Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats

The serotonin (5-HT)(2A/2c) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 microl/side and was inhibited by the 5-HT2A antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT(2C/2B) antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50 of 1.5 nmoles/0.5 microl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A receptors. Pretreatment of rats with the 5-HT1A agonist (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1A receptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A receptors.     

Tryptophan pretreatment augmentation of p-chloroamphetamine-induced serotonin and dopamine release and reduction of long-term neurotoxicity

The impact of tryptophan (TRP) pretreatment on the neurochemical effects of p-chloroamphetamine (PCA) was investigated. The neurotoxic effects of PCA on serotonin (5-HT) neurons, the acute effects of PCA on extracellular 5-HT and dopamine (DA), and the displacement by PCA of whole blood 5-HT were examined. TRP pretreatment (400 mg/kg of the methyl ester) significantly reduced the long-term (1 week) decrease in tissue 5-HT resulting from PCA (2 mg/kg, i.p., of the hydrochloride salt) in the prefrontal cortex and striatum, but not in the dorsal hippocampus. Microdialysis studies in awake animals showed that this pretreatment regimen resulted in augmented PCA-induced increases in extracellular 5-HT (4-fold) and DA (2-fold). TRP pretreatment also resulted in increased displacement of 5-HT from whole blood. The implications of these results toward possible mechanisms of action of PCA-induced neurotoxicity are discussed.     

In vivo assessment of basal and drug-induced dopamine release in cortical and subcortical regions of the anesthetized primate

There is an acute interest in studying the functional characteristics of dopamine systems in the cortex of primates. In particular, the prefrontal cortical dopamine projections have received a great deal of attention. This system is essential for proper functioning of the prefrontal cortex, and dysfunction within the system may be involved in some psychiatric and neurological illnesses. In vivo assessments of cortical dopamine in the primate have been scarce. This has been due, in part, to technical difficulties associated with these studies and with quantifying the relatively low levels of dopamine found in cortical regions. In the present study, intracerebral microdialysis was utilized to assess the extracellular concentration of dopamine in cortical and subcortical areas of the pentobarbital-anesthetized rhesus monkey. Basal extracellular dopamine levels were consistently detected in the medial prefrontal cortex, premotor cortex, and caudate-putamen. The basal extracellular concentration of dopamine in the dorsolateral prefrontal cortex was reliably detected in 1 of 4 animals. Intravenous administration of amphetamine (1 mg/kg) enhanced extracellular dopamine levels in the caudate-putamen area by more than 20-fold. In cortical areas, amphetamine's effect was less profound: An increase of 400-500 percent over basal extracellular dopamine levels was observed in each region. These studies demonstrate the feasibility of microdialysis for detecting extracellular fluxes of dopamine in the cortex of nonhuman primates. They further provide direct evidence that the dopamine released within the prefrontal cortex and the premotor cortex of nonhuman primates responds to pharmacological manipulation.     

Evidence that an OX-2-positive cell can inhibit the stimulation of type 1 cytokine production by bone marrow-derived B7-1 (and B7-2)-positive dendritic cells

The present study was designed to compare the effects of typical and atypical antipsychotic drugs on extracellular dopamine (DA) levels in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis with dual probe implantation in awake, freely moving rats. Amperozide (2 and 10 mg/kg), clozapine (5 and 20 mg/kg), and olanzapine (10 mg/kg), all of which are atypical antipsychotics, produced greater increases in extracellular DA levels in the mPFC than in the NAC. Olanzapine (1 mg/kg), risperidone (0.1 and 1 mg/kg), also an atypical antipsychotic, and S-(-)-sulpiride (25 mg/kg), a typical antipsychotic, produced comparable increases in extracellular DA levels in the mPFC and the NAC. S-(-)-sulpiride (10 mg/kg) and haloperidol (0.1 and 1 mg/kg), another typical antipsychotic, significantly increased extracellular DA levels in the NAC but not in the mPFC. The effects of the six antipsychotic drugs to increase extracellular DA levels in the mPFC relative to those in the NAC was positively correlated with the difference between their pKi values for serotonin (5-hydroxytryptamine, 5-HT2A) and DA-D2 receptors and was inversely correlated to their pKi values for D2 or D3 receptors, but was not for 5-HT2A receptors alone. These results are consistent with the hypothesis that the ability of antipsychotic drugs to produce a greater increase in prefrontal compared with NAC extracellular DA levels may be related, in part, to weak D2 and D3 receptor affinity relative to 5-HT2A receptor antagonism.     

5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus

5-Hydroxytryptamine (5-HT; serotonin) administration enhances GABAergic synaptic activity recorded in pyramidal neurons of the CA1 region of hippocampus. Previous studies have attributed this effect to the activation of HT-5(3) receptors located on GABAergic interneurons. During unrelated experiments, we noticed that under our recording conditions, 5-HT can still increase GABAergic synaptic activity after the complete blockade of 5-HT3 receptors. This indicated the involvement of an additional 5-HT receptor subtype. Therefore, we reinvestigated the effects of 5-HT on GABAergic synaptic activity recorded in pyramidal cells of the CA1 region. The ability of 5-HT to increase GABAergic synaptic activity in the presence of 5-HT3 receptor blockade was mimicked by the selective 5-HT2 agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane and blocked by the selective 5-HT2 antagonist ketanserin. This indicated that the additional 5-HT receptor belongs to 5-HT2 receptor family. 5-HT2 receptor activation resulted in an increase in the frequency of spontaneous inhibitory postsynaptic currents as well as a shift in their amplitude distribution toward larger sizes. These effects were absent in the presence of tetrodotoxin. We interpret these results to indicate that 5-HT2 receptors activate GABAergic interneurons in the slice, leading to an increase in GABAergic synaptic activity onto pyramidal cells of the CA1 region.     

