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PubMed1980

An intrahemispheric columnar projection between two cortical multisensory convergence areas (inferior parietal lobule and prefrontal cortex): an anterograde study in macaque using HRP gel.

Horseradish peroxidase (HRP) gel and tetramethylbenzidine neurohistochemistry were used successfully in demonstrating the columnar organization of an intrahemispheric projection from the inferior parietal lobule to the prefrontal cortex in the macaque monkey. Following an HRP gel implant within the upper portion of the posterior (caudal) bank of the intraparietal sulcus, a prominent anterograde terminal projection field, consisting of alternate light and dark (300-500 microns) columns, was observed using low-power dark-field microscopy in the caudal third of the sulcus principalis cortex (area 46). At higher magnification large numbers of small retrogradely-labeled pyramidal cells were present in layers III and V of the same cortex. The regionally-specific projection, coupled with its discrete anatomical organization, lends support to the reputed functional/behavioral subsectors within the prefrontal cortex and its apparent capacity for spatial representation.

Afferent Pathways↗

PubMed2004

Human dysbindin (DTNBP1) gene expression in normal brain and in schizophrenic prefrontal cortex and midbrain.

CONTEXT: The schizophrenia-susceptibility gene dysbindin (DTNBP1 on 6p22.3) encodes a neuronal protein that binds to beta-dystrobrevin and may be part of the dystrophin protein complex. Little is known about dysbindin expression in normal or schizophrenic brain. OBJECTIVES: To determine whether brain regions implicated in schizophrenia express dysbindin and whether abnormal levels of dysbindin messenger RNA (mRNA) may be found in this disorder and to test whether sequence variations in the dysbindin gene in the promoter region, 5' and 3' untranslated regions, or introns would affect dysbindin mRNA levels. METHODS: In patients with schizophrenia and controls, we compared dysbindin, synaptophysin, spinophilin, and cyclophilin mRNA levels in the dorsolateral prefrontal cortex and dysbindin mRNA levels in the midbrain by in situ hybridization. We genotyped brain DNA at 11 single nucleotide polymorphisms to determine whether genetic variation in the dysbindin gene affects cortical dysbindin mRNA levels. MAIN OUTCOME MEASURES: Quantitative assessment of dysbindin mRNA levels across various brain regions and comparative studies of dysbindin mRNA levels in brains of patients with schizophrenia compared with normal controls. RESULTS: Dysbindin mRNA was detected in the frontal cortex, temporal cortex, hippocampus, caudate, putamen, nucleus accumbens, amygdala, thalamus, and midbrain of the adult brain. Patients with schizophrenia had statistically significantly reduced dysbindin mRNA levels in multiple layers of the dorsolateral prefrontal cortex, whereas synaptophysin, spinophilin, and cyclophilin mRNA levels were unchanged. Dysbindin mRNA levels were quantitatively reduced in the midbrain of patients with schizophrenia, but not statistically significantly. Cortical dysbindin mRNA levels varied statistically significantly according to dysbindin genotype. CONCLUSIONS: Dysbindin mRNA is expressed widely in the brain, and its expression is reduced in schizophrenia. Variation in dysbindin mRNA levels may be determined in part by variation in the promoter and the 5' and 3' untranslated regions. These data add to the evidence that dysbindin is an etiologic factor in schizophrenia risk.

3' Untranslated Regions↗

PubMed1999

Up-regulation of immunolabeled alpha2A-adrenoceptors, Gi coupling proteins, and regulatory receptor kinases in the prefrontal cortex of depressed suicides.

