Postnatal manganese exposure alters the expression of D2L and D2S receptor isoforms: relationship to PKA activity and Akt levels

Postnatal manganese chloride (Mn) exposure causes persistent changes in presynaptic dopamine (DA) functioning (e.g., Mn reduces DA transporter levels and DA uptake), but evidence that Mn affects postsynaptic DA receptors and their associated second messenger systems is equivocal. Therefore, a goal of the present study was to determine whether exposing rats to Mn on postnatal days (PD) 1-21 would cause long-term alterations in D2 long (D2L) and D2 short (D2S) receptors that were detectible in adulthood (i.e., on PD 90). Signaling systems associated with D2 receptors were also assessed. Specifically, we measured protein kinase A (PKA) activity in the dorsal striatum and prefrontal cortex (PFC), whereas immunoblotting was used to quantify phosphorylated Akt (p-Akt) and phosphorylated ERK. Results showed that early Mn exposure caused a persistent elevation of D2L and D2S protein expression in the dorsal striatum, as well as an increase in the number of D2 binding sites. Conversely, Mn reduced D2 specific binding in the PFC on PD 90. PKA activity of Mn-treated rats was enhanced in both the dorsal striatum and PFC, whereas p-Akt levels were elevated in the dorsal striatum. When considered together, these results suggest that postnatal Mn exposure either directly or indirectly alters the functioning of postsynaptic DA receptors. One possibility is that early Mn exposure depresses presynaptic dopaminergic functioning and reduces DA levels, thereby causing an up-regulation of D2 receptors and a dysregulation of DA-associated signaling pathways. An alternative explanation is that early Mn exposure affects D2 receptors and PKA/p-Akt levels via independent mechanisms.     

Protein kinase C inhibition differentially affects 3,4-methylenedioxymethamphetamine-induced dopamine release in the striatum and prefrontal cortex of the rat

The acute administration of 3,4-methylenedioxymethamphetamine (MDMA) elevates extracellular concentrations of dopamine (DA) and serotonin (5-HT) in the rat striatum and medial prefrontal cortex (mPFC). The release of DA induced by MDMA is thought to involve both transporter and impulse-mediated processes. Furthermore, the impulse-dependent release of DA in the striatum elicited by MDMA appears to involve 5-HT2 receptor activation. Since 5-HT2 receptors are known to utilize protein kinase C (PKC) for intracellular signaling, we examined the effects of modulators of PKC activity on DA release stimulated by MDMA. Reverse dialysis of the PKC inhibitors bisindolylmaleimide I (BIM; 30 microM) or chelerythrine chloride (100 microM) through a microdialysis probe significantly attenuated the MDMA (10 mg/kg, i.p.)-induced increase in the extracellular concentration of DA in the striatum. In contrast, BIM did not significantly alter the increase in the extracellular concentration of DA in the striatum elicited by amphetamine (5 mg/kg, i.p.). Reverse dialysis of a PKC activator, phorbol 12,13-dibutyrate (PDBu) (0.5 microM), through the microdialysis probe into the striatum, significantly increased MDMA-induced DA release. In contrast to the inhibitory effects of the PKC inhibitors on MDMA-induced DA release in the striatum, intracortical infusion of BIM enhanced MDMA-induced release of DA in the mPFC. These data suggest that PKC-mediated signaling pathways differentially modulate MDMA-induced DA release from mesocorticolimbic and nigrostriatal neurons.     

Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymethamphetamine.

The effect of repeated administration of either methamphetamine (MA), 3,4-methylenedioxymethamphetamine (MDMA) or vehicle on the extracellular concentrations of glutamate (GLU), aspartate, taurine, dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), was studied in awake, freely moving rats using in vivo microdialysis. MA (7.5 mg/kg, i.p.) administered every 2 h for a total of 3 injections, increased the extracellular concentration of GLU in the anteromedial striatum. By contrast, neither vehicle nor MDMA (9.2 and 13.8 mg/kg) increased GLU efflux following repeated administration. Both MA and MDMA increased the extracellular concentration of DA in the striatum. However, the cumulative increase in DA was significantly greater in the MDMA treated animals as compared to the MA group. The concentrations of DA, serotonin (5-HT) and their metabolites were determined in the striatum 7 days following the repeated administration of MA, MDMA and vehicle. MA, but not MDMA or vehicle, decreased the concentration of DA in the striatum. Conversely, MDMA (13.8 mg/kg) decreased the concentration of 5-HT, whereas MA, MDMA (9.2 mg/kg) and vehicle had no effect on striatal 5-HT content. These data are suggestive that the long-term (7 day) DA neurotoxicity produced by the repeated administration of MA is mediated, in part, by a delayed increase in extracellular concentrations of GLU. In contrast, repeated administration of MDMA, at a dose which produced a long-term (7 day) depletion of striatal 5-HT content, had no effect on GLU efflux in the striatum.     