BIMG 80, a novel potential antipsychotic drug: evidence for multireceptor actions and preferential release of dopamine in prefrontal cortex

In radioligand binding studies, BIMG 80, a new putative antipsychotic, displayed good affinity at certain serotonin (5-HT1A, 5-HT2A, 5-HT6), dopamine (D1, D2L, D4), and noradrenergic (alpha1) receptors. The effect of acute subcutaneous BIMG 80, clozapine, haloperidol, risperidone, amperozide, olanzapine, and Seroquel was then investigated on dopamine release in medial prefrontal cortex, nucleus accumbens, and striatum in freely moving rats using the microdialysis technique. Four different neurochemical profiles resulted from the studies: (a) Systemic administration of BIMG 80, clozapine, and amperozide produced greater percent increases in dopamine efflux in medial prefrontal cortex than in the striatum or the nucleus accumbens. (b) Haloperidol induced a similar increase in dopamine concentrations in the striatum and nucleus accumbens with no effect in the medial prefrontal cortex. (c) Risperidone and olanzapine stimulated dopamine release to a similar extent in all brain regions investigated. (d) Seroquel failed to change significantly dopamine output both in the medial prefrontal cortex and in the striatum. Because an increase in dopamine release in the medial prefrontal cortex may be predictive of effectiveness in treating negative symptoms and in the striatum may be predictive of induction of extrapyramidal side effects, BIMG 80 appears to be a potential antipsychotic compound active on negative symptoms of schizophrenia with a low incidence of extrapyramidal side effects.     

Hippocampal interneurons are excited via serotonin-gated ion channels

Hippocampal interneurons are excited via serotonin-gated ion channels. J. Neurophysiol. 78: 2493-2502, 1997. Serotonergic neurons of the median raphe nucleus heavily innervate hippocampal GABAergic interneurons located in stratum radiatum of area CA1, suggesting that this strong subcortical projection may modulate interneuron excitability. Using whole cell patch-clamp recording from interneurons in brain slices, we tested the effects of serotonin (5-HT) on the physiological properties of these interneurons. Serotonin produces a rapid inward current that persists when synaptic transmission is blocked by tetrodotoxin and cobalt, and is unaffected by ionotropic glutamate and gamma-aminobutyric acid (GABA) receptor antagonists. The 5-HT-induced current was independent of G-protein activation. Pharmacological evidence indicates that 5-HT directly excites these interneurons through activation of 5-HT3 receptors. At membrane potentials negative to -55 mV, the current-voltage (I-V) relationship of the 5-HT current displays a region of negative slope conductance. Therefore the response of interneurons to 5-HT strongly depends on membrane potential and increases greatly as cells are depolarized. Removal of extracellular calcium, but not magnesium, increases the amplitude of 5-HT-induced currents and removes the region of negative slope conductance, thereby linearizing the I-V relationship. The axons of 5-HT-responsive interneurons ramify widely within CA1; some of these interneurons also project to and arborize extensively in the dentate gyrus. The organization of these inhibitory connections strongly suggests that these cells regulate excitability of both CA1 pyramidal cells and dentate granule cells. As our results indicate that 5-HT may mediate fast excitatory synaptic transmission onto these interneurons, serotonergic inputs can simultaneously modulate the output of both hippocampus and dentate gyrus.     

Characterization of the phencyclidine-induced increase in prefrontal cortical dopamine metabolism in the rat

1. We have investigated the effects of a schizophrenomimetic drug phencyclidine (PCP) and N-methyl-D-aspartate (NMDA)-related agents alone or in combination on dopamine metabolism in the medial prefrontal cortex and striatum of the rats by measuring the tissue concentrations of dopamine and its metabolite, 3,4-dihyroxyphenylacetic acid (DOPAC), and the rate of dopamine disappearance (dopamine utilization) after its synthesis inhibition. 2. Systemic injection of PCP and selective, non-competitive, NMDA antagonists caused an increase of both tissue concentrations of DOPAC and dopamine utilization in the prefrontal cortex but not in the striatum. The PCP-induced augmentation of cortical dopamine metabolism was not influenced by selective lesion of ascending noradrenergic neurones. 3. Intra-prefrontal cortical infusion of PCP or selective competitive or non-competitive antagonists of the NMDA receptor mimicked the ability of systemic PCP injection to enhance DOPAC levels and dopamine utilization in the prefrontal cortex. However, an NMDA antagonist injected into the cell body area of the mesocortical dopaminergic neurones failed to affect dopamine metabolism in the prefrontal cortex. 4. The increasing effects of PCP and selective NMDA antagonists on cortical dopamine utilization were not additive, although a dopamine receptor antagonist, haloperidol, still accelerated the disappearance of dopamine, even in the presence of PCP. 5. Intra-cortical or intra-ventricular infusion of NMDA or D-alanine but not L-alanine, attenuated the ability of systemic PCP administration to facilitate prefrontal dopamine utilization. 6. These data suggest that PCP might activate prefrontal cortical dopaminergic neurones, at least in part, by blocking the NMDA receptor in the prefrontal cortex which participates in a tonic inhibitory control of the mesoprefrontal dopaminergic projections.     

The role of cortical serotonin in anxiety and locomotor activity in Wistar rats.

The brain's serotonergic system is known to play an important role in the modulation of anxiety. While the role of serotonin (5-HT) in subcortical structures is well investigated, little is known about the function of cortical 5-HT. The present series of studies used local injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the medial prefrontal cortex (mPFC), entorhinal cortex (EC), or occipital cortex (OccC) of rats to chronically reