Effects of repeated cocaine on medial prefrontal cortical GABAB receptor modulation of neurotransmission in the mesocorticolimbic dopamine system

Increased excitatory output from medial prefrontal cortex is an important component in the development of cocaine sensitization. Activation of GABAergic systems in the prefrontal cortex can decrease glutamatergic activity. A recent study suggested that sensitization might be associated with a decrease in GABAB receptor responsiveness in the medial prefrontal cortex. Therefore, the present study examined whether repeated exposure to cocaine-modified neurochemical changes in the mesocorticolimbic dopamine system induced by infusion of baclofen into the medial prefrontal cortex. In vivo microdialysis studies were conducted to monitor dopamine, glutamate and GABA levels in the medial prefrontal cortex and glutamate levels in the ipsilateral nucleus accumbens and ventral tegmental area during the infusion of baclofen into medial prefrontal cortex. Baclofen minimally affected glutamate levels in the medial prefrontal cortex, nucleus accumbens or ventral tegmental area of control animals, but dose-dependently increased glutamate levels in each of these regions in animals sensitized to cocaine. This effect was not the result of changes in GABAB receptor-mediated modulation of dopamine or GABA in the medial prefrontal cortex. The data suggest that alterations in GABAB receptor modulation of medial prefrontal cortical excitatory output may play an important role in the development of sensitization to cocaine.     

Structural rearrangements of the cerebral cortex in children and adolescents

The cortical formations of the brain involved in visual functions (the occipital and temporo-parieto- occipital areas, the oculomotor area of the prefrontal cortex), as well as the motor cortex in the representation zone of the arm and the medial region of the frontal cortex adjacent to the limbic lobe, were studied in post-mortem material. The thickness of the cortex and cortical layer III, the sizes of pyramidal neurons, the specific volumes of neurons and intracortical vessels were studied in subjects of both sexes, from birth to the age of 20 years, at yearly intervals (103 observations) using histological techniques, computer morphometric and stereological analysis. The thickness of the cortex of the cerebral hemispheres was observed to intensively increase from birth to the age of 3 years in the occipital, temporo-parieto-occipital and prefrontal cortical areas involved in visual recognition processes. The increase in thickness of the cerebral cortex continues until the age of 6 in the occipital cortex and in the oculomotor area, until the age of 7 years in the temporo-parietooccipital area and the medial prefrontal area, and until the age of 8–9 years in the motor cortex. The sizes of pyramidal neurons increase until the age of 6 years in the motor cortex, until the age of 8 years on the medial surface of the frontal lobe, and until the age of 9–10 years in the temporo-parieto-occipital area and in the dorsolateral area of the prefrontal cortex. The specific volume of neurons and blood vessels in the cortex of the cerebral hemispheres decreases and the volume of intracortical fibers increases throughout the ascending ontogeny, which is manifested most intensively in the prefrontal cortex.     

Effect of Excitotoxin Lesions in the Medial Prefrontal Cortex on Cortical and Subcortical Catecholamine Turnover in the Rat

Catecholamine turnover in brain areas innervated by dopaminergic neurons was examined 2, 6, and 12 days after bilateral, N-methyl-D-aspartate lesions confined to the rat medial prefrontal cortex. The lesion produced a significant regional increase in the concentration of 3,4-dihydroxyphenylethylamine (DA, dopamine) in both the medial prefrontal cortex and the ventral tegmental area. DA concentrations were increased in the nucleus accumbens on day 6 (128% of control), in the ventral tegmental area on day 2 (130% of control), and in the medial prefrontal cortex on days 2 (145% of control) and 6 (127% of control). The only significant changes in the concentration of 3,4-dihydroxyphenylacetic acid (DOPAC) (197% of control), and in the ratio DOPAC/DA (163% of control) were found in the medial prefrontal cortex on day 6 post-lesion. All parameters had returned to control levels by day 12. DA depletion after the administration of alpha-methyl-p-tyrosine (AMPT) was not significantly different between excitotoxin-lesioned and sham animals on day 6 in all brain regions. Noradrenaline (NA) and 3,4-dihydroxyphenylethyleneglycol concentrations and their ratios, and the depletion of noradrenaline after AMPT were also determined, and the lesion resulted in a significant regional increase in NA in both the nucleus accumbens and the ventral tegmental area. An elevation of NA (147% of control) in the nucleus accumbens was found on day 12. Since the excitotoxin lesion destroys corticofugal efferents from medial prefrontal cortex to the nucleus accumbens, the anterior corpus striatum and the ventral tegmental area, our results provide no evidence for a role of these cortical projections in the regulation of subcortical DA metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Peptides and self-stimulation of the medial prefrontal cortex in the rat: effects of intracerebral microinjections of substance P and cholecystokinin

The effects of intracerebral microinjections of substance P and cholecystokinin on self-stimulation of the medial prefrontal cortex of the rat were studied. Intracerebroventricular administration of substance P at doses of 2.5, 5, 10 and 20 micrograms produced a dose-related decrease in self-stimulation of the medial prefrontal cortex; spontaneous motor activity, measured as a control, was not affected. Unilateral microinjections into the medial prefrontal cortex of substance P at doses of 10 and 20 micrograms produced a decrease of self-stimulation of the ipsilateral side, but self-stimulation of the contralateral cortex, used as a control, was not affected. On the contrary, cholecystokinin in both intracerebroventricular administration at doses of 100, 200 and 400 ng, or intracortical microinjections into the medial prefrontal cortex at doses of 200, 400 and 800 ng, had no effect on self-stimulation of this cortical area. These results suggest that substance P, but not cholecystokinin, could be part of the neurochemical substrate underlying self-stimulation of the medial prefrontal cortex in the rat.     

Repeated exposure to cocaine alters medial prefrontal cortex dopamine D₂-like receptor modulation of glutamate and dopamine neurotransmission within the mesocorticolimbic system

Repeated exposure to cocaine progressively increases drug-induced locomotor activity, which is termed behavioral sensitization. Previous studies have demonstrated that sensitization to cocaine is associated with a decrease in dopamine D? receptor function in the medial prefrontal cortex. The present report tested the hypothesis that reduced medial prefrontal cortex D? receptor function as a result of repeated cocaine exposure results in augmented excitatory transmission to the nucleus accumbens and ventral tegmental area, possibly as a partial result of enhanced inhibition of local dopamine release. Dual probe microdialysis experiments were conducted in male Sprague-Dawley rats 1, 7 or 30 days following the last of four daily injections of saline (1.0 mL/kg) or cocaine (15 mg/kg). Infusion of quinpirole (0.01, 1.0 and 100 μM), a D?-like receptor agonist, into the medial prefrontal cortex produced a dose-dependent decrease in cortical, nucleus accumbens and ventral tegmental area extracellular glutamate levels in control but not sensitized animals. Quinpirole also reduced basal dopamine levels in the medial prefrontal cortex in sensitized animals following 1 day of withdrawal from cocaine. Following 30 days of withdrawal, quinpirole also reduced dopamine levels in sensitized animals relative to saline controls, but not relative to baseline levels. These findings indicate that the expression of sensitization to cocaine is associated with altered modulation of mesocorticolimbic glutamatergic transmission at the level of the medial prefrontal cortex.     

Prefrontal norepinephrine determines attribution of "high" motivational salience

Intense motivational salience attribution is considered to have a major role in the development of different psychopathologies. Numerous brain areas are involved in "normal" motivational salience attribution processes; however, it is not clear whether common or different neural mechanisms also underlie intense motivational salience attribution. To elucidate this a brain area and a neural system had to be envisaged that were involved only in motivational salience attribution to highly salient stimuli. Using intracerebral microdialysis, we found that natural stimuli induced an increase in norepinephrine release in the medial prefrontal cortex of mice proportional to their salience, and that selective prefrontal norepinephrine depletion abolished the increase of norepinephrine release in the medial prefrontal cortex induced by exposure to appetitive (palatable food) or aversive (light) stimuli independently of salience. However, selective norepinephrine depletion in the medial prefrontal cortex impaired the place conditioning induced exclusively by highly salient stimuli, thus indicating that prefrontal noradrenergic transmission determines approach or avoidance responses to both reward- and aversion-related natural stimuli only when the salience of the unconditioned natural stimulus is high enough to induce sustained norepinephrine outflow. This affirms that prefrontal noradrenergic transmission determines motivational salience attribution selectively when intense motivational salience is processed, as in conditions that characterize psychopathological outcomes.     