Neonatal 3,4-methylenedioxymethamphetamine (ecstasy) alters dopamine and serotonin neurochemistry and increases brain-derived neurotrophic factor in the forebrain and brainstem of the rat

Growing concerns surround the risk of fetal exposure to 3,4-methylenedioxymethamphetamine (MDMA; ecstasy). Prior animal studies using neonatal rats administered MDMA from postnatal days (P) 11-20 (a period approximating third trimester brain development in humans) have demonstrated long-lasting decrements in serotonin (5-HT) and learning; however, no studies have examined the acute post-MDMA response of the brain at this early age. Specifically, it is of interest whether MDMA administration to neonatal rats produces the expected depletion of monoamines and whether the brain exhibits any ameliorative response to the pharmacologic insult. In the current study, this model was employed to determine whether forebrain and brainstem dopamine (DA) and 5-HT neurochemistry were altered 24 h after the last injection (P21), and whether brain-derived neurotrophic factor (BDNF) was upregulated in response to MDMA exposure. All forebrain structures examined (frontal cortex, hippocampus, and striatum) showed significant MDMA-induced reductions in 5-HT and its metabolite, 5-HIAA, and significant increases in the DA metabolite, HVA, as well as DA turnover (HVA/DA). In the brainstem, there were significant increases in 5-HIAA, HVA and DA turnover. BDNF was significantly increased (19-38%) in all forebrain structures and in the brainstem in MDMA-exposed neonates versus saline controls. These data suggest that MDMA exposure to the developing rat brain from P11-20 produces similar alterations in serotonin and dopamine neurochemistry to those observed from adult administrations. In addition, a compensatory increase in BDNF was observed and may be the brains ameliorative response to minimize MDMA effects. This is the first report demonstrating that MDMA exposure results in increased levels of BDNF and that such increases are correlated with changes in monoamine levels. Future research is needed to elucidate any deleterious effects MDMA-induced increases in trophic activity might have on the developing brain and to examine earlier gestational exposure periods in order to assess the risk throughout pregnancy.     

Site-specific activation of dopamine and serotonin transmission by aniracetam in the mesocorticolimbic pathway of rats

The effects of aniracetam on extracellular levels of dopamine (DA), serotonin (5-HT) and their metabolites were examined in five brain regions in freely moving stroke-prone spontaneously hypertensive rats (SHRSP) using in vivo microdialysis. Basal DA release in SHRSP was uniformly lower in all regions tested than that in age-matched control Wistar Kyoto rats. 3,4-Dihydroxyphenylacetic acid and homovanillic acid levels were altered in the basolateral amygdala, dorsal hippocampus and prefrontal cortex of SHRSP. While basal 5-HT release decreased in the striatum and increased in the basolateral amygdala, there was no associated change in 5-hydroxyindoleacetic acid levels. Systemic administration of aniracetam to SHRSP enhanced both DA and 5-HT release with partly associated change in their metabolite levels in the prefrontal cortex, basolateral amygdala and dorsal hippocampus, but not in the striatum and nucleus accumbens shell, in a dose-dependent manner (30 and/or 100 mg/kg p.o.). Microinjection (1 and 10 ng) of aniracetam or its metabolites (N-anisoyl-GABA and 2-pyrrolidinone) into the nucleus accumbens shell produced no turning behavior. These findings indicate that SHRSP have a dopaminergic hypofunction throughout the brain and that aniracetam elicits a site-specific activation in mesocorticolimbic dopaminergic and serotonergic pathways in SHRSP, possibly via nicotinic acetylcholine receptors in the ventral tegmental area and raphe nuclei. The physiological roles in the aniracetam-sensitive brain regions may closely link with their clinical efficacy towards emotional disturbances appearing after cerebral infarction.     