Suicide and depression are associated with an increased density of alpha2-adrenoceptors (radioligand receptor binding) in specific regions of the human brain. The function of these inhibitory receptors involves various regulatory proteins (Gi coupling proteins and G protein-coupled receptor kinases, GRKs), which work in concert with the receptors. In this study we quantitated in parallel the levels of immunolabeled alpha2A-adrenoceptors and associated regulatory proteins in brains of suicide and depressed suicide victims. Specimens of the prefrontal cortex (Brodmann area 9) were collected from 51 suicide victims and 31 control subjects. Levels of alpha2A-adrenoceptors, Galphai1/2 proteins, and GRK 2/3 were assessed by immunoblotting techniques by using specific polyclonal antisera and the immunoreactive proteins were quantitated by densitometry. Increased levels of alpha2A-adrenoceptors (31-40%), Galphai1/2 proteins (42-63%), and membrane-associated GRK 2/3 (24-32%) were found in the prefrontal cortex of suicide victims and antidepressant-free depressed suicide victims. There were significant correlations between the levels of GRK 2/3 (dependent variable) and those of alpha2A-adrenoceptors and Galphai1/2 proteins (independent variables) in the same brain samples of suicide victims (r = 0.56, p = 0.008) and depressed suicide victims (r = 0.54, p = 0.041). Antemortem antidepressant treatment was associated with a significant reduction in the levels of Galphai1/2 proteins (32%), but with modest decreases in the levels of alpha2A-adrenoceptors (6%) and GRK 2/3 (18%) in brains of depressed suicide victims. The increased levels in concert of alpha2A-adrenoceptors, Galphai1/2 proteins, and GRK 2/3 in brains of depressed suicide victims support the existence of supersensitive alpha2A-adrenoceptors in subjects with major depression.

Adult↗

PubMed2003

Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia.

OBJECTIVE: The identification of neurobiological intermediate phenotypes may hasten the search for susceptibility genes in complex psychiatric disorders such as schizophrenia. Earlier family studies have suggested that deficits in executive cognition and working memory may be related to genetic susceptibility for schizophrenia, but the biological basis for this behavioral phenotype has not been identified. METHOD: The authors used functional magnetic resonance imaging (fMRI) during performance of the N-back working memory task to assess working memory-related cortical physiology in nonschizophrenic, cognitively intact siblings of patients with schizophrenia. They compared 23 unaffected siblings of schizophrenic patients to 18 matched comparison subjects. As a planned replication, they studied another 25 unaffected siblings and 15 comparison subjects. RESULTS: In both cohorts, there were no group differences in working memory performance. Nevertheless, both groups of siblings showed an exaggerated physiological response in the right dorsolateral prefrontal cortex that was qualitatively similar to results of earlier fMRI studies of patients with schizophrenia. CONCLUSIONS: These fMRI data provide direct evidence of a primary physiological abnormality in dorsolateral prefrontal cortex function in individuals at greater genetic risk for schizophrenia, even in the absence of a manifest cognitive abnormality. This exaggerated fMRI response implicates inefficient processing of memory information at the level of intrinsic prefrontal circuitry, similar to earlier findings in patients with schizophrenia. These data predict that inheritance of alleles that contribute to inefficient prefrontal information processing will increase risk for schizophrenia.

Adult↗

PubMed2005

Amphetamine sensitization impairs cognition and reduces dopamine turnover in primate prefrontal cortex.

BACKGROUND: Amphetamine (AMPH) sensitization in monkeys produces long-lasting behavioral changes that model positive (hallucinatory-like behaviors) and negative (psychomotor depression) symptoms of schizophrenia. The extent to which this model produces the core deficit in schizophrenia--working memory impairment--is unknown. METHODS: Two groups of rhesus monkeys were sensitized to AMPH over 6 weeks. In one group, acquisition of cognitive tasks (delayed response, visual discrimination, delayed nonmatch-to-sample) was examined beginning 6+ months postsensitization. The second group was pretrained to stability on delayed response before sensitization. Regional postmortem concentrations of dopamine and its metabolites were examined in tissue from age-matched AMPH-naive and AMPH-sensitized monkeys using high-performance liquid chromatography with electrochemical detection (HPLC-ECD). RESULTS: The AMPH-sensitized monkeys were profoundly impaired in their ability to acquire cognitive tasks compared with AMPH-naïve monkeys. Pretrained monkeys showed impaired delayed response performance for several months following sensitization. Analysis by HPLC revealed that AMPH sensitization significantly reduced dopamine turnover in prefrontal cortex and striatum. CONCLUSIONS: Impairments in the acquisition and performance of spatial delayed response in association with reduced dopamine turnover in prefrontal cortex following AMPH sensitization provide further support for the relevance of this model to both the etiology and the treatment of cognitive dysfunction in schizophrenia.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1987

Selective enhancement of dopamine utilization in the rat prefrontal cortex by food deprivation.

