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.     

Effects of neonatal fluvoxamine administration to white rats and their correction by semax treatment

The aim of this work was to study the delayed effects of chronic neonatal administration of the selective serotonin reuptake inhibitor fluvoxamine (FA) to white rat pups and to estimate the possibility to correct these effects by treatment with semax. Fluvoxamine was injected intraperitoneally at a dose of 10 mg/kg from postnatal days 1 to 14, and semax was injected intranasally at a dose of 0.05 mg/kg from postnatal days 15 to 28. It was shown that neonatal FA administration produced a significant delay in animal somatic growth. A loss in body weight was detected both during FA administration and 4–6 weeks after the last injection. Furthermore, FA administration increased the anxiety level and disturbed the learning ability of animals. The negative consequences of neonatal FA administration were largely compensated by Semax.     

Effects of visual experience on the representation of objects in the prefrontal cortex

The perception and recognition of objects are improved by experience. Here, we show that monkeys' ability to recognize degraded objects was improved by several days of practice with these objects. This improvement was reflected in the activity of neurons in the prefrontal (PF) cortex, a brain region critical for a wide range of visual behaviors. Familiar objects activated fewer neurons than did novel objects, but these neurons were more narrowly tuned, and the object representation was more resistant to the effects of degradation, after experience. These results demonstrate a neural correlate of visual learning in the PF cortex of adult monkeys.     

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.     

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.     

Blockade of the Noradrenaline Carrier Increases Extracellular Dopamine Concentrations in the Prefrontal Cortex: Evidence that Dopamine Is Taken up In Vivo by Noradrenergic Terminals

The effect of systemic administration of desmethylimipramine (DMI) and oxaproptiline (OXA), two inhibitors of the noradrenaline (NA) reuptake carrier, on the in vivo extracellular concentrations of dopamine (DA) was studied by transcerebral dialysis in the prefrontal cortex and in the dorsal caudate of freely moving rats. In the NA-rich prefrontal cortex, either drug increased extracellular DA concentrations whereas in the dorsal caudate neither was effective. Haloperidol increased extracellular DA concentrations more effectively in the dorsal caudate than in the prefrontal cortex. Pre-treatment with DMI or OXA, which failed to modify the effect of haloperidol in the dorsal caudate, potentiated its action in the prefrontal cortex. 6-Hydroxydopamine lesioning of the dorsal NA bundle prevented the ability of OXA to increase DA concentrations. The results suggest that reuptake into NA terminals in an important mechanism by which DA is cleared from the extracellular space in a NA-rich area such as the prefrontal cortex. The elevated extracellular concentrations of DA resulting from blockade of such mechanism by tricyclic antidepressants may play a role in the therapeutic effects of these drugs.     

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)     

Prefrontal cortex aspiration in pups and juvenile rats: behavioural changes and recovery of function

Male Wistar rats sustaining prefrontal cortex aspiration or sham operation at 6 days or 30 days of age were submitted to the following behavioural tests: open-field, acquisition and retention of two-way active as well as passive avoidance tasks. In the open-field the locomotor activity proved enhanced in all the aspirated animals and this enhancement lasted for 30 days. In the two-day active avoidance task, an acquisition deficit was observed in both aspirated groups; but when retrained one month later, they were able to acquire the avoidance task like sham-operated rats and no difference appeared between the groups aspirated at 6 or at 30 days of age. Concerning the passive avoidance task, no difference could be detected between aspirated and sham-operated animals of both groups except that the rats aspirated at an early age (6 days) seemed to display a better avoidance ability in the retention test. These behavioural alterations (hyperactivity and impairment of the acquisition of the 2-way active avoidance) resulted from the prefrontal cortex aspiration, at whatever age this aspiration was performed (6 days or 30 days). They disappeared after a postoperative recovery period of about one month, as evidenced by this longitudinal study.     