Prenatal lipopolysaccharide exposure increases anxiety-like behaviors and enhances stress-induced corticosterone responses in adult rats

Maternal infection during pregnancy may affect fetal brain development and lead to neurological and mental disorders. Previously, we used lipopolysaccharide [LPS, 33 μg/kg, intraperitoneal injection] exposure on gestation day 10.5 to mimic maternal bacterial infection in rats and found reduced dopaminergic and serotoninergic neurons in the offspring. In the present study, we examined the anxiety and stress responses of the affected offspring and the neurophysiological changes in their brains. Our results show that LPS rats displayed more anxiety-like behaviors and heightened stress responses. Dopamine (DA) in the nucleus accumbens and serotonin (5-HT) in the medial prefrontal cortex and the hippocampus were significantly reduced in LPS rats. Their glucocorticoid receptors in the dorsal hippocampus and the 5-HT(1A) receptors in the dorsal and ventral hippocampus were also reduced. In addition, chronic but not acute fluoxetine treatment reversed the behavioral changes and increased hippocampal 5-HT(1A) receptor expression. This study demonstrates that LPS exposure during a critical time of embryonic development could produce long-term reduction of DA and 5-HT and other neurophysiological changes; such alterations may be associated with the increases in stress response and anxiety-like behaviors in the offspring.     

Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice

MDMA (3,4-methylenedioxymethamphetamine) is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA acts at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) and is known to induce damage of dopamine and serotonin neurons. MDMA is often ingested with caffeine. Caffeine as a non-selective adenosine A1/A2A receptor antagonist affects dopaminergic and serotonergic transmissions. The aim of the present study was to determine the changes in DA and 5-HT release in the mouse striatum induced by MDMA and caffeine after their chronic administration. To find out whether caffeine aggravates MDMA neurotoxicity, the content of DA and 5-HT, density of brain DAT and SERT, and oxidative damage of nuclear DNA were determined. Furthermore, the effect of caffeine on MDMA-induced changes in striatal dynorphin and enkephalin and on behavior was assessed. The DA and 5-HT release was determined with in vivo microdialysis, and the monoamine contents were measured by HPLC with electrochemical detection. DNA damage was assayed with the alkaline comet assay. DAT and SERT densities were determined by immunohistochemistry, while prodynorphin (PDYN) and proenkephalin were determined by quantitative PCR reactions. The behavioral changes were measured by the open-field (OF) test and novel object recognition (NOR) test. Caffeine potentiated MDMA-induced DA release while inhibiting 5-HT release in the mouse striatum. Caffeine also exacerbated the oxidative damage of nuclear DNA induced by MDMA but diminished DAT decrease in the striatum and worsened a decrease in SERT density produced by MDMA in the frontal cortex. Neither the striatal PDYN expression, increased by MDMA, nor exploratory and locomotor activities of mice, decreased by MDMA, were affected by caffeine. The exploration of novel object in the NOR test was diminished by MDMA and caffeine. Our data provide evidence that long-term caffeine administration has a powerful influence on functions of dopaminergic and serotonergic neurons in the mouse brain and on neurotoxic effects evoked by MDMA.     

Acute and long-term effects of 17beta-estradiol on G(i/o) coupled neurotransmitter receptor function in the female rat brain as assessed by agonist-stimulated [35S]GTPgammaS binding

