleus accumbens only in animals challenged after a 2-day withdrawal period. After a 2-week withdrawal period, sensitized animals no longer showed any differences in the density of c-fos nuclei in any of the areas examined, with the exception of a significant increase in the intermediate zone of the shell.The results indicate that distinct adaptations in neural activation take place in cocaine-sensitized rats that have been drug-free for various lengths of time. Furthermore, while specific subregions of brain areas known to play a role in drug abuse can be uniquely involved in the manifestations of cocaine sensitization, the functional roles of these subregions may differ depending on the time at which the behavior is assessed.     

Neuroleptics increase c-fos expression in the forebrain: contrasting effects of haloperidol and clozapine.

The mechanisms by which the atypical neuroleptic clozapine produces its therapeutic effects in the treatment of schizophrenia without causing the extrapyramidal side effects that are characteristic of most antipsychotic drugs remain unclear. Recently, a single injection of the typical antipsychotic haloperidol has been shown to increase c-fos expression in the striatum [Dragunow et al. (1990) Neuroscience 37, 287-294]. C-fos is a proto-oncogene that encodes a 55,000 mol. wt phosphoprotein, Fos, which is thought to assist in the regulation of "target genes" containing an AP-1 binding site. Because a wide variety of physiological and pharmacological stimuli increase c-fos expression, it has been proposed that Fos immunohistochemistry might be useful in mapping functional pathways in the central nervous system. The present experiments examined some potential neuroanatomical differences in the actions of clozapine and haloperidol by comparing their effects on c-fos expression in the medial prefrontal cortex, nucleus accumbens, striatum and lateral septum. The effects of the selective dopamine receptor antagonists SCH 23390 (D1) and raclopride (D2) were also examined. Haloperidol (0.5, 1 mg/kg) and raclopride (1, 2 mg/kg) produced large increases in the number of Fos-containing neurons in the striatum and nucleus accumbens. SCH 23390 (0.5, 1 mg/kg) reduced the number of Fos-positive neurons in the nucleus accumbens and striatum, and had no effect in the other regions. Neither haloperidol nor raclopride increased the number of Fos-positive neurons in the medial prefrontal cortex. Haloperidol, but not raclopride, produced a modest increase in c-fos expression in the lateral septal nucleus. Clozapine (10, 20 mg/kg) was without effect in the striatum; however, it significantly increased the number of Fos-positive neurons in the nucleus accumbens, medial prefrontal cortex and lateral septal nucleus. Destruction of mesotelencephalic dopaminergic neurons with 6-hydroxydopamine abolished the increase in Fos expression in the nucleus accumbens and striatum produced by haloperidol and raclopride, and also blocked the clozapine-induced increase in the nucleus accumbens. However, the inductive effects of clozapine and haloperidol on c-fos expression in the lateral septal nucleus and of clozapine in the medial prefrontal cortex were not affected by the 6-hydroxydopamine lesions. These results suggest that clozapine's unique therapeutic profile may be related to its failure to induce Fos in the striatum as well as its idiosyncratic actions in the lateral septum and medial prefrontal cortex. The effects of clozapine in these latter regions do not appear to be mediated by dopaminergic mechanisms.     

External incentives and internal states guide goal-directed behavior via the differential recruitment of the nucleus accumbens and the medial prefrontal cortex

Goal-directed behavior is governed by internal physiological states and external incentives present in the environment (e.g. hunger and food). While the role of the mesocorticolimbic dopamine (DA) system in behavior guided by environmental incentives has been well studied, the effect of relevant physiological states on the function of this system is less understood. The current study examined the role of the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAcc) in the kind of food-reinforced behaviors known to be sensitive to the internal state produced by food deprivation conditions. Operant lever-press reinforced on fixed ratio 1 (FR1) and progressive ratio (PR) schedules was tested after temporary inactivation of, or DA receptor blockade in, the prelimbic mPFC or NAcc core of rats with differing levels of food deprivation (0, 12 and 36-h). Food deprivation increased PR breakpoints, as well as the number of lever-presses emitted on the FR1 schedule. Both temporary inactivation and DA blockade of NAcc reduced breakpoints across deprivation conditions, while temporary inactivation and DA blockade of mPFC reduced breakpoints only in food-deprived rats. Neither manipulation of mPFC and NAcc had any effect on behavior reinforced on the FR1 schedule. Thus, mPFC and NAcc were differentially relevant to the behaviors tested–NAcc was recruited when the behavioral cost per reinforcer was rising or high regardless of food deprivation conditions, while mPFC was recruited when food-deprived animals behaved through periods of sparse reinforcement density in order to maximize available gain.     

Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome

Rearing rats in isolation has been shown to be a relevant paradigm for studying early life stress and understanding the genesis of depression and related affective disorders. Recent studies from our laboratory point to the relevance of studying the social isolation syndrome as a function of home caging conditions. Accordingly, the present series of experiments assessed the contribution of each condition to the expression of the prepulse inhibition of the acoustic startle, food hoarding and spontaneous locomotor activity. In addition, ex vivo neurochemical changes in the brains of isolated and grouped rats reared either in sawdust-lined or in grid-floor cages were determined by measuring dopamine and serotonin as well as their major metabolites in a “psychosis circuit” that includes mainly the hippocampus and selected hippocampal efferent pathways projecting towards the anterior cingulate and infralimbic cortices, nucleus accumbens, dorsolateral caudate nucleus, amygdala and entorhinal cortex. The results of the present study demonstrate that rearing rats in isolation (i) produces a syndrome of generalized locomotor hyperactivity; (ii) increases the startle response; (iii) impairs prepulse inhibition; (iv) tends to increase food hoarding behavior; (v) increases basal dopamine turnover in the amygdaloid complex; (vi) decreases basal dopamine turnover in the infralimbic part of the medial prefrontal cortex; and (vii) decreases basal turnover of serotonin in the nucleus accumbens. In the entorhinal cortex, dopamine neurotransmission seemed to be more sensitive to the caging conditions since a decreased basal turnover of dopamine was observed in grid-reared animals. Plasma corticosterone levels were also increased in grid-reared animals compared with rats reared in sawdust cages. Finally, isolates reared on grids showed a significant positive correlation between plasma corticosterone levels and dopamine in the left nucleus accumbens.

Altogether, these results support the contention that there is a link between social isolation, attention deficit, spontaneous locomotor hyperactivity and reduced dopamine turnover in the medial prefrontal cortex. Furthermore, our data demonstrate that rearing rats in grid-floor cages represents a form of chronic mild stress associated with increased corticosterone levels, decreased basal turnover of entorhinal dopamine and increased dopamine activity in the left nucleus accumbens. Finally, a significant and selective decrease in the basal turnover of serotonin in the nucleus accumbens of isolated rats may be linked to the isolation-induced locomotor hyperactivity.