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Rationale: We previously reported that stressors increase medial prefrontal cortex (PFC) glutamate (GLU) levels as a result of activating callosal neurons located in the opposite hemisphere and that this PFC GLU stress response is regulated by GLU-, dopamine- (DA-), and GABA-sensitive mechanisms (Lupinsky et al. 2010)., Objectives: Here, we examine the possibility that PFC DA regulates the stress responsivity of callosal neurons indirectly by acting at D 1 and D 2 receptors located on GABA interneurons., Methods: Microdialysis combined with drug perfusion (reverse dialysis) or microinjections was used in adult male Long-Evans rats to characterize D 1 , D 2 , and GABA B receptor-mediated regulation of the PFC GABA response to tail-pinch (TP) stress., Results: We report that TP stress reliably elicited comparable increases in extracellular GABA in the left and right PFCs. SCH23390 (D 1 antagonist; 100 μM perfusate concentration) perfused by reverse microdialysis attenuated the local GABA stress responses equally in the left and right PFCs. Intra-PFC raclopride perfusion (D 2 antagonist; 100 μM) had the opposite effect, not only potentiating the local GABA stress response but also causing a transient elevation in basal (pre-stress) GABA. Moreover, unilateral PFC raclopride microinjection (6 nmol) attenuated the GLU response to TP stress in the contralateral PFC. Finally, intra-PFC baclofen perfusion (GABA B agonist; 100 μM) inhibited the local GLU and GABA stress responses., Conclusions: Taken together, these findings implicate PFC GABA interneurons in processing stressful stimuli, showing that local D 1 , D 2 , and GABA B receptor-mediated changes in PFC GABA transmission play a crucial role in the interhemispheric regulation of GLU stress responsivity.

Rationale: Signaling through the netrin-1 receptor, deleted in colorectal cancer (DCC), in dopamine neurons controls the extent of their innervation to the medial prefrontal cortex (mPFC) during adolescence. In mice, dcc haploinsufficiency results in increased mPFC dopamine innervation and concentrations in adulthood. In turn, dcc haploinsufficiency leads to resilience to the effects of stimulant drugs of abuse on dopamine release in the nucleus accumbens and behavior., Objectives: First, we set out to determine whether increased mPFC dopamine innervation causes blunted behavioral responses to amphetamine in adult dcc haploinsufficient mice. Second, we investigated whether unc5c, another netrin-1 receptor expressed by dopamine neurons, is involved in these effects. Third, we assessed whether haploinsufficiency of netrin-1 itself leads to blunted behavioral responding to amphetamine, whether this phenotype emerges before or after adolescence and whether increased mPFC dopamine input is the underlying mechanism., Results: Adult, but not adolescent, dcc, unc5c and netrin-1 haploinsufficient mice exhibit blunted behavioral responses to amphetamine. Furthermore, adult dcc, unc5c, and netrin-1 haploinsufficient mice have exaggerated mPFC dopamine concentrations in comparison to their wild-type littermates. Importantly, resilience to amphetamine-induced behavioral activation in all the three mouse models is abolished by selective dopamine depletion in the medial prefrontal cortex., Conclusions: dcc, unc5c, or netrin-1 haploinsufficiency leads to increased dopamine content in the mPFC and to resilience against amphetamine-induced behavioral activation. Our findings raise the hypothesis that DCC, UNC5C, and netrin-1 act in concert to organize the adolescent development of mesocortical dopamine innervation and, in turn, determine behavioral responses to drugs of abuse.

Glutamate in the prefrontal cortex (PFC) plays a significant role in several mental illnesses, including schizophrenia, addiction and anxiety. Previous studies on PFC glutamate-mediated function have used techniques that raise questions on the neuronal versus astrocytic origin of glutamate. The present studies used enzyme-based microelectrode arrays to monitor second-by-second resting glutamate levels in the PFC of awake rats. Locally applied drugs were employed in an attempt to discriminate between the neuronal or glial components of the resting glutamate signal. Local application of tetrodotoxin (sodium channel blocker), produced a significant (∼ 40%) decline in resting glutamate levels. In addition significant reductions in extracellular glutamate were seen with locally applied ω-conotoxin (MVIIC; ∼ 50%; calcium channel blocker), and the mGluR(2/3) agonist, LY379268 (∼ 20%), and a significant increase with the mGluR(2/3) antagonist LY341495 (∼ 40%), effects all consistent with a large neuronal contribution to the resting glutamate levels. Local administration of D,L-threo-β-benzyloxyaspartate (glutamate transporter inhibitor) produced an ∼ 120% increase in extracellular glutamate levels, supporting that excitatory amino acid transporters, which are largely located on glia, modulate clearance of extracellular glutamate. Interestingly, local application of (S)-4-carboxyphenylglycine (cystine/glutamate antiporter inhibitor), produced small, non-significant bi-phasic changes in extracellular glutamate versus vehicle control. Finally, pre-administration of tetrodotoxin completely blocked the glutamate response to tail pinch stress. Taken together, these results support that PFC resting glutamate levels in rats as measured by the microelectrode array technology are at least 40-50% derived from neurons. Furthermore, these data support that the impulse flow-dependent glutamate release from a physiologically -evoked event is entirely neuronally derived., (© 2010 The Authors. Journal of Neurochemistry © 2010 International Society for Neurochemistry.)

While stressors are known to increase medial prefrontal cortex (PFC) glutamate (GLU) levels, the mechanism(s) subserving this response remain to be elucidated. We used microdialysis and local drug applications to investigate, in male Long-Evans rats, whether the PFC GLU stress response might reflect increased interhemispheric communication by callosal projection neurons. We report here that tail-pinch stress (20 min) elicited comparable increases in GLU in the left and right PFC that were sodium and calcium dependent and insensitive to local glial cystine-GLU exchanger blockade. Unilateral ibotenate-induced PFC lesions abolished the GLU stress response in the opposite hemisphere, as did contralateral mGlu(2/3) receptor activation. Local dopamine (DA) D(1) receptor blockade in the left PFC potently enhanced the right PFC GLU stress response, whereas the same treatment applied to the right PFC had a much weaker effect on the left PFC GLU response. Finally, the PFC GLU stress response was attenuated and potentiated, respectively, following alpha(1)-adrenoreceptor blockade and GABA(B) receptor activation in the opposite hemisphere. These findings indicate that the PFC GLU stress response reflects, at least in part, activation of callosal neurons located in the opposite hemisphere and that stress-induced activation of these neurons is regulated by GLU-, DA-, norepinephrine-, and GABA-sensitive mechanisms. In the case of DA, this control is asymmetrical, with a marked regulatory bias of the left PFC DA input over the right PFC GLU stress response. Together, these findings suggest that callosal neurons and their afferentation play an important role in the hemispheric specialization of PFC-mediated responses to stressors.

Rationale: The medial prefrontal cortex (PFC) receives stress-sensitive dopamine (DA) and noradrenergic (NE) projections from the ventral tegmental area and locus coeruleus, respectively, and evidence from various sources point to a complex functional interaction between these two systems. Stress will also stimulate DA transmission in the nucleus accumbens (NAcc), and our previous work has shown that this response is under the indirect inhibitory control of a DA-sensitive mechanism in PFC., Objective: We examined the possibility that the NAcc DA stress response is also modulated by prefrontal cortical NE., Materials and Methods: We used voltammetry to study in freely behaving rats the effects of local applications of alpha(1) (benoxathian 0.1, 1, 10 nmol), alpha(2) (SKF86466), and beta(1/2) (alprenolol) receptor selective antagonists into the PFC on the NAcc DA response to tail-pinch stress., Results: The NAcc DA stress response was dose-dependently inhibited by local PFC blockade of alpha(1) receptors. Additional tests revealed, however, that the DA stress response in NAcc is unaffected after local alpha(1) receptor activation with cirazoline. Furthermore, at equivalent doses, neither alpha(2) nor beta(1/2) receptor blockade significantly affected the NAcc DA stress response., Conclusions: These data indicate that stress-induced activation of subcortical DA transmission is modulated by the NE input to PFC acting at alpha(1) receptors. They suggest that, under normal circumstances, this system exerts a facilitatory or enabling influence on the NAcc DA stress response.

Excitotoxic neonatal ventral hippocampus (NVH) lesions in rats result in characteristic post-pubertal hyper-responsiveness to stress and cognitive abnormalities analogous to those described in schizophrenia and suggestive of alterations in dopamine (DA) neurotransmission. Converging lines of evidence also point to dysfunctions in the cortical cholinergic system in neuropsychiatric disorders. In previous studies, we observed alterations in dopaminergic modulation of acetylcholine (Ach) release in the prefrontal cortex (PFC) in post-pubertal NVH-lesioned rats. These two neurotransmitter systems are involved in the stress response as PFC release of DA and Ach is enhanced in response to some stressful stimuli. As adult NVH-lesioned rats are behaviorally more reactive to stress, we investigated the effects of NVH lesions on tail-pinch stress-induced Ach and DA release in the PFC. Using in vivo microdialysis, we observed that tail-pinch stress resulted in significantly greater increases in prefrontal cortical Ach release in post-pubertal NVH-lesioned rats (220% baseline) compared with sham-operated controls (135% baseline). Systemic administration of the D1-like receptor antagonist SCH 23390 (0.5 mg/kg i.p.) or the D2-like receptor antagonist haloperidol (0.2 mg/kg i.p.), as well as intra-PFC administration of the D2-like antagonist sulpiride (100 microm), reduced stress-induced Ach release in PFC of adult NVH-lesioned rats. By contrast, intra-PFC administration of SCH 23390 (100 microm) failed to affect stress-induced Ach release in PFC of NVH-lesioned rats. Interestingly, using in vivo voltammetry, stress-induced stimulation of PFC DA release was found to be attenuated in adult NVH-lesioned rats. Taken together, these data suggest developmentally specific reorganization of prefrontal cortical cholinergic innervation notably regarding its regulation by DA neurotransmission.

The ventral region of the medial prefrontal cortex (mPFC) is highly sensitive to stressful inputs and implicated in a variety of behaviors. Studies have also demonstrated numerous functional hemispheric asymmetries within this brain area of the rat. The present study examines the effects of ibotenic acid or sham lesions targeting the left, right or bilateral infralimbic cortex, on a variety of behaviors. Lesions (which destroyed infralimbic and ventral prelimbic cortex) were without effect on acquisition or reversal of a spatial learning task in the Morris water maze. Similarly unaffected were spontaneous and amphetamine-induced locomotor activity and sensitization, and prepulse inhibition of the acoustic startle response. In contrast, lesions significantly affected behavior in the elevated plus maze, as right-lesioned animals spent more time exploring the open arms of the maze than shams or left-lesioned rats, while not differing in closed arm entries. As well, in a simple taste aversion paradigm, right-lesioned rats drank significantly more of a sweetened milk/quinine solution than shams and left-lesioned rats, despite not differing in consumption of sweetened milk alone. The anxiolytic effects of right, but not left lesions of ventral mPFC, parallel the asymmetrical suppression of physiological stress responses previously reported for similar lesions. It is suggested that the right ventral mPFC plays a primary role in optimizing cautious and adaptive behavior in potentially threatening situations.

In recent years, dysfunction of hypothalamic-pituitary-adrenal (HPA) axis function has been implicated in a wide variety of psychiatric conditions. The importance of this system in responding to and coping with stress is well documented, and the integrity of such systems is of obvious significance to good mental health. The prefrontal cortex (PFC) is also heavily implicated in numerous psychopathological conditions. There is thus a growing interest in the potential role the PFC might play in regulating HPA function, and whether abnormalities of these systems are linked. The present paper reviews a number of recent animal studies which have attempted to elucidate the role of the PFC in regulation of HPA axis function, and how these systems may interact. It is concluded that the PFC is involved both in activating HPA responses to stress and in the negative feedback regulation of this system. Cerebral laterality is an important feature of this regulation, with the right PFC being most directly linked to stress-regulatory systems. On this basis, a number of parallels are drawn to the human literature, where asymmetrical disturbances in PFC activity may help explain associated patterns of HPA dysfunction.

BackgroundMost studies investigating the neurobiology of depression and suicide have focused on the serotonergic system. While it seems clear that serotonergic alterations play a role in the pathogenesis of these major public health problems, dysfunction in additional neurotransmitter systems and other molecular alterations may also be implicated. Microarray expression studies are excellent screening tools to generate hypotheses about additional molecular processes that may be at play. In this study we investigated brain regions that are known to be implicated in the neurobiology of suicide and major depression are likely to represent valid global molecular alterations.Methodology/Principal FindingsWe performed gene expression analysis using the HG-U133AB chipset in 17 cortical and subcortical brain regions from suicides with and without major depression and controls. Total mRNA for microarray analysis was obtained from 663 brain samples isolated from 39 male subjects, including 26 suicide cases and 13 controls diagnosed by means of psychological autopsies. Independent brain samples from 34 subjects and animal studies were used to control for the potential confounding effects of comorbidity with alcohol. Using a Gene Ontology analysis as our starting point, we identified molecular pathways that may be involved in depression and suicide, and performed follow-up analyses on these possible targets. Methodology included gene expression measures from microarrays, Gene Score Resampling for global ontological profiling, and semi-quantitative RT-PCR. We observed the highest number of suicide specific alterations in prefrontal cortical areas and hippocampus. Our results revealed alterations of synaptic neurotransmission and intracellular signaling. Among these, Glutamatergic (GLU) and GABAergic related genes were globally altered. Semi-quantitative RT-PCR results investigating expression of GLU and GABA receptor subunit genes were consistent with microarray data.Conclusions/SignificanceThe observed results represent the first overview of global expression changes in brains of suicide victims with and without major depression and suggest a global brain alteration of GLU and GABA receptor subunit genes in these conditions.

We have previously reported that interhemispheric regulation of medial prefrontal cortex (PFC)-mediated stress responses is subserved by glutamate (GLU)- containing callosal neurons. Evidence of chronic stress-induced dendritic and spine atrophy among PFC pyramidal neurons led us to examine how chronic restraint stress (CRS) might alter the apical dendritic morphology of callosal neurons and the acute GLU stress responses in the left versus right PFC. Morphometric analyses of retrogradely labeled, dye-filled PFC callosal neurons revealed hemisphere-specific CRS-induced dendritic retraction; whereas significant dendritic atrophy occurred primarily within the distal arbor of left PFC neurons, it was observed within both the proximal and distal arbor of right PFC neurons. Overall, CRS also significantly reduced spine densities in both hemispheres with the greatest loss occurring among left PFC neurons, mostly at the distal extent of the arbor. While much of the overall decrease in dendritic spine density was accounted by the loss of thin spines, the density of mushroom-shaped spines, despite being fewer in number, was halved. Using microdialysis we found that, compared to controls, basal PFC GLU levels were significantly reduced in both hemispheres of CRS animals and that their GLU response to 30 min of tail-pinch stress was significantly prolonged in the left, but not the right PFC. Together, these findings show that a history of chronic stress alters the dendritic morphology and spine density of PFC callosal neurons and suggest a mechanism by which this might disrupt the interhemispheric regulation of PFC-mediated responses to subsequent stressors. [ABSTRACT FROM PUBLISHER]

This article presents a study regarding the alternative splicing, methylation state, and expression profile of Tropomyosin-related kinase B (TrkB.T1) in the frontal cortex of suicide completers. The postmortem case-control study aims to validate the hypothesis that TrkB.T1 expression is downregulated in suicide completers and to test that this downregulation is mediated by an epigenetic process. It discusses that a reduction of TrkB.T1 expression in the frontal cortex of a subpopulation of suicide completers is linked with the methylation state of the promoter region.

Early environment can shape the development and function of the mesocorticolimbic dopamine (DA) system and represents a possible risk factor for adult pathologies. One critical variable in the early environment is nutrition, and exposure to high fat (HF) in adulthood is known to change this DA system. We tested whether perinatal HF intake in rats could have long-term effects on DA function and behavior in adult offspring. Rat dams were fed either a control (5% fat, CD) or high fat (30% fat, HF) diet during the last week of gestation and lactation, and adult offspring were tested (PND 56–90) after weaning on CD. Locomotor responses to acute and repeated doses of d-amphetamine (AMP, 0.75 mg/kg bw) were determined as were indices of DA function in the ventral tegmental area (VTA), nucleus accumbens (NAc), and the prefrontal cortex (PFC). Adult HF offspring displayed increased tyrosine hydroxylase expression in the VTA and NAc and significant increases in DA and DOPAC content in the NAc, suggesting an elevated DA tone in this target field. In the NAc, there were no significant changes in D1, D2 receptors, or DA transporter (DAT) levels between diet groups. Perinatal HF feeding reduced AMP-induced locomotion and behavioral sensitization to AMP, suggesting that early diet might have caused long-lasting desensitization of postsynaptic receptor mechanisms in the NAc. Our results demonstrate that both synthetic activity in VTA neurons and the responsiveness of accumbens DA neurons is altered by maternal nutrition. These effects subside long after termination of exposure to the HF diet. [ABSTRACT FROM AUTHOR]

Abstract: Evidence indicates that dopamine (DA) transmission in nucleus accumbens (NAcc) is modulated by glutamate (GLUT) projections from medial prefrontal cortex (PFC) to NAcc and the ventral tegmental area (VTA). Local NMDA receptor blockade in NAcc has previously been shown to enhance the DA stress response in this region as well as in the VTA. This raises the possibility that the NAcc DA stress response is regulated by GLUT acting at NMDA receptors located on NAcc GABA output neurons that project to the VTA where GABA is known to regulate DA cell activity. Thus, in the present study, we used voltammetry to examine the effects of intra-VTA administration of GABAA and GABAB agonists and antagonists on restraint stress-induced increases in NAcc DA. The results show that local VTA GABAB receptor activation with baclofen (0.01, 0.1 and 1.0 nmol) dose-dependently inhibited the NAcc DA stress response whereas GABAB receptor blockade with phaclofen had the opposite effect, resulting in a dose-dependent potentiation of the stress response. A similar potentiation of the NAcc DA stress response was observed following VTA GABAA receptor blockade with bicuculline, but only at the highest dose (1.0 nmol). Interestingly, intra-VTA injection of the GABAA receptor agonist, muscimol, at the lowest dose (0.01 nmol) but not at the higher doses (0.1 or 1.0 nmol) also potentiated the NAcc DA stress response, suggesting an action mediated primarily at GABAA receptors located on non-DA neurons. These results indicate that the NAcc DA stress response is regulated by GABA afferents to VTA DA cells and that this action is differentially mediated by GABAA and GABAB receptors. The data suggest that the relevant GABAB receptors are located on DA neurons whereas the GABAA receptors are located on GABA interneurons and perhaps also on DA cells. The present findings are also consistent with the idea that the corticofugal GLUT input to NAcc indirectly regulates stress-induced DA release in this region through the GABA feedback pathway to VTA. [Copyright &y& Elsevier]

Backgound Alcohol use disorder (AUD) is devastating and poorly treated, and innovative targets are actively sought for prevention and treatment. The orphan G protein–coupled receptor GPR88 is enriched in mesocorticolimbic pathways, and Gpr88 knockout mice show hyperactivity and risk-taking behavior, but a potential role for this receptor in drug abuse has not been examined. Methods We tested Gpr88 knockout mice for alcohol-drinking and -seeking behaviors. To gain system-level understanding of their alcohol endophenotype, we also analyzed whole-brain functional connectivity in naïve mice using resting-state functional magnetic resonance imaging. Results Gpr88 knockout mice showed increased voluntary alcohol drinking at both moderate and excessive levels, with intact alcohol sedation and metabolism. Mutant mice also showed increased operant responding and motivation for alcohol, while food and chocolate operant self-administration were unchanged. Alcohol place conditioning and alcohol-induced dopamine release in the nucleus accumbens were decreased, suggesting reduced alcohol reward in mutant mice that may partly explain enhanced alcohol drinking. Seed-based voxelwise functional connectivity analysis revealed significant remodeling of mesocorticolimbic centers, whose hallmark was predominant weakening of prefrontal cortex, ventral tegmental area, and amygdala connectional patterns. Also, effective connectivity from the ventral tegmental area to the nucleus accumbens and amygdala was reduced. Conclusions Gpr88 deletion disrupts executive, reward, and emotional networks in a configuration that reduces alcohol reward and promotes alcohol seeking and drinking. The functional connectivity signature is reminiscent of alterations observed in individuals at risk for AUD. The Gpr88 gene, therefore, may represent a vulnerability/resilience factor for AUD, and a potential drug target for AUD treatment. [ABSTRACT FROM AUTHOR]