Estrogens exert effects on mood, mental state, memory and other central nervous system (CNS) functions by modulating neurotransmitter receptor systems in the brain. Studies were designed to investigate the effect of 17beta-estradiol (E(2)) on agonist-stimulated [35S]GTPgammaS binding in membranes to assess the first step in the intracellular signal transduction cascade in a functional assay following: (1) an acute, one-time bolus subcutaneous injection, or (2) 14-day continuous exposure by a slow-release pellet implanted subcutaneously. In rats treated with E(2) acutely, the maximal response produced by activation of serotonin(1A) (5-HT(1A)) receptors was decreased approximately 25% in the hippocampus, cortex, and amygdala. Similarly, acute E(2) administration desensitized 5-HT(1B) and GABA(B) receptors in hypothalamus and cerebellum, respectively, and cannabinoid receptors in hippocampus and cortex. Although the maximal responses were decreased, acute E(2) treatment did not alter the EC(50) of any of the aforementioned receptors. The incubation of membranes prepared from the cortex of ovariectomized (OVX) rats with E(2) (1 microM) in vitro did not alter 5-HT(1A) or cannabinoid receptor-mediated [35S]GTPgammaS binding. By contrast to acute treatment in vivo, 14-day E(2) administration to OVX rats did not alter the maximal responses produced by activation of 5-HT(1A), 5-HT(1B), GABA(B), or cannabinoid receptors in any of the brain regions examined. Thus, it is concluded that acute E(2) administration in vivo modulates multiple G(i/o) coupled receptors in various regions of the female rat brain. Because these effects are observed only in vivo, it is concluded that cytosolic, nuclear and/or extraneuronal factors are required.     

Prenatal 3,4-methylenedioxymethamphetamine (ecstasy) exposure induces long-term alterations in the dopaminergic and serotonergic functions in the rat

We investigated several aspects of the dopaminergic and serotonergic functions throughout brain development in rats prenatally exposed to MDMA ("ecstasy"). Pregnant rats were treated with MDMA (10 mg/kg s.c.) or saline from the 13th to the 20th day of gestation and studies were conducted on the progeny from both groups: (i) quantification of whole brain contents of DA, 5-HT and metabolites from the 14th day of embryonic life (E14) to weaning (21st day of postnatal life, P21); (ii) quantification of DA and 5-HT membrane transporters by autoradiography from E18 to adult age (P70); (iii) measurement of pharmacologically induced release of DA and 5-HT using microdialysis on adult (P70) freely moving rats; (iv) measurement of sucrose preference in adults (P70). Prenatally MDMA-exposed rats showed (i) a two-fold decrease of whole brain levels of 5-HT and 5-HIAA at P0; (ii) no effect on the DAT and SERT density; (iii) a strongly reduced pharmacologically induced release of DA and 5-HT at P70 in the striatum and hippocampus; and (iv) a significant 20% decrease in sucrose preference at P70. This study suggests that a prenatal exposure to MDMA induces transient and long-term neurochemical and behavioural modifications in dopaminergic and serotonergic functions.     

Behavioural and neurochemical responses evoked by repeated exposure to an elevated open platform

Increased psychophysiological resistance to chronic stress has been related to increased 5-HT release in the dorsal hippocampus. This study investigated the changes in 5-HT release and turnover in the hippocampus evoked by acute and repeated exposure to an inescapable stressor, an elevated open platform, and compared them to the changes evoked in the frontal cortex. Repeated exposure to this stressor results in habituation of the plasma corticosterone response to the test, with full habituation being observed after 20 trials. Repeated exposure to the stressor for 5 or 10 occasions increased 5-HT turnover in the hippocampus. By contrast, 5-HT turnover in frontal cortex was increased by acute exposure to the stressor. Microdialysis studies showed that acute stress increased 5-HT overflow in prefrontal cortex but not dorsal hippocampus whereas repeated daily (10 days) exposure to the stressor increased basal extracellular 5-HT in the dorsal hippocampus, but not the prefrontal cortex. Prior exposure to the stressor on up to 10 occasions enhanced the plasma corticosterone response to a challenge in an elevated plus-maze performed 24h later whereas repeated, but not acute, exposure to the stressor, elicited anxiolytic-like behavioural responses in this test. It is concluded that acute exposure to this form of inescapable stress selectively stimulates the 5-HT projections to the frontal cortex; repeated stress elicits a sustained increase in 5-HT release and turnover in the hippocampus. The data are consistent with the hypothesis that increased 5-HT release in the hippocampus may be implicated in the mechanisms underlying habituation to inescapable stress.     