Effects of clozapine on the efflux of serotonin and dopamine in the rat brain: the role of 5-HT1A receptors

In vivo microdialysis in conscious rats was used to examine the effect of clozapine on serotonin (5-hydroxytryptamine, 5-HT) efflux in the prefrontal cortex and dorsal raphe nucleus and dopamine efflux in the prefrontal cortex. Both systemic and local administration of clozapine (systemic, 10 or 20 mg/kg, i.p.; local, 100 microM) increased 5-HT efflux in the dorsal raphe. However, in the prefrontal cortex, dialysate 5-HT increased when clozapine (100 microM) was administered through the probe, while no effect was observed when it was administered systemically. By pretreatment with the selective 5-HT1A receptor antagonist p-MPPI (3 mg/kg, i.p.), systemic treatment of clozapine (10 mg/kg, i.p.) significantly increased 5-HT efflux in the prefrontal cortex. This result suggests that the ability of clozapine to enhance the extracellular concentrations of 5-HT in the dorsal raphe attenuates this drug's effect in the frontal cortex, probably through the stimulation of 5-HT1A somatodendritic autoreceptors in the dorsal raphe. We also found that pretreatment with p-MPPI (3 mg/kg, i.p.) attenuated by 45% the rise in cortical dopamine levels induced by clozapine (10 mg/kg, i.p.). These findings imply that the reduction in serotonergic input from the dorsal raphe nucleus induced by clozapine could lead to an increase in dopamine release in the prefrontal cortex.     

BDNF Level in the Rat Prefrontal Cortex Increases Following Chronic but Not Acute Treatment with Duloxetine, a Dual Acting Inhibitor of Noradrenaline and Serotonin Re-uptake

Aims Brain-Derived Neurotrophic Factor (BDNF) has a central role in neuronal survival, differentiation, and plasticity. The brain level of BDNF is changed by several mood stabilizers and antidepressant drugs acting on neurotransmitters such as noradrenaline and serotonin. We investigated the effects of acute and chronic treatment with Duloxetine, a new drug blocking the re-uptake of serotonin and noradrenaline (SNRI), on BDNF level in the prefrontal cortex, cerebrospinal fluid, plasma, and serum. Methods Wistar male rats were treated with acute (single treatment) and chronic oral administration (14 days) of different concentrations of Duloxetine (10, 30, and 100 mg/kg/day). At the end of the treatment periods, samples of blood, CSF and the prefrontal cortex were collected. BDNF levels were measured by ELISA. Levels of mature and precursor form of BDNF were measured by Western blot analysis. Results Animals treated with the Duloxetine at all concentrations and examined after 1 and 24 h (single treatment) did not reveal a significant change in the total BDNF level. In animals treated for 14 days with Duloxetine at 30 and 100 mg/kg, the total BDNF level increased significantly in the prefrontal cortex and CSF, but not in the plasma and serum. Using a specific antibody and Western blot we showed that the mature, but not the precursor, form of BDNF was significantly increased in the prefrontal cortex of rats treated for 14 days with Duloxetine at 30 mg/kg/day. Conclusions Our results show a major finding that repeated, but not single, Duloxetine treatment increases the level of BDNF in the prefrontal cortex. Claudio Mannari and Nicola Origlia are contributed equally to this work.     

Effects of Apomorphine on In Vivo Release of Dopamine and Its Metabolites in the Prefrontal Cortex and the Striatum, Studied by a Microdialysis Method

The effects of apomorphine (0.1-2.5 mg/kg) on release of endogenous dopamine and extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the prefrontal cortex and the striatum were examined in vivo by a microdialysis method. Apomorphine significantly reduced release of dopamine and the extracellular levels of dopamine metabolites, DOPAC and HVA, not only in the striatum, but also in the prefrontal cortex. These findings indicate that dopamine autoreceptors modulate in vivo release of dopamine in the prefrontal cortex.     

Chronic treatment with a dopamine uptake blocker changes dopamine and acetylcholine but not glutamate and GABA concentrations in prefrontal cortex, striatum and nucleus accumbens of the awake rat

The present study was aimed to investigate the effects of a chronic treatment with the dopamine uptake blocker nomifensine on the in vivo extracellular concentrations of dopamine, acetylcholine, glutamate and GABA in the prefrontal cortex, striatum and nucleus accumbens. Male Wistar rats received intraperitoneal (i.p.) daily injections of nomifensine (10 mg/kg) or saline for 22 days. Microdialysis experiments were performed on days 1, 8, 15 and 22 of treatment to evaluate the effects of the injection of nomifensine or saline. Motor activity of the animals was monitored during microdialysis experiments. Injections of nomifensine increased extracellular concentration of dopamine in striatum and nucleus accumbens, but not in prefrontal cortex. Acetylcholine concentrations in striatum but not in nucleus accumbens were increased by nomifensine on days 15 and 22 of treatment. In prefrontal cortex, nomifensine increased acetylcholine levels without differences among days. No changes were found on glutamate and GABA concentrations in the three areas studied. Injections of nomifensine also increased spontaneous motor activity and stereotyped behaviour without differences among days. These results show that systemic chronic treatment with a dopamine uptake blocker produces differential effects on extracellular concentrations of dopamine and acetylcholine, but not glutamate and GABA, in different areas of the brain.     

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.     

Subtle Alterations in Brain Anatomy May Change an Individual’s Personality in Chronic Pain

It is well established that gross prefrontal cortex damage can affect an individual’s personality. It is also possible that subtle prefrontal cortex changes associated with conditions such as chronic pain, and not detectable until recent advances in human brain imaging, may also result in subtle changes in an individual’s personality. In an animal model of chronic neuropathic pain, subtle prefrontal cortex changes including altered basal dendritic length, resulted in altered decision making ability. Using multiple magnetic resonance imaging techniques, we found in humans, although gray matter volume and on-going activity were unaltered, chronic neuropathic pain was associated with reduced free and bound proton movement, indicators of subtle anatomical changes, in the medial prefrontal cortex, anterior cingulate cortex and mediodorsal thalamus. Furthermore, proton spectroscopy revealed an increase in neural integrity in the medial prefrontal cortex in neuropathic pain patients, the degree of which was significantly correlated to the personality temperament of novelty seeking. These data reveal that even subtle changes in prefrontal cortex anatomy may result in a significant change in an individual’s personality.     

The effect of semax and its C-end peptide PGP on expression of the neurotrophins and their receptors in the rat brain during incomplete global ischemia

Neurotrophins regulate key function of nervous tissue cells. Analysis of neurotrophins mRNA expression is an appropriate tool to assess therapeutic efficiency of the anti-stroke drugs. We have analyzed the effect of synthetic peptide semax and its C-terminal Pro-Gly-Pro tripeptide upon mRNAs expression of neurotrophins Ngf, Bdrf, Nt-3 and their receptors TrkA, TrkB, TrkC, p75 in rat frontal lobes, hippocampus and cerebellum after bilateral common carotid artery occlusion. The animals were decapitated 30 min, 1, 2, 4, 8, 12, 24 h after the operation. The mRNA expression of neurotrophins and their receptors was assessed by relative quantification using real-time RT-PCR. Our showed that ischemia causes a significant decrease in gene expression in the hippocampus. Semax and PGP affected the expression of neurotrophins and their receptors predominantly in the frontal cortex and hippocampus of the ischemized animals. In the frontal cortex, Semax treatment resulted in a decrease of mRNA level of receptors, while PGP treatment increased the level of these mRNA. Maximal neuroprotective effect of both peptides has been observed in the hippocampus 12 h after occlusion. A decrease of gene expression of neurotrophins and their receptors caused by the occlusion was overcome by Semax and PGP. These results clarify the semax mechanism of and present certain features of mRNA's expression of neurotrophins and their receptors in experimental conditions.     

Acute Effects of Typical and Atypical Antipsychotic Drugs on the Release of Dopamine from Prefrontal Cortex, Nucleus Accumbens, and Striatum of the Rat: An In Vivo Microdialysis Study

In vivo microdialysis has been used to study the acute effects of antipsychotic drugs on the extracellular level of dopamine from the nucleus accumbens, striatum, and prefrontal cortex of the rat. (-)-Sulpiride (20, 50, and 100 mg/kg i.v.) and haloperidol (0.1 and 0.5 mg/kg i.v.) enhanced the outflow of dopamine in the striatum and nucleus accumbens. In the medial prefrontal cortex, (-)-sulpiride at all doses tested did not significantly affect the extracellular level of dopamine. The effect of haloperidol was also attenuated in the medial prefrontal cortex; 0.1 mg/kg did not increase the outflow of dopamine and the effect of 0.5 mg/kg haloperidol was of shorter duration in the prefrontal cortex than that observed in striatum and nucleus accumbens. The atypical antipsychotic drug clozapine (5 and 10 mg/kg) increased the extracellular concentration of dopamine in all three regions. In contrast to the effects of sulpiride and haloperidol, that of clozapine in the medial prefrontal cortex was profound. These data suggest that different classes of antipsychotic drugs may have distinct effects on the release of dopamine from the nigrostriatal, mesolimbic, and mesocortical terminals.     

Stimulation of 5-hydroxytryptamine (5-HT(2C) ) receptors in the ventrotegmental area inhibits stress-induced but not basal dopamine release in the rat prefrontal cortex

The present study investigated whether 5-HT(2C) receptors in the ventrotegmental area and prefrontal cortex regulate basal and stimulus-evoked dopamine release in the prefrontal cortex. Using the in vivo microdialysis technique in conscious rats, we studied the effect of a selective 5-HT(2C) receptor agonist, Ro60-0175, on basal and immobilization stress-induced dopamine release in the prefrontal cortex. Ro60-0175 intraperitoneally (2.5 mg/kg) and into the ventrotegmental area (10 microg/0.5 microL) completely antagonized the effect of stress on extracellular dopamine without altering basal levels. Infusion of 10 microm Ro60-0175 through the cortical probe had no significant effect on basal and stress-induced dopamine release. SB242084 (10 mg/kg), a selective antagonist of 5-HT(2C) receptors, significantly increased basal extracellular dopamine and completely prevented the effect of intraperitoneal and intraventrotegmental Ro60-0175 on the stress-induced rise of extracellular dopamine, but had no effect itself in stressed rats. The results show that Ro60-0175 suppresses cortical dopamine release induced by immobilization stress through the stimulation of 5-HT(2C) receptors in the ventrotegmental area. While confirming that endogenous 5-HT acting on 5-HT(2C) receptors tonically inhibit basal dopamine release in the prefrontal cortex, the present findings suggest that the stimulation of 5-HT(2C) receptors with an exogenous agonist preferentially inhibit stimulated release.     

早期干预改善缺氧缺血性脑损伤大鼠认知能力及其机制分析

目的研究早期干预对缺氧缺血性脑损伤(HIBD)大鼠学习记忆功能的影响及其作用机制。方法选用SD大鼠建立宫内HIBD动物模型,随机分为非干预组和干预组,非干预组与正常对照组常规饲养,对干预组采取早期触摸和丰富环境刺激。干预28d后,通过三等臂Y型迷宫试验检测各组大鼠的学习记忆功能,而后取大鼠额皮质和海马组织进行病理观察,并采用DNA缺口原位末端标记法(TUNEL反应法)检测凋亡细胞,观察脑组织神经元凋亡情况。结果单纯HIBD组大鼠学习获得与记忆保持能力明显低于正常对照组(P<0·01),但HIBD干预组Y迷宫测试成绩则优于HIBD非干预组(P<0·01)。同时,HIBD非干预组脑额皮质和海马CA1区神经元缺失远较正常组多(P<0·01),而HIBD干预组与HIBD非干预组之间神经元数量的差异则不那么显著。但HIBD干预组脑额皮质和海马神经元凋亡百分率明显低于HIBD非干预组(P<0·01)。结论早期干预可减轻缺氧缺血性损伤脑组织神经细胞凋亡,该作用可能是早期干预促进HIBD大鼠脑功能修复的机制之一。     

Contribution of Noradrenergic Neurons to the Regulation of Dopaminergic (D1) Receptor Denervation Supersensitivity in Rat Prefrontal Cortex

3,4-Dihydroxyphenylethylamine (DA, dopamine) levels in the rat prefrontal cortex were selectively decreased by 52%, leaving noradrenaline (NA) levels unaffected, 4 weeks following restricted bilateral electrolytic lesions of the ventral mesencephalic tegmentum (VMT). These lesions also induced a significant increase in DA-sensitive, but not isoproterenol-sensitive, adenylate cyclase activity in tissue homogenates (+38%). We had shown previously that chemical (6-hydroxydopamine, 6-OHDA) lesions of the VMT destroy both ascending DA and NA fibers but do not alter the D1-receptor density in the prefrontal cortex. In this study, electrolytic lesions of the VMT were combined with bilateral injections of 6-OHDA made laterally in the pedunculus cerebellaris superior to assess the role of NA fibers in the development of D1-receptor supersensitivity. This combined treatment produces a large decrease of cortical NA levels (-95%), an increase in beta-adrenergic-sensitive adenylate cyclase activity (+110%), and a decrease in DA levels (-60%), but does not alter D1-receptor density in the prefrontal cortex. These results indicate that the development of D1-receptor supersensitivity in the prefrontal cortex following electrolytic lesion of the VMT depends on the presence of an intact NA innervation.     

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.