Ketamine increases striatal dopamine release and hyperlocomotion in adult rats after postnatal functional blockade of the prefrontal cortex.

Schizophrenia is a complex psychiatric disorder that may result from defective connectivity, of neurodevelopmental origin, between several integrative brain regions. Different anomalies consistent with brain development failures have been observed in patients' left prefrontal cortex (PFC). A striatal dopaminergic functional disturbance is also commonly acknowledged in schizophrenia and could be related to a dysfunctioning of dopamine-glutamate interactions. Non-competitive NMDA antagonists, such as ketamine, can induce psychotic symptoms in healthy individuals and worsen these symptoms in patients with schizophrenia. Our study set out to investigate the consequences of neonatal functional blockade of the PFC for dopaminergic and behavioral reactivity to ketamine in adult rats. Following tetrodotoxin (TTX) inactivation of the left PFC at postnatal day 8, dopaminergic responses induced by ketamine (5 mg/kg, 10 mg/kg, 20 mg/kg sc) were monitored using in vivo voltammetry in the left part of the dorsal striatum in freely moving adult rats. Dopaminergic responses and locomotor activity were followed in parallel. Compared to PBS animals, in rats microinjected with TTX, ketamine challenge induced a greater release of dopamine in the dorsal striatum for the highest dose (20 mg/kg sc) and the intermediate dose (10mg/kg sc). A higher increase in locomotor activity in TTX animals was observed only for the highest dose of ketamine (20 mg/kg sc). These data suggest transient inactivation of the PFC during early development results in greater behavioral and striatal dopaminergic reactivity to ketamine in adulthood. Our study provides an anatomo-functional framework that may contribute toward a better understanding of the involvement of NMDA glutamatergic receptors in schizophrenia.

Postnatal functional inactivation of the entorhinal cortex or ventral subiculum has different consequences for latent inhibition-related striatal dopaminergic responses in adult rats.

Latent inhibition has been found to be disrupted in patients with acute schizophrenia. Striatal dopaminergic dysregulation is commonly acknowledged in schizophrenia. This disease may be consecutive to a functional disconnection between integrative regions, stemming from neurodevelopmental failures. Various anomalies suggesting early abnormal brain development have been described in the entorhinal cortex (ENT) and ventral subiculum (SUB) of patients. This study examines the consequences of a neonatal transitory blockade of the left ENT or left SUB for latent inhibition-related dopamine responses in the anterior part of the dorsal striatum using in-vivo voltammetry in freely moving adult rats. Reversible inactivation of both structures in different animals was achieved by local microinjection of tetrodotoxin (TTX) at postnatal day 8. Results obtained during the retention session of a three-stage latent inhibition protocol showed that the functional neonatal disconnection of the ENT or SUB caused the behavioural latent inhibition expression in pre-exposed (PE)-TTX-conditioned adult rats to disappear. After postnatal inactivation of the SUB, PE-TTX-conditioned rats displayed a reversal of the latent inhibition-related striatal dopamine responses, whereas after neonatal blockade of the ENT, dopamine changes in PE-TTX-conditioned rats monitored in the anterior striatum were between those observed in PE-phosphate-buffered-saline-conditioned and non-PE-TTX-conditioned animals. These data suggest that neonatal functional inactivation of the SUB disrupts latent inhibition-related striatal dopamine responses in adult animals more than that of the ENT. They may help improve understanding of the pathophysiology of schizophrenia.

Differential influence of the ventral subiculum on dopaminergic responses observed in core and dorsomedial shell subregions of the nucleus accumbens in latent inhibition.

It has previously been reported that dopamine (DA) responses observed in the core and dorsomedial shell parts of the nucleus accumbens (Nacc) in latent inhibition (LI) are dependent on the left entorhinal cortex (ENT). The present study was designed to investigate the influence of the left ventral subiculum (SUB) closely linked to the ENT on the DA responses obtained in the Nacc during LI, using an aversive conditioned olfactory paradigm and in vivo voltammetry in freely moving rats. In the first (pre-exposure) session, functional blockade of the left SUB was achieved by local microinjection of tetrodotoxin (TTX). In the second session, rats were aversively conditioned to banana odor, the conditional stimulus (CS). In the retention (test) session the results were as follows: (1) pre-exposed (PE) conditioned animals microinjected with TTX, displayed aversion toward the CS; (2) in the core part of the Nacc, for PE-TTX-conditioned rats as for non-pre-exposed (NPE) conditioned animals, DA levels remained close to the baseline whereas DA variations in both groups were significantly different from the DA increases observed in PE-conditioned rats microinjected with the solvent (phosphate-buffered saline (PBS)); (3) in the shell part of the Nacc, for PE-TTX-conditioned rats, DA variations were close to or above the baseline. They were situated between the rapid DA increases observed in NPE-conditioned animals and the transient DA decreases obtained in PE-PBS-conditioned animals. These findings suggest that, in parallel to the left ENT, the left SUB controls DA LI-related responses in the Nacc. The present data may also offer new insight into the pathophysiology of schizophrenia.

Neonatal functional blockade of the entorhinal cortex results in disruption of accumbal dopaminergic responses observed in latent inhibition paradigm in adult rats.

Latent inhibition (LI) has been found to be disrupted in non-treated patients with schizophrenia. Dopaminergic (DAergic) dysfunctioning is generally acknowledged to occur in schizophrenia. Various abnormalities in the entorhinal cortex (ENT) have been described in patients with schizophrenia. Numerous data also suggest that schizophrenia has a neurodevelopmental origin. The present study was designed to test the hypothesis that reversible inactivation of the ENT during neonatal development results in disrupted DA responses characteristic of LI in adult rats. Tetrodotoxin (TTX) was microinjected locally in the left ENT at postnatal day 8 (PND8). DA variations were recorded in the dorsomedial shell and core parts of the nucleus accumbens (Nacc) using in vivo voltammetry in freely-moving grown-up rats in a LI paradigm. In the first session the animals were pre-exposed (PE) to the conditional stimulus (banana odour) alone. In the second they were aversively conditioned to banana odour. In the third (test) session the following results were obtained in PE animals subjected to temporary inactivation of the ENT at PND8: (1) aversive behaviour was observed in TTX-PE conditioned animals; (2) DA variations in the dorsomedial shell and core parts of the Nacc were similar in TTX-PE and non-pre-exposed conditioned rats. These findings strongly suggest that neonatal disconnection of the ENT disrupts LI in adult animals. They may further our understanding of the pathophysiology of schizophrenia.

Striatal dopaminergic responses observed in latent inhibition are dependent on the hippocampal ventral subicular region.

We showed recently that behavioural and striatal dopaminergic (DA) responses obtained in latent inhibition are crucially dependent on the parahippocampal region, the entorhinal cortex. In the present study, we investigated the influence exerted by the hippocampal ventral subicular region (SUB) on the DA responses in the anterior part of the dorsal striatum using in vivo voltammetry in freely moving rats and the same latent inhibition paradigm. To that end, the left SUB was temporarily blocked with tetrodotoxin (TTX) during pre-exposure to a new olfactory stimulus (banana odour). During the second session the animals were aversively conditioned to banana odour. With respect to the results obtained during the test session (third presentation of banana odour), similar changes in behaviour and DA levels were obtained in control and conditioned rats microinjected with the solvent, phosphate-buffered saline (PBS), in the SUB, consistently with a latent inhibition phenomenon. In contrast, after reversible inactivation of the SUB during the pre-exposure session, TTX-pre-exposed conditioned animals displayed aversive behaviour in the test session, and anterior striatal DA variations in these animals differed significantly from those obtained in pre-exposed rats injected locally with PBS. Striatal DA variations obtained in conditioned animals microinjected with TTX were also significantly different from those observed in conditioned non-pre-exposed animals. The present data suggest that, in parallel to the entorhinal cortex, the SUB regulates the latent inhibition-related behavioural and DA responses in the anterior part of the dorsal striatum. These data may provide new insight into the pathophysiology of schizophrenic psychoses.

Influence of the entorhinal cortex on accumbal and striatal dopaminergic responses in a latent inhibition paradigm.

The use of latent inhibition paradigms is one means of investigating the involvement of mesencephalic dopaminergic (DA) neurons in cognitive processes. We have shown recently that DA neurons reaching the core and the dorsomedial shell parts of the nucleus accumbens and the anterior part of the striatum are differentially involved in latent inhibition. In other respects, theoretical, behavioral and anatomo-functional data suggest that the entorhinal cortex (ENT) may control latent inhibition expression. In this study, using in vivo voltammetry in freely moving rats, we investigated the influence of the ENT on the DA responses obtained in the core and dorsomedial shell parts of the nucleus accumbens and the anterior part of the striatum. For this purpose a reversible inactivation of the left ENT was achieved by the local microinjection of tetrodotoxin, 3 h before pre-exposure to the conditional stimulus (banana odour). During the second session, animals were aversively conditioned to banana odour. Results obtained during the third session (test session), in animals submitted to the reversible blockade of the ENT before the first session were as follows: (1) pre-exposed conditioned animals displayed behavioral aversive responses; (2) where core DA responses were concerned, responses were situated between those observed in pre-exposed and non-pre-exposed conditioned animals; (3) by contrast, where the dorsomedial shell part of the nucleus accumbens and the anterior striatum were concerned, DA variations were not statistically different in pre-exposed and non-pre-exposed conditioned rats. These data suggest that the left ENT exerts a crucial influence over the latent-inhibition-related DA responses in the left dorsomedial shell part of the nucleus accumbens and the left anterior part of the striatum, whereas one or more other brain regions control DA variations in the left core part of the nucleus accumbens. These data may help us to understand the pathophysiology of schizophrenic psychoses.

Differential involvement of dopamine in the anterior and posterior parts of the dorsal striatum in latent inhibition.

The involvement of mesostriatal dopaminergic neurons in cognitive operations is not well understood, and needs to be further clarified. The use of latent inhibition paradigms is a means of investigating cognitive processes. In this study, we investigated the involvement in latent inhibition of dopaminergic inputs in the anterior part and posterior part of the dorsal striatum. The latent inhibition phenomenon was observed in a conditioned olfactory aversion paradigm. Changes in extracellular dopamine levels induced by the conditioned olfactory stimulus (banana odor) were monitored in the two parts of the dorsal striatum in the left hemisphere after pre-exposure to the olfactory stimulus using in vivo voltammetry in freely moving rats. During the conditioning session animals received either an i.p. injection of NaCl (0.9%) (control groups) or an i.p. injection of LiCl (0.15 M) (conditioned groups). Dopamine variations and place preference or aversion toward the stimulus were analyzed simultaneously in pre-exposed and non-pre-exposed animals. Data collected during the retention (test) session were as follows. Where the anterior part of the striatum was concerned, similar enhancements in dopamine levels (+100%) were obtained in pre-exposed and non-pre-exposed control animals, as well as in the pre-exposed experimental animals. In contrast, dopamine levels in the non-pre-exposed experimental group (conditioned animals) remained fairly consistently close to the baseline after the presentation of the olfactory stimulus. Where the posterior part of the striatum was concerned, increases in extracellular dopamine levels were similar (+50%) for the different groups. The present results suggested that dopaminergic neurons reaching the anterior part of the dorsal striatum are implicated in the latent inhibition phenomenon and affective perception, whereas dopaminergic terminals in the posterior part of the dorsal striatum appeared to be involved neither in latent inhibition nor in affective perception of the stimulus, seeming only to be affected by the intrinsic properties of the stimulus. Cognitive as well as affective deficits have been reported in patients with schizophrenia. Thus the present data may be considered in the context of the pathophysiology of schizophrenic psychoses.

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.

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.

Asymmetrical increases in dopamine turn-over in the nucleus accumbens and lack of changes in locomotor responses following unilateral dopaminergic depletions in the entorhinal cortex.

Functional interdependence between mesencephalic dopaminergic pathways is an emerging concept. Using in vivo voltammetry and acute manipulation of dopaminergic transmission with pharmacological agents, we have previously reported the existence of a preferentially left lateralized functional interdependence between the entorhinal cortex and the nucleus accumbens. The aim of the present work was to test if this phenomenon is only a dynamic process or if compensation occurs when interdependent functioning is considered in a more long-term perspective. In this study 6-OHDA lesions of the dopamine terminals of the entorhinal cortex were performed separately in the left and right hemispheres. Spontaneous and (+)-amphetamine stimulated locomotor activity were recorded 3 weeks after unilateral interventions in the Ent. Variations in DA and DOPAC levels were measured in the nucleus accumbens 5 weeks after the lesion. The following results were obtained. After unilateral 6-OHDA in the left Ent, DA and DOPAC tissue contents as well as the DOPAC/DA ratio were found significantly changed in nucleus accumbens in the two hemispheres. After dopaminergic destruction in the right Ent only the DOPAC/DA ratio in the left Acc was found statistically elevated. No differences in spontaneous or (+)-amphetamine-stimulated locomotor activity were observed after either left or right lesions. These data confirm those previously obtained with the voltammetric approach and further support the existence of an asymmetrical functional interdependence between mesencephalic DAergic pathways reaching the Ent and the Acc. These results may provide new insights in the pathophysiology of schizophrenic psychoses.

Striatal dopaminergic changes depend on the attractive or aversive value of stimulus.

Using a conditioned aversion paradigm we reported previously that dopaminergic (DA) responses were opposite in the core part of the nucleus accumbens depending on the affective value of the stimulus. The opposite responses were more marked in the left hemisphere. Anatomo-functional similarities between the core part of the nucleus accumbens and the dorsal striatum have been described. In the present study we tested the hypothesis that DA responses in the left ventromedial part of dorsal striatum (VMS) depend on the affective value of the stimulus. Responses of DA neurons were studied using in vivo voltammetry coupled with computer-assisted numerical analysis. A rapid and marked DA increase and a delayed DA decrease were observed in rats presented to the appetitive and the aversive olfactory stimulus, respectively.

Asymmetrical involvement of mesolimbic dopaminergic neurons in affective perception.

Pharmacological studies suggest that increases and decreases in dopamine levels in the nucleus accumbens contribute to positive and negative affective states, respectively. In vivo neurochemical investigations have led to contradictory conclusions, since increases and decreases in dopamine release have been observed in aversive situations. Clinical and experimental observations argue for a hemispheric asymmetry in the processing of appetitive and aversive stimuli. Mesolimbic dopaminergic neurons are part of integrative networks which appear specifically organized in the right and left hemispheres. Dopaminergic neurons may thus be involved in affective processes but in a different manner in the two hemispheres. We tested this hypothesis in the nucleus accumbens of male rats using in vivo voltammetry and a conditioned aversion paradigm to an olfactory stimulus. We found that dopaminergic responses were similar in the two hemispheres following the initial encounter with the stimulus. After conditioning, however, dopaminergic responses to a naturally attractive olfactory stimulus were more elevated in the right nucleus accumbens and responses to an aversive stimulus more marked in the left nucleus. In addition, dopaminergic responses displayed an intraaccumbal regionalization, in particular opposite variations were obtained in the core and shell subterritories in response to the aversive situation. These results may provide new insights in the understanding of the relative contribution of the two hemispheres in affective perception in normal and psychopathological conditions.

Lateralized interdependence between limbicotemporal and ventrostriatal dopaminergic transmission.

The antipsychotic effects of dopaminergic antagonists suggest dopaminergic hyperactivity plays a role in schizophrenia. However, an elevated number of D2 dopamine receptors in the left putamen of non-treated schizophrenics has been reported which is consistent with a diminution of dopaminergic transmission in the ventral striatum. Morphological and functional studies have shown marked alterations in the left medial temporal lobe (entorhinal cortex, hippocampus, parahippocampus gyrus) of schizophrenics. As the entorhinal cortex and the ventral hippocampus project to the ventral striatum, the functional relationship between left temporal structures and the left ventral striatum may be impaired in schizophrenics. To assess the validity of this hypothesis, we investigated the existence of a preferentially left hemispheric interdependency between dopaminergic pathways in male rats. We found that dopaminergic projections in the entorhinal cortex and the ventral hippocampus regulate dopaminergic transmission in the nucleus accumbens, particularly in the left hemisphere. Temporal D2 dopamine receptors seem to be primarily involved in this effect. This lateralized interdependent functioning appears structurally based. These results may provide new insights into the pathophysiology of schizophrenic psychoses.

Sex-related olfactory stimuli induce a selective increase in dopamine release in the nucleus accumbens of male rats. A voltammetric study.

Changes in the dopaminergic (DA) transmission in the nucleus accumbens were investigated in male rats exposed to sociosexual olfactory stimuli from different conspecifics: receptive female, non-receptive female and intact male. DAergic transmission was assessed by measurement of extracellular levels of DA and dihydroxyphenylacetic acid (DOPAC). Both compounds were recorded by using differential normal pulse voltammetry (DNPV) with electrochemically pretreated carbon fiber electrodes and numerical analysis of the catechol peak. Exposition to receptive female odors induced a marked and selective increase in DA release compared to control values. Exposition to non-receptive female odors and male odors induced an increase in DA release not significantly different from that following the change of environment. In conclusion, mesencephalic DAergic neurons reaching the nucleus accumbens appear to be involved in the perception of behaviorally significant olfactory cues.

Increased dopamine release in the nucleus accumbens of copulating male rats as evidenced by in vivo voltammetry.

This report describes the changes in extracellular levels of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) detected in the nucleus accumbens of male rats engaged in copulatory activity. They were monitored by using differential normal pulse voltammetry (DNPV) with electrochemically pretreated carbon fiber microelectrodes and numerical analysis of the catechol signal. The copulatory pattern displayed during the voltammetric recordings was similar to those recorded prior to surgery. Copulating animals showed a conspicuous increase in the DA and DOPAC electrochemical signals up to, respectively, 170% and 150% of baseline levels. This response was much attenuated when the experimental animals were exposed to either non-receptive castrated females or intact males. These data are consistent with the permissive role currently ascribed to the dopaminergic innervation of the n. accumbens in the selection and the initiation of behavioral adaptive sequences.

Difference in the effects of the antidepressant tianeptine on dopaminergic metabolism in the prefrontal cortex and the nucleus accumbens of the rat. A voltammetric study.

The effects of the new tricyclic antidepressant tianeptine were investigated on dopaminergic (DAergic) metabolism in the anteromedian prefrontal cortex and the nucleus accumbens of the rat. DAergic metabolism was assessed by the measurement of DOPAC, the main presynaptic metabolite of dopamine, using in vivo voltammetry in rats ventilated with halothane (0.5-0.75% in air). Acute treatment with tianeptine (10 mg/kg, 20 mg/kg) only increased significantly DOPAC levels in the anteromedian prefrontal cortex. After chronic treatment with tianeptine (15 days, 2 times/day) the increases in DOPAC levels in this structure were altered and less pronounced with the 20 mg/kg dose. Previous studies led to suggest that both acute and chronic effects on DAergic terminals in the anteromedian prefrontal cortex may be involved in the therapeutic action of this new antidepressant.

Opposite influences of dopaminergic pathways to the prefrontal cortex or the septum on the dopaminergic transmission in the nucleus accumbens. An in vivo voltammetric study.

Modulation of dopaminergic transmission in the nucleus accumbens by the dopaminergic pathways reaching the prefrontal cortex (anteromedian and the suprarhinal parts) and the lateral septum was investigated. Changes in dopaminergic transmission in the nucleus accumbens were assessed by in vivo voltammetry using pretreated carbon fiber electrodes. This technique allows the selective detection of 3,4-dihydroxyphenylacetic acid, the main presynaptic metabolite of dopamine. Dopaminergic transmission in the prefrontal cortex (anteromedian and suprarhinal parts) and the lateral septum was altered by local injection of the dopaminergic agonist (d-amphetamine) and the dopaminergic antagonists (alpha-flupenthixol and sulpiride). Pharmacological interventions, either stimulation or blockade, in the anteromedian and suprarhinal parts of the prefrontal cortex induced, respectively, a decrease or an increase in extracellular 3,4-dihydroxyphenylacetic acid in the nucleus accumbens. The same pharmacological interventions in the lateral septum had exactly opposite effects in the nucleus accumbens. The inhibitory action of the mesocortical and mesorhinal dopaminergic projections and the facilitatory action of the mesoseptal dopaminergic projection on dopaminergic input in the nucleus accumbens were shown to rely on the activity of inhibitory fugal pathways which could be blocked by local injection of tetrodotoxin in the three structures. In a previous work, it was demonstrated that dopaminergic projections in the amygdala exert an inhibitory influence on dopaminergic transmission in the nucleus accumbens. Thus the present results suggest that functional interdependence between the different dopaminergic pathway arising in the ventral mesencephalon is a general property of this neuronal group. Data obtained after manipulation of dopaminergic transmission in these various projection areas may need to be interpret in a different light. Similarly, neurological and psychiatric observations may need to be reconsidered in view of the interdependence of the dopaminergic mesencephalic pathways.

Limbic system, basal ganglia, and dopaminergic neurons. Executive and regulatory neurons and their role in the organization of behavior.

Mesencephalic dopaminergic neurons appear to be involved in the organization of the behavioral response. They seem to facilitate the functioning of the integrative structures they innervate and to have a coordinated functioning, thus regulating the information transfer between these structures. In the present paper these two aspects have been investigated by behavioral and neurochemical approaches. Experimental studies were focused on the dopaminergic innervation of the nucleus accumbens.

Lesion of dopaminergic terminals in the amygdala produces enhanced locomotor response to D-amphetamine and opposite changes in dopaminergic activity in prefrontal cortex and nucleus accumbens.

In a previous study using differential pulse voltammetry we demonstrated an interaction between dopaminergic activity in the amygdala and the nucleus accumbens. In the present study, by post-mortem biochemical measurements, we showed that bilateral 6-OHDA lesions of DA innervation of the amygdala leads to an increase in DA activity in the nucleus accumbens (DOPAC/DA ratio +24%) and a reduction (DOPAC/DA ratio -40%) in the prefrontal cortex. In addition, after these lesions in the amygdala, there was an increased behavioral sensitivity to D-amphetamine, demonstrated by enhanced locomotor activity. Increased understanding of the interregulations between dopaminergic activity in forebrain structures may help explain forebrain functions and/or dysfunctions.

Presynaptic control of dopamine metabolism in the nucleus accumbens. Lack of effect of buspirone as demonstrated using in vivo voltammetry.

Buspirone is a non-benzodiazepine drug with anxiolytic properties. It has been reported to induce a marked increase in the metabolism of dopamine in the striatum and the nucleus accumbens which is similar to that induced by neuroleptics. It has been suggested that the effect observed in the striatum reflects an action of buspirone on dopaminergic autoreceptors in both terminals and cell bodies. In the present study, presynaptic effects of buspirone on dopaminergic metabolism in the nucleus accumbens were investigated, and they were compared to the effects of the classical neuroleptic, haloperidol. Dopaminergic terminals were isolated by infusion of tetrodotoxin into the median forebrain bundle in order to evaluate the effects of buspirone and haloperidol on presynaptic receptors. Changes in dopamine metabolism were determined by in vivo voltammetry. Buspirone administered after interruption of the impulse flow did not affect dopamine metabolism. In contrast haloperidol treatment led to an increase in metabolism of dopamine. It is concluded that buspirone did not act at the presynaptic level and furthermore on dopaminergic autoreceptors.