Methamphetamine exposure during the preweanling period causes prolonged changes in dorsal striatal protein kinase A activity,dopamine D2-like binding sites,and dopamine content

Exposure to methamphetamine (METH) during the preweanling period produces few, if any, neurotoxic effects (using criteria established in adult rats), yet it has substantial long-term effects on a variety of behavioral measures (e.g., locomotor activity, acoustic startle response, and spatial learning). The purpose of the present study was to examine the long-term changes in dopaminergic functioning brought about by early METH exposure. Rats were injected with METH (10 mg/kg) or saline four times daily on postnatal days (PD) 11-20 and housed undisturbed until PD 90, at which time they were killed and their dorsal striata (i.e., caudate-putamen) were removed and frozen for assay. The ability of early METH exposure to alter protein kinase A (PKA) activity and dopamine (DA) D(2)-like binding sites, as well as DA and DOPAC content, were assessed. Results showed that METH exposure on PD 11-20 caused long-term reductions in all of the dopaminergic markers assayed. METH-induced reductions in DA content and D(2)-like receptors were observed. Some sex differences were apparent, as the METH-induced decreases in PKA activity and DOPAC content were more evident in male rats. In conclusion, preweanling METH exposure caused changes in DA markers that were still detectable at PD 90; however the magnitude of many of these effects (e.g., the reductions in DA and DOPAC levels) was substantially less than typically reported for rats treated with METH in adulthood. The ability of METH to cause long-term reductions in PKA activity may partially account for some of behavioral deficits exhibited by rats exposed to METH prior to weaning.     

The N-methyl-D-aspartate antagonist MK-801 protects against serotonin depletions induced by methamphetamine, 3,4-methylenedioxymethamphetamine and p-chloroamphetamine.

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 blocks the ability of D-methamphetamine (MA) to deplete striatal dopamine (DA). We now report that MK-801 attenuates decreases in serotonin (5-HT) concentration induced by MA and two other amphetamine analogues, 3,4-methylenedioxymethamphetamine (MDMA) and p-chloroamphetamine (PCA). Rats were injected with saline (1.0 ml/kg) or MK-801 (0.5, 1.0 or 2.5 mg/kg) followed by either saline (1.0 mg/kg), MA (4, 2 or 1 injection(s); 10.0, 20.0 or 40.0 mg/kg), MDMA (20.0 or 40.0 mg/kg) or PCA (5.0 or 10.0 mg/kg). In some experiments, two injections of MK-801 or saline were used. Seventy-two hours after the last injection rats were sacrificed and concentrations of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) and DA were determined in hippocampus and striatum. MA caused a depletion of 5-HT to 33% of control in hippocampus and to 50% of control in striatum after the 4 x 10.0 mg/kg dose regimen. When MK-801 (2.5 mg/kg) was co-administered with MA, concentrations of 5-HT did not differ from control levels in either brain region. MDMA depleted 5-HT to approximately 58% of control in hippocampus and 66% of control in striatum at the 40 mg/kg dose.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for a role of energy dysregulation in the MDMA-induced depletion of brain 5-HT

Although the exact mechanism involved in the long-term depletion of brain serotonin (5-HT) produced by substituted amphetamines is not completely known, evidence suggests that oxidative and/or bioenergetic stress may contribute to 3,4-methylenedioxymethamphetamine (MDMA)-induced 5-HT toxicity. In the present study, the effect of supplementing energy substrates was examined on the long-term depletion of striatal 5-HT and dopamine produced by the local perfusion of MDMA (100 microM) and malonate (100 mM) and the depletion of striatal and hippocampal 5-HT concentrations produced by the systemic administration of MDMA (10 mg/kg i.p. x4). The effect of systemic administration of MDMA on ATP levels in the striatum and hippocampus also was examined. Reverse dialysis of MDMA and malonate directly into the striatum resulted in a 55-70% reduction in striatal concentrations of 5-HT and dopamine, and these reductions were significantly attenuated when MDMA and malonate were co-perfused with nicotinamide (1 mM). Perfusion of nicotinamide or ubiquinone (100 microM) also attenuated the depletion of 5-HT in the striatum and hippocampus produced by the systemic administration of MDMA. Finally, the systemic administration of MDMA produced a 30% decrease in the concentration of ATP in the striatum and hippocampus. These results support the conclusion that MDMA produces a dysregulation of energy metabolism which contributes to the mechanism of MDMA-induced 5-HT neurotoxicity.     

In vitro autoradiography of serotonin 5-HT(2A/2C) receptor-activated G protein: guanosine-5'-(gamma-[(35)S]thio)triphosphate binding in rat brain

Agonist activation of G protein-coupled receptors induces an increase in the binding of guanosine 5'-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS); this increase in binding has been used as a tool to investigate receptor interaction with the heterotrimer guanine nucleotide-binding regulatory protein (G protein). The present study uses agonist-stimulated [(35)S]GTPgammaS binding to characterize serotonin 5-HT(2A/2C) receptors in rat brain membrane fractions and demonstrate the anatomical localization of the receptors by in vitro autoradiography on slide-mounted sections. The stimulatory effect of the agonist [1-(2,5-dimethoxy-4-iodophenyl)]-2 aminopropane (DOI) is compared to that of serotonin (5-HT). Autoradiography revealed a similar localization of DOI- and 5-HT-stimulated binding of [(35)S]GTPgammaS in distinct areas of prefrontal and parietal cortex, consistent with previously reported 5-HT(2A) receptor distribution. Specific binding was demonstrated in the frontal and parietal cortex, medial prefrontal, and cingular and orbital-insular areas as well as in the hippocampal formation, septal areas, the nucleus accumbens, and the choroid plexus. MDL 100105, a specific 5-HT(2A) antagonist, and ketanserin, an antagonist of 5-HT(2A/2C) receptors, blocked DOI stimulation in all labeled areas, whereas 5-HT stimulation was only partially blocked (70-80%). A small but significant inhibition was observed with the specific antagonist of 5-HT(2C/2B), SB 206553. This autoradiographic technique provides a useful tool for measuring in situ changes in specific receptor-Gq protein coupling in anatomically discrete brain regions, under physiological and pathological conditions.     

Prefrontal cortex,hippocampus, and basolateral amygdala plasticity in a rat model of autism spectrum

We aimed to investigate the effect of prenatal administration of valproic acid (VPA) (500 mg/kg) at embryonic day 12.5 on the anatomical properties of the prefrontal cortex, hippocampus, and basolateral amygdala, at three different ages: immediately after weaning (postnatal day 21 [PD21]), prepubertal (PD35), and postpubertal (PD70) ages in a rat model of autistic spectrum disorder. Quantitative analysis of the thickness of the prefrontal cortex revealed a reduced size at all study ages in the cingulate 1 area of the prefrontal cortex and CA1 of the dorsal hippocampus in prenatally exposed animals compared to controls. At the level of the basolateral amygdala, a reduction in the size was observed at PD35 and PD70 in the VPA group. In addition, a reduced thickness was observed in the prelimbic region of the prefrontal cortex in VPA animals at PD35. Interestingly, no differences in cortical thickness were observed between control and VPA animals in the infralimbic region of the prefrontal at any age. Our results suggest that prenatal exposure to VPA differentially alters cortical limbic regions anatomical parameters, with implication in the autistic spectrum disorder. Synapse 68:468–473, 2014 . © 2014 Wiley Periodicals, Inc.     

Effect of corticotropin releasing factor receptor 1 antagonist on extracellular norepinephrine, dopamine and serotonin in hippocampus and prefrontal cortex of rats in vivo

Corticotropin releasing factor (CRF) is a major mediator of adaptive responsiveness to stress. We measured changes in extracellular concentrations of catecholamine and indoleamines in freely moving rats in response to administration of CRF1 antagonist CP-154,526 by using in vivo microdialysis. Dialysis probes were placed stereotaxically in either the hippocampus or the prefrontal cortex. We examined the response in the hippocampus or the prefrontal cortex to 32.0 mg/kg i.p. administration of CP-154,526. CP-154,526 reduced the extracellular concentration of norepinephrine (NE) from 30 min to 180 min and 5-hydroxytryptamine (5-HT) from 30 min to 60 min after injection in the hippocampus. CP-154,526 did not remarkably change dopamine (DA). There were no significant differences between CP-154,526 and vehicle in NE, 5-HT and DA in the prefrontal cortex. The present results indicate that CRF1 receptor antagonist produced a decrease in dialysate concentration of NE and 5-HT, but not DA, in the hippocampus. These results suggest that the CRH-1 receptor antagonist suppresses the release of NE and 5-HT in the hippocampus.     

Direct effects of 3,4-methylenedioxymethamphetamine (MDMA) on serotonin or dopamine release and uptake in the caudate putamen, nucleus accumbens, substantia nigra pars reticulata, and the dorsal raphé nucleus slices

We examined the effects of pressure ejected 3, 4-methylenedioxymethamphetamine (MDMA) from a micropipette on direct chemically stimulated release, and on electrically stimulated serotonin (5-HT) or dopamine (DA) release in the caudate putamen (CPu), nucleus accumbens (NAc), substantia nigra pars reticulata (SNr), and the dorsal raphé nucleus (DRN) brain slices of rat, using fast cyclic voltammetry (FCV). MDMA is electroactive, oxidising at +1100 mV. When the anodic input waveform was reduced from +1.4 to +1.0 volt, MDMA was not electroactive. Using this waveform, pressure ejection of MDMA did not release 5-HT or DA in brain slices prepared from any of the nuclei studied. MDMA significantly potentiated electrically stimulated 5-HT release in the SNr and DA release in CPu. In the DRN or in the NAc, MDMA was without effect on peak electrically stimulated 5-HT or DA release. The rates of neurotransmitter uptake, expressed as t(1/2), were in all cases significantly decreased after MDMA. The results indicate that MDMA, unlike (+)amphetamine, is not as a releaser of DA or 5-HT, it is a potent inhibitor of both DA and 5-HT uptake.     

Selective changes in the contents of noradrenaline, dopamine and serotonin in rat brain areas during aging

This study examines the age-associated changes in noradrenaline (NA), dopamine (DA), 3,4-dihydroxyphenyl-acetic acid (DOPAC), serotonin (5-HT) and 5-hydroxy-3-indoleacetic acid (5-HIAA) in different brain areas of rats. DA and DOPAC concentrations in striatum increased at third month of age, remaining without significant variations until 12th month of age, and decreasing in 24-month-old rats. DA concentration dropped in hippocampus, amygdala and brainstem of 24-month-old-rats, whereas DOPAC levels decreased only in hippocampus. These changes suggest an age-dependent deficit of the dopaminergic system, presumably related to a reduced number/activity of DA nigrostriatal and mesolimbic neurons. An age-induced decline in NA content was found in the pons-medulla, the area containing NA neuronal bodies. Concentrations of 5-HT were reduced with aging in frontal cortex, showing a tendency to decrease in all brain areas examined. The increased 5-HIAA/5-HT ratio found in frontal cortex, amygdala and striatum suggests an age-related decreased synthesis and an accelerated 5-HT metabolism. The 5-HIAA content decreased in brainstem of the oldest rats. These findings point to a selective impairment of nigrostriatal and mesolimbic DA in aging rats, whereas reductions in NA were restricted to cell bodies region and 5-HT showed changes of different extent in areas of terminals and neuronal cell bodies.     

Regulation of serotonin-1A receptor function in inducible brain-derived neurotrophic factor knockout mice after administration of corticosterone.

BACKGROUND: We examined the effects of a forebrain-specific reduction in brain-derived neurotrophic factor (BDNF) on the regulation of serotonin-1A (5-HT1A) receptor function in serotonergic cell body areas as well as in limbic and cortical structures of mice chronically treated with corticosterone. METHODS: 5-HT1A receptor function, at the level of receptor-G protein interaction, was assessed with quantitative autoradiography of [35S]GTPgammaS binding stimulated by the 5-HT1A receptor agonist 8-OH-DPAT. 5-HT1A receptor number was assessed by measuring the binding of the antagonist radioligand [3H] WAY100635. RESULTS: We observed a significant attenuation of 5-HT1A receptor function, in the absence of a change in receptor number, in the dorsal hippocampus of BDNF knockout versus control mice. There was no difference between control and BDNF knockout mice in 5-HT1A receptor number or function in the dorsal or median raphe nuclei or medial prefrontal cortex or anterior cingulate cortex. Corticosterone treatment of control mice decreased 5-HT1A receptor function in the dorsal and median raphe but not in hippocampus or frontal cortical areas. The regulation of 5HT1A receptor number or function in the dorsal and median raphe by corticosterone was lost in BDNF knockout mice. CONCLUSIONS: Attenuation of BDNF expression in forebrain regions produces differential effects on distinct 5-HT1A receptor populations and on the regulation of these receptor populations by corticosterone.