Previous studies have indicated that food deprivation exerts various effects on brain neurotransmitters and that mild stress causes a selective enhancement of dopamine activity in the rat medial prefrontal cortex. In the present study it was found that in rats 24 h of food deprivation produced an increase in levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the medial prefrontal cortex but not in the nucleus accumbens or caudate-putamen. This selective increase in mesocortical dopamine activity is comparable to that found with mild footshock stress exposure and indicates that food deprivation may function as a stressor.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2005

Association of the functional -1019C/G 5-HT1A polymorphism with prefrontal cortex and amygdala activation measured with 3 T fMRI in panic disorder.

Serotonergic genes have been implicated in the pathogenesis of panic disorder and amygdala function in response to fearful stimuli. Regional brain activation on visual presentation of emotional facial stimuli was investigated in 20 patients with panic disorder by means of fMRI at 3 T. All patients were genotyped for the functional -1019C/G 5-HT1A and 5-HTTLPR polymorphisms. In patients homozygous for the 5-HT1A -1019G risk allele (n=5), fearful stimuli were associated with a decreased activation of right prefrontal cortex regions. Patients homozygous for the 5-HT1A -1019G risk allele or patients carrying the short risk allele of the 5-HTTLPR (n=13) showed higher amygdala activation in response to happy faces. This exploratory study suggests a role of the functional -1019C/G 5-HT1A and 5-HTTLPR polymorphisms on prefrontal cortex and amygdala activation patterns in response to emotional facial stimuli. These serotonergic polymorphisms might increase the risk for panic disorder by contributing to an altered processing of emotional stimuli.

Adult↗

PubMed1993

Dopamine-immunoreactive axon varicosities form nonrandom contacts with GABA-immunoreactive neurons of rat medial prefrontal cortex.

Recent postmortem studies have suggested that reduced gamma-aminobutyric acid (GABA)ergic activity in limbic cortex may be one component to the pathophysiology of schizophrenia. This hypothesis has underscored the importance of knowing whether midbrain dopamine afferents interact extensively enough with inhibitory interneurons to suggest a direct functional relationship. Toward this end, a double immunofluorescence approach combined with confocal laser scanning microscopy has been used to localize dopamine and GABA simultaneously in rat medial prefrontal cortex. The results confirm studies from other laboratories showing a rich network of dopamine-immunoreactive fibers forming a gradient across the cortical laminae, with deeper layers having the highest density. When viewed with oil immersion optics, dopamine-immunoreactive fibers were frequently found to be in close apposition with GABA-immunoreactive cell bodies. The percentage of GABA-containing neurons showing such contacts was highest in layer VI (65%) and progressively decreased toward layer I (9%). Varicose regions of the dopamine fibers were typically present at the point of contact with a GABA-immunoreactive cell body. Using an immunoperoxidase technique to localize dopamine fibers and cresyl violet staining to visualize neurons simultaneously, two separate statistical analyses were performed to assess whether the frequency of contacts between dopamine fibers and cell bodies in general may be due to random effects. In layer VI, a high percentage of both pyramidal and nonpyramidal neurons were found to be in contact with dopamine varicosities (71% and 76%, respectively), but these were not significantly different from that observed for GABA-containing cells (65%) in double-immunofluorescence specimens. A Chi-square statistical test was used to compare the observed and predicted number of varicosities forming cell body contacts. This analysis indicated that the percentage of dopamine varicosities (30%) that form appositions with cell bodies is much greater than would be expected if these appositions were due to random effects (15%). Moreover, using an estimate of intensity for a stationary Poisson process, it was again found that random effects can not account for these interactions (P = 0.01). Taken together with earlier electron microscopic studies from other laboratories, the present findings support the idea that GABAergic interneurons have extensive interactions with dopamine varicosities. While these interactions are not unique to GABAergic cell bodies, they suggest that inhibitory interneurons can play a direct role in mediating the effects of midbrain dopamine afferents in rat medial prefrontal cortex.

Animals↗

PubMed1995

Abnormal regional benzodiazepine receptor uptake in the prefrontal cortex in patients with panic disorder.

The neuroanatomical networks involved in the initiation of panic attack and the maintenance of panic disorder are poorly understood. This study aimed to elucidate the possible abnormalities in benzodiazepine receptor uptake in the brain of patients with panic disorder. Seventeen unmedicated patients with panic disorder were investigated using 123I-iomazenil single photon emission tomography (SPET). Seventeen healthy age- and sex-matched volunteers served as controls. The SPET scan was taken 90 min after injection of tracer. Eleven of 17 patients (65%) showed an increased (> 2 S.D. higher than the mean of the controls) right-to-left ratio of benzodiazepine receptor uptake in the prefrontal cortex. Also, the mean right-to-left ratio of benzodiazepine receptor uptake in all 17 patients with panic disorder was higher than in the controls (P < 0.001). Our SPET study demonstrated focally altered benzodiazepine receptor uptake in the prefrontal cortices in patients with panic disorder. Magnetic resonance imaging indicated that the affected region was located in the right middle and inferior frontal gyri. The deterioration in information processing in the right prefrontal cortex may be implicated in the generation of panic disorder.

Female↗

PubMed2000

The medial prefrontal cortex plays an important role in the excitation of A10 dopaminergic neurons following intravenous muscimol administration.

Intravenous muscimol administration increases the activity of dopaminergic neurons of the A10 cell group, located in the ventral tegmental area. Evidence suggests that this increase in activity is produced by disinhibition following the inhibition of GABAergic ("non-dopaminergic") cells in the ventral tegmental area. We hypothesized that the activation of A10 cells by muscimol is likely to be at least partly caused by the action of excitatory afferents. To verify this, A10 cells were isolated from ipsilateral afferent sources which utilise excitatory amino acids (which play an important role in the activity of these neurons), using hemisections at the level of the subthalamic nucleus (or just anterior to the subthalamic nucleus), electrolytic lesions of the pedunculopontine tegmental nucleus, or a combination of both. Following hemisections, and hemisections combined with lesions of the pedunculopontine tegmental nucleus, muscimol inhibited rather than excited A10 dopaminergic neurons. The pedunculopontine tegmental nucleus itself appeared to make little intrinsic contribution to muscimol-induced excitation, although the results suggested that part of the excitation which originates in the forebrain may be conducted to A10 cells via the pedunculopontine tegmental nucleus. The source of the effective forebrain excitation was investigated using electrolytic lesions of documented sources of excitatory amino acidergic afferents to the ventral tegmental area: the medial prefrontal cortex, certain nuclei of the amygdalar complex and the lateral habenular nucleus. In the medial prefrontal cortex-lesioned group, muscimol again produced inhibition, an effect qualitatively and quantitatively similar to that in the hemisected groups. Habenular lesions blocked muscimol-induced excitation without producing inhibition, whilst amygdalar lesions produced no significant change in the effects of muscimol. The results suggest that under normal circumstances, an active excitation counteracts and exceeds the direct inhibitory effects of muscimol on the activity of A10 dopaminergic neurons. Furthermore, this activation appears to be produced by the action of excitatory (probably excitatory amino acidergic) afferents arising from the medial prefrontal cortex, and possibly the lateral habenular nucleus. Insofar as the excitation of A10 dopaminergic neurons, which is produced by certain drugs of abuse, and which may play a crucial role in their sustained use, has its basis in excitation following disinhibition, this excitation may provide a novel target for therapeutic intervention in addiction.

Amygdala↗

PubMed2004

Upregulation of CB1 receptors and agonist-stimulated [35S]GTPgammaS binding in the prefrontal cortex of depressed suicide victims.

Endogenous and exogenous cannabinoids (CBs) acting through the CB(1) receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB(1) receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS). [(3)H]CP-55,940 and CB(1) receptor-stimulated [(35)S]GTPgammaS binding sites were analyzed in membranes obtained from DLPFC of DS (10) and matched normal controls (10). Upregulation (24%, P<0.0001) of CB(1) receptor density (B(max)) was observed in DS (644.6+/-48.8 fmol/mg protein) compared with matched controls (493.3+/-52.7 fmol/mg protein). However, there was no significant alteration in the affinity of receptor (DS; 1.14+/-0.08 vs control; 1.12+/-0.10 nM). Higher density of CB(1) receptors in DS (38%, P<0.001) was also demonstrated by Western blot analysis. The CB(1) receptor-stimulated [(35)S]GTPgammaS binding was significantly greater (45%, P<0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB(1) receptors with concomitant increase in the CB(1) receptor-mediated [(35)S]GTPgammaS binding suggests a role for enhanced cannabinoidergic signaling in the prefrontal cortex of DS. The cannabinoidergic system may be a novel therapeutic target in the treatment of depression and/or suicidal behavior.

Adolescent↗

PubMed2005

Distorted images of one's own body activates the prefrontal cortex and limbic/paralimbic system in young women: a functional magnetic resonance imaging study.

BACKGROUND: Our aim was to study the gender differences in brain activation upon viewing visual stimuli of distorted images of one's own body. METHODS: We performed functional magnetic resonance imaging on 11 healthy young men and 11 healthy young women using the "body image tasks" which consisted of fat, real, and thin shapes of the subject's own body. RESULTS: Comparison of the brain activation upon performing the fat-image task versus real-image task showed significant activation of the bilateral prefrontal cortex and left parahippocampal area including the amygdala in the women, and significant activation of the right occipital lobe including the primary and secondary visual cortices in the men. Comparison of brain activation upon performing the thin-image task versus real-image task showed significant activation of the left prefrontal cortex, left limbic area including the cingulate gyrus and paralimbic area including the insula in women, and significant activation of the occipital lobe including the left primary and secondary visual cortices in men. CONCLUSIONS: These results suggest that women tend to perceive distorted images of their own bodies by complex cognitive processing of emotion, whereas men tend to perceive distorted images of their own bodies by object visual processing and spatial visual processing.

Adult↗

PubMed2004

Effects of chronic treatment with escitalopram or citalopram on extracellular 5-HT in the prefrontal cortex of rats: role of 5-HT1A receptors.

1 Microdialysis was used to study the acute and chronic effects of escitalopram (S-citalopram; ESCIT) and chronic citalopram (CIT), together with the 5-HT1A receptor antagonist WAY100,635 (N-[2-[methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide trihydrochloride) and the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), on extracellular 5-hydroxytryptamine (5-HT) levels in the rat prefrontal cortex. 2 Extracellular 5-HT rose to 234 and 298% of basal values after subcutaneous (s.c.) acute doses of 0.15 and 0.63 mg kg(-1) ESCIT. No further increase was observed at 2.5 mg kg(-1) ESCIT (290%). 3 The effect of 13-day s.c. infusion of 10 mg kg(-1) day(-1) ESCIT on extracellular 5-HT (422% of baseline) was greater than after 2 days (257% of baseline), whereas exposure to ESCIT was similar. In contrast, the increase in extracellular 5-HT induced by the infusion of CIT for 2 (306%) and 13 days (302%) was similar. However, brain and plasma levels of S-citalopram in rats infused with CIT for 13 days were lower than after 2 days. 4 Acute treatment with 2.5 mg kg(-1) ESCIT or 5 mg kg(-1) CIT raised extracellular 5-HT by 243 and 276%, respectively, in rats given chronic vehicle but had no effect in rats given ESCIT (10 mg kg(-1) day(-1)) or CIT (20 mg kg(-1) day(-1)) for 2 or 13 days, suggesting that the infused doses had maximally increased extracellular 5-HT. WAY100,635 (0.1 mg kg(-1) s.c.) increased extracellular 5-HT levels by 168, 174 and 169% of prechallenge values in rats infused with vehicle or ESCIT for 2 or 13 days, respectively. WAY100,635 enhanced extracellular 5-HT levels to 226, 153 and 164% of prechallenge values in rats infused with vehicle or CIT for 2 and 13 days, respectively. 5 8-OH-DPAT (0.025 mg kg(-1)) reduced extracellular 5-HT by 54% in control rats, but had no effect in those given ESCIT and CIT for 13 days. 6 This series of experiments led to the conclusion that chronic treatment with ESCIT desensitizes the 5-HT1A receptors, regulating the release of 5-HT in the prefrontal cortex and enhances the effect of the drug on extracellular 5-HT. They also indicate that chronic treatment with ESCIT and CIT did not prevent WAY100,635 from raising extracellular 5-HT.

Animals↗

PubMed2001

Abnormal kainate receptor expression in prefrontal cortex in schizophrenia.

Abnormalities of molecules associated with the glutamate synapse have been implicated in the pathophysiology of schizophrenia. Of the many glutamate receptors, those most commonly suggested to be involved in schizophrenia are the ionotropic subtypes, the NMDA, AMPA, and kainate receptors. Both the NMDA and AMPA subtypes have been extensively studied in postmortem brains of individuals with schizophrenia, but relatively little is known about the expression of the kainate subtype of glutamate receptor. In this study, we have determined cortical and striatal kainate receptor expression in brains from persons with schizophrenia and a comparison group, using both in situ hybridization and receptor autoradiography. At the level of subunit mRNA expression, a shift in subunit stoichiometry was evident in multiple regions of the prefrontal cortex, with increased expression of gluR7 mRNA and decreased expression of KA2 mRNA. Decreased kainate receptor binding was also observed in the subjects with schizophrenia, but was restricted to infragranular laminae of the prefrontal cortex. No differences in kainate receptor binding or subunit mRNA levels were found in striatum or occipital cortex, suggesting that these findings may be restricted to association cortex. These data add to the growing literature implicating ionotropic glutamate receptor disturbances in schizophrenia, and indicate that in addition to AMPA and NMDA receptors, the kainate receptors are also abnormally expressed in this illness.

Aged↗

PubMed1999

Dopamine release in the prefrontal cortex in response to memantine following sub-chronic NMDA receptor blockade with memantine: a microdialysis study in rats.

Memantine is an uncompetitive N-methyl-D-aspartate receptor antagonist which blocks the NMDA receptor with moderate-affinity in a use- and voltage dependent manner. In clinical practice it is used chronically in the treatment of dementia and does not induce psychotomimetic effects as, high affinity, uncompetitive antagonists. Thus, it was of interest to determine dopamine (DA) and metabolite (DOPAC - dihydroxyphenylacetic acid and HVA - homovanillic acid) concentrations in the prefrontal cortex (PFC) in response to 14 days administration of memantine (20 mg/kg/day). It was previously determined that in rats this treatment induces sensitization to the locomotor effect and tolerance to the learning impairing properties of high doses of memantine. Acute administration of memantine (20 mg/kg, i.p.) did not affect dopamine levels in the PFC. It did however increase DA metabolite (DOPAC and HVA) concentrations. Administration of memantine (20 mg/kg/day) for 14 days before the acute challenge only slightly changed memantine's effect on PFC neurochemistry even though pharmacokinetic tolerance was observed. When memantine was administered to the sham group, which had been repeatedly treated with Hypnorm (including neuroleptic), an increase in PFC dopamine and metabolite content was seen. In accordance with the fact that memantine does not possess psychotomimetic activity at therapeutically relevant doses, these experiments showed that it does not affect the prefrontal cortex dopamine levels.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Engagement of the prefrontal cortex in representational momentum: an fMRI study.

Behavioral studies have identified a robust phenomenon that an observer's memory of the final position of a moving target is shifted a little further in its motion direction, which is usually called representational momentum (RM). However, the neural substrates underlying RM are poorly understood. The current study measured hemodynamic responses in association with RM using functional magnetic resonance imaging (fMRI). Two experiments using block and event-related designs, respectively, were conducted in which subjects compared the orientation of a probe rectangle with the remembered orientation of the final inducing figures in a set of rotating rectangles. Both experiments showed that, relative to the control task in which behavioral data did not show RM effects, RM task induced stronger activation in the prefrontal cortex. However, no activation was found in MT/MST complex in association with RM. The fMRI results suggest that RM may not simply reflect implicit motion perception and high level cognitive mechanisms underpinned by the prefrontal cortex may be involved in the RM effect.

Adult↗

PubMed2003

The non-steroidal anti-inflammatory drug diclofenac sodium attenuates IFN-alpha induced alterations to monoamine turnover in prefrontal cortex and hippocampus.

Interferon-alpha (IFN-alpha) administration induces major depression in a significant number of patients undergoing treatment for viral illnesses and other chronic diseases. Non-steroidal anti-inflammatory drugs (NSAIDs) are known to counteract a number of IFN-alpha-induced side effects, including pro-inflammatory cytokine activation and stress hormone release. To investigate this possibility further, we sought to determine the effect of the NSAID diclofenac sodium on monoamine turnover in brain induced by acute IFN-alpha exposure. Eleven male, Wistar rats (8 weeks old) were pretreated with diclofenac (20 mg/kg, s.c.) or saline, followed by intracerebroventricular (i.c.v.) infusion of IFN-alpha (1000 IU in 5 microl) or vehicle. The prefrontal cortex, striatum, and hippocampus were isolated and samples were assayed for monoamines and major metabolites by high-pressure liquid chromatography with electrochemical detection. The data show that acute IFN-alpha increased serotonin turnover in prefrontal cortex and increased dopamine turnover in hippocampus, while pre-treatment with diclofenac completely prevented these neurochemical responses. Importantly, these changes were recorded in two brain areas known to be important in depression and antidepressant action. These data offer support for a novel role of NSAIDs in modulating IFN-alpha-induced neurochemical alterations, and raise the possibility of the use of NSAIDs for the prevention of IFN-alpha-induced depression.

Animals↗

PubMed1991

Synergism between D1 and D2 dopamine receptors in the inhibition of the evoked release of [3H]GABA in the rat prefrontal cortex.

In order to examine a possible interaction between D1 and D2 receptors in the dopaminergic control of the electrically-evoked release of [3H]GABA in the rat prefrontal cortex, the effects of D1 and D2 dopamine agonists were studied in vitro on cortical slices. The D1 agonist SKF38393 (10(-5) M) inhibited the electrically-evoked release of [3H]GABA. This effect was totally reversed by both the D1 antagonist SCH23390 (10(-7) M) and the D2 antagonist sulpiride (10(-5) M). We previously observed that maximal D2-mediated inhibition of the electrically-evoked release of [3H]GABA was obtained with 10(-7) M RU24926 and 10(-8) M LY171555. Here we showed that the inhibition produced by these two D2 agonists is also abolished by 10(-7) M SCH23390. In dopamine-depleted slices from reserpine-treated animals, it was not possible to detect an effect of either RU24926 (10(-7) M) or SKF38393 (10(-5) M), suggesting a permissive role of endogenous dopamine in the effect of either D2 or D1 agonist. Finally, SKF38393 used at a subliminar concentration (10(-6) M) was able to potentiate the effect of a liminar concentration of RU24926 (1.5 x 10(-8) M). Taken together these results strongly suggest that in the rat prefrontal cortex a D1-D2 receptor synergism is involved in the dopaminergic control of the electrically-evoked release of [3H]GABA.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