An Excitant Amino Acid Projection from the Medial Prefrontal Cortex to the Anterior Part of Nucleus Accumbens in the Rat

High-affinity uptake of neurotransmitter substrates in synaptosome-containing homogenates and tissue concentrations of amino acids were examined in subcortical areas 5-6 days after bilateral N-methyl-D-aspartate lesions confined to rat medial prefrontal cortex. D-[3H]Aspartate (32% of control) and [3H] gamma-aminobutyric acid ( [3H]GABA) (60% of control) uptakes were significantly reduced in medial prefrontal cortex, whereas [3H]choline (110% of control) uptake was unchanged, suggesting the production of axon-sparing lesions. The uptake of D-[3H]aspartate (76% of control), but not of [3H]GABA or [3H]choline, was significantly reduced in nucleus accumbens, with no concomitant reduction in amino acid concentrations. When examined in serial coronal sections, reduced D-[3H]aspartate uptake was confined to the most anterior 500 micron of nucleus accumbens (67% of contralateral sample). No significant reductions of uptake or amino acid concentrations were observed in caudate putamen or ventral tegmental area. These results suggest a role for glutamate or aspartate as neurotransmitters in projections from medial prefrontal cortex to anterior nucleus accumbens. Medial prefrontal cortex may represent the major excitatory cortical input to the nucleus accumbens.     

The effect of the antipsychotic drug mosapramine on the expression of Fos protein in the rat brain: comparison with haloperidol, clozapine and risperidone

In this study, we examined the effect of the acute p.o. administration of the antipsychotic drug mosapramine, as well as the antipsychotic drugs clozapine, haloperidol and risperidone, on the expression of Fos protein in the medial prefrontal cortex, nucleus accumbens and dorsolateral striatum of rat brain. The administration of mosapramine (1 or 3 mg/kg) significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex, but not in the dorsolateral striatum. In addition, mosapramine (1, 3 or 10 mg/kg) produced a dose-dependent increase in the number of Fos protein positive neurons in the nucleus accumbens. The acute administration of 10 mg/kg of mosapramine significantly increased the number of Fos protein positive neurons in all brain regions. The acute administration of clozapine (30 mg/kg), similarly to mosapramine at lower doses (1 or 3 mg/kg), significantly increased the number of Fos protein positive neurons in the medial prefrontal cortex and nucleus accumbens, but not dorsolateral striatum. In contrast, haloperidol (0.3 mg/kg) significantly increased the number of Fos protein positive neurons in the nucleus accumbens and dorsolateral striatum, but not medial prefrontal cortex. The acute administration of risperidone (0.3 or 1 mg/kg) did not affect the number of Fos protein positive neurons in the medial prefrontal cortex, nucleus accumbens or dorsolateral striatum of rat brain, whereas a 3 mg/kg dose of risperidone significantly increased the number of Fos protein positive neurons in all brain regions. These results suggest that the ability of mosapramine to enhance expression of Fos protein in the medial prefrontal cortex may contribute to a clozapine-like profile with respect to actions on negative symptoms in schizophrenia. Furthermore, the lack of effect of low doses of mosapramine on Fos protein expression in the dorsolateral striatum, an area believed to play a role in movement, suggests that it may have a lower tendency to induce neurological side effects.     

Repeated exposure to methamphetamine, cocaine or morphine induces augmentation of dopamine release in rat mesocorticolimbic slice co-cultures

Repeated intermittent exposure to psychostimulants and morphine leads to progressive augmentation of its locomotor activating effects in rodents. Accumulating evidence suggests the critical involvement of the mesocorticolimbic dopaminergic neurons, which project from the ventral tegmental area to the nucleus accumbens and the medial prefrontal cortex, in the behavioral sensitization. Here, we examined the acute and chronic effects of psychostimulants and morphine on dopamine release in a reconstructed mesocorticolimbic system comprised of a rat triple organotypic slice co-culture of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex regions. Tyrosine hydroxylase-positive cell bodies were localized in the ventral tegmental area, and their neurites projected to the nucleus accumbens and medial prefrontal cortex regions. Acute treatment with methamphetamine (0.1-1000 μM), cocaine (0.1-300 μM) or morphine (0.1-100 μM) for 30 min increased extracellular dopamine levels in a concentration-dependent manner, while 3,4-methylenedioxyamphetamine (0.1-1000 μM) had little effect. Following repeated exposure to methamphetamine (10 μM) for 30 min every day for 6 days, the dopamine release gradually increased during the 30-min treatment. The augmentation of dopamine release was maintained even after the withdrawal of methamphetamine for 7 days. Similar augmentation was observed by repeated exposure to cocaine (1-300 μM) or morphine (10 and 100 μM). Furthermore, methamphetamine-induced augmentation of dopamine release was prevented by an NMDA receptor antagonist, MK-801 (10 μM), and was not observed in double slice co-cultures that excluded the medial prefrontal cortex slice. These results suggest that repeated psychostimulant- or morphine-induced augmentation of dopamine release, i.e. dopaminergic sensitization, was reproduced in a rat triple organotypic slice co-cultures. In addition, the slice co-culture system revealed that the NMDA receptors and the medial prefrontal cortex play an essential role in the dopaminergic sensitization. This in vitro sensitization model provides a unique approach for studying mechanisms underlying behavioral sensitization to drugs of abuse.     

Uniquely human social cognition

Recent data identify distinct components of social cognition associated with five brain regions. In posterior temporal cortex, the extrastriate body area is associated with perceiving the form of other human bodies. A nearby region in the posterior superior temporal sulcus is involved in interpreting the motions of a human body in terms of goals. A distinct region at the temporo-parietal junction supports the uniquely human ability to reason about the contents of mental states. Medial prefrontal cortex is divided into at least two subregions. Ventral medial prefrontal cortex is implicated in emotional empathy, whereas dorsal medial prefrontal cortex is implicated in the uniquely human representation of triadic relations between two minds and an object, supporting shared attention and collaborative goals.     

Effects of gonadectomy on performance in operant tasks measuring prefrontal cortical function in adult male rats

Previous studies have shown that gonadectomy in adult male rats influences the acquisition and performance of spatial and other working memory tasks that depend in part on the medial prefrontal cortex and its dopamine innervation. Stimulated by previous findings that gonadectomy alters dopamine axon density in not only medial but several other prefrontal fields, the present studies asked whether gonadectomy might also broadly impact dopamine-dependent prefrontal functions, and whether these effects bore any relation to hormone modulation of mesoprefrontal dopamine afferents. Specifically, control, gonadectomized, and gonadectomized rats given estradiol or testosterone propionate were tested on a series of operant tasks that together measured medial prefrontal functions of spatial working memory, impulsivity and extradimensional set shifting and orbital prefrontal functions of reversal learning/perseveration and motivation. Afterwards, animals were sacrificed, their bulbospongiosus muscles were removed and weighed, their brains were processed for immunocytochemistry for the dopamine-synthesizing enzyme tyrosine hydroxylase, and axon densities were measured in orbital and medial prefrontal fields. Statistical evaluations of group effects on behavior and regression analyses comparing individual performance with muscle weights and axon density measures revealed androgen-reversible effects of gonadectomy on acquisition of spatial working memory and extradimensional set shifting that were correlated with bulbospongiosus weight and medial prefrontal dopamine axon density, estrogen-sensitive influences of gonadectomy on motivation and response withholding that were correlated with bulbospongiosus weight but not with dopamine innervation, and still other prefrontal functions, i.e., impulsivity, reversal learning, that were insensitive to gonadectomy and unrelated to gonadectomy-induced changes in muscle weight or prefrontal dopamine innervation.     

Repeated exposure to cocaine alters the modulation of mesocorticolimbic glutamate transmission by medial prefrontal cortex Group II metabotropic glutamate receptors

Repeated cocaine exposure enhances glutamatergic output from the medial prefrontal cortex to subcortical brain regions. Loss of inhibitory control of cortical pyramidal neurons may partly account for this augmented cortical glutamate output. Recent research indicated that repeated cocaine exposure reduced the ability of cortical Group II metabotropic glutamate receptors to modulate behavioral and neurochemical responses to cocaine. Thus, experiments described below examined whether repeated cocaine exposure alters metabotropic glutamate receptor regulation of mesocorticolimbic glutamatergic transmission using in vivo microdialysis. Infusion of the Group II metabotropic glutamate receptor antagonist LY341495 into the medial prefrontal cortex enhanced glutamate release in this region, the nucleus accumbens and the ventral tegmental area in sensitized animals, compared to controls, following short-term withdrawal but not after long-term withdrawal. Additional studies demonstrated that vesicular (K(+)-evoked) and non-vesicular (cystine-evoked) glutamate release in the medial prefrontal cortex was enhanced in sensitized animals, compared to controls, that resulted in part from a reduction in Group II metabotropic glutamate receptor modulation of these pools of glutamate. In summary, these findings indicate that the expression of sensitization to cocaine is correlated with an altered modulation of mesocorticolimbic glutamatergic transmission via reduction of Group II metabotropic glutamate receptor function.     

Effect of 6-Hydroxydopamine Lesions of the Medial Prefrontal Cortex on Neurotransmitter Systems in Subcortical Sites in the Rat

The effect of lesions of the catecholamine nerve terminals in the medial prefrontal cortex of the rat on neurotransmitter mechanisms within the basal ganglia has been investigated. Bilateral 6-hydroxydopamine lesions were stereotaxically placed in the dopamine-rich (DA) area of th frontal cortex. Animals were pretreated with desmethylimipramine to block the uptake of neurotoxin into noradrenergic (NA) terminals and to make it more selective for DA terminals. The lesion produced a selective reduction of both NA and DA from the medial prefrontal cortex, a result related to falls in tyrosine hydroxylase activity at this site. Lesioned animals showed enhanced DA turnover and utilisation in striatal and limbic regions. There was no change in subcortical tyrosine hydroxylase activity. In addition there were significant falls in other putative neurotransmitters within basal sites, including 5-hydroxytryptamine and GABA. Decreased activity of the neurotransmitter-synthesizing enzyme glutamate decarboxylase and choline acetyltransferase was also recorded in certain regions of the basal ganglia. The results suggest that frontal cortical catecholamine systems may serve to regulate various neurotransmitter mechanisms in the basal ganglia.     

Increase of Extracellular Glutamate and Expression of Fos-Like Immunoreactivity in the Ventral Tegmental Area in Response to Electrical Stimulation of the Prefrontal Cortex

Abstract: Electrical stimulation of the medial prefrontal cortex caused glutamate release in the ventral tegmental area (VTA) of freely moving animals. Cathodal stimulation was given through monopolar electrodes in 0.1-ms pulses at an intensity of 300 µA and frequencies of 4–120 Hz. Glutamate was measured in 10-min perfusate samples by HPLC coupled with fluorescence detection following precolumn derivatization with o -phthaldialdehyde/β-mercaptoethanol. The stimulation-induced glutamate release was frequency dependent and was blocked by the infusion of the sodium channel blocker tetrodotoxin (10 µ M ) through the dialysis probe. The stimulation also induced bilateral Fos-like immunoreactivity in ventral tegmental neurons, with a significantly greater number of Fos-positive cells on the stimulated side. These findings add to a growing body of evidence suggesting that the medial prefrontal cortex regulates dopamine release in the nucleus accumbens via its projection to dopamine cell bodies in the VTA.     

In Vivo Assessment of Dopamine Uptake in Rat Medial Prefrontal Cortex: Comparison with Dorsal Striatum and Nucleus Accumbens

Abstract: In vivo electrochemistry was used to characterize dopamine clearance in the medial prefrontal cortex and to compare it with clearance in the dorsal striatum and nucleus accumbens. When calibrated amounts of dopamine were pressure-ejected into the cortex from micropipettes adjacent to the recording electrodes, transient and reproducible dopamine signals were detected. The local application of the selective uptake inhibitors GBR-12909, desipramine, and fluoxetine before the application of dopamine indicated that at the lower recording depths examined (2.5–5.0 mm below the brain surface), locally applied dopamine was cleared from the extracellular space primarily by the dopamine transporter. The norepinephrine transporter played a greater role at the more superficial recording sites (0.5–2.25 mm below the brain surface). To compare clearance of dopamine in the medial prefrontal cortex (deeper sites only), striatum, and nucleus accumbens, varying amounts of dopamine were locally applied in all three regions of individual animals. The signals recorded from the cortex were of greater amplitude and longer time course than those recorded from the striatum or accumbens (per picomole of dopamine applied), indicating less efficient dopamine uptake in the medial prefrontal cortex. The fewer number of transporters in the medial prefrontal cortex may be responsible, in part, for this difference, although other factors may also be involved. These results are consistent with the hypothesis that regulation of dopaminergic function is unique in the medial prefrontal cortex.     

A PET Study of the Brain Mechanisms Underlying Perception of Phrases with Syntagmatic Splitting

Positron emission tomography (PET) was used to localize the brain regions involved in the processing of pauses and intonation changes, which underlie the syntactically correct perception of auditory verbal stimuli. Subjects were asked to listen to a phrase and to choose a correct answer from two variants presented on a monitor screen. Differences in cerebral blood circulation were mapped for perception of phrases containing or lacking a pause determining the meaning. Conscious analysis of the phrase structure was associated with activation of the right lower prefrontal area and the right posterior medial area of the cerebellum. The possible role of these brain structures in analyzing factors of syntagmatic splitting is discussed.     

Neural Basis of Anticipatory Anxiety Reappraisals

Reappraisal is a well-known emotion regulation strategy. Recent neuroimaging studies suggest that reappraisal recruits both medial and lateral prefrontal brain regions. However, few studies have investigated neural representation of reappraisals associated with anticipatory anxiety, and the specific nature of the brain activity underlying this process remains unclear. We used functional magnetic resonance imaging (fMRI) to investigate neural activity associated with reappraisals of transient anticipatory anxiety. Although transient anxiety activated mainly subcortical regions, reappraisals targeting the anxiety were associated with increased activity in the medial and lateral prefrontal regions (including the orbitofrontal and anterior cingulate cortices). Reappraisal decreased fear circuit activity (including the amygdala and thalamus). Correlational analysis demonstrated that reductions in subjective anxiety associated with reappraisal were correlated with orbitofrontal and anterior cingulate cortex activation. Reappraisal recruits medial and lateral prefrontal regions; particularly the orbitofrontal and anterior cingulate cortices are associated with successful use of this emotion regulation strategy.     

Evoked Extracellular Dopamine In Vivo in the Medial Prefrontal Cortex

Abstract: The measurement of evoked extracellular dopamine in the medial prefrontal cortex by using fast-scan cyclic voltammetry with carbon-fiber microelectrodes was established and release characteristics of mesoprefrontal dopamine neurons were examined in vivo in anesthetized rats. Despite the sparse dopaminergic innervation and the presence of more dense noradrenergic and serotonergic innervations overall in the medial prefrontal cortex, the measurement of extracellular dopamine was achieved by selective recording in dopamine-rich terminal fields and selective activation of ascending dopamine neurons. This was confirmed by electrochemical, pharmacological, and anatomical evidence. An increased release capacity for mesoprefrontal dopamine neurons was also demonstrated by the slower decay of the evoked dopamine response after inhibition of catecholamine synthesis and the maintenance of the evoked dopamine response at higher levels in the medial prefrontal cortex compared with the striatum during supraphysiological stimulation.     

Reading hidden intentions in the human brain

When humans are engaged in goal-related processing, activity in prefrontal cortex is increased. However, it has remained unclear whether this prefrontal activity encodes a subject's current intention. Instead, increased levels of activity could reflect preparation of motor responses, holding in mind a set of potential choices, tracking the memory of previous responses, or general processes related to establishing a new task set. Here we study subjects who freely decided which of two tasks to perform and covertly held onto an intention during a variable delay. Only after this delay did they perform the chosen task and indicate which task they had prepared. We demonstrate that during the delay, it is possible to decode from activity in medial and lateral regions of prefrontal cortex which of two tasks the subjects were covertly intending to perform. This suggests that covert goals can be represented by distributed patterns of activity in the prefrontal cortex, thereby providing a potential neural substrate for prospective memory. During task execution, most information could be decoded from a more posterior region of prefrontal cortex, suggesting that different brain regions encode goals during task preparation and task execution. Decoding of intentions was most robust from the medial prefrontal cortex, which is consistent with a specific role of this region when subjects reflect on their own mental states.     

The Prefrontal Cortex Regulates the Basal Release of Dopamine in the Limbic Striatum: An Effect Mediated by Ventral Tegmental Area

Abstract: The present study examined whether the prefrontal cortex (PFC) exerts a tonic control over the basal release of dopamine in the limbic striatum and whether this control is mediated by glutamatergic afferents to the dopamine cell body or terminal regions. Using intracerebral microdialysis in freely moving rats, it was demonstrated that application of tetrodotoxin in the contralateral PFC significantly decreased the release of dopamine in the medial striatum. Conversely, blockade of the tonic inhibitory GABAergic input in the PFC with bicuculline increased the release of dopamine in the medial striatum. Application of excitatory amino acid receptor antagonists into the striatum, while bicuculline was perfused in the PFC, did not affect the bicuculline-evoked dopamine increase in the striatum. However, infusion of tetrodotoxin or excitatory amino acid receptor antagonists into the ventral tegmental area, a region containing dopamine cell bodies that project to the medial striatum, blocked the stimulation of striatal dopamine release induced by infusion of bicuculline into the PFC. These data demonstrate that the basal output of dopamine terminals in the medial striatum is under a tonic excitatory control of the PFC. Furthermore, this control occurs primarily through glutamatergic projections to the dopamine cell body area rather than the terminal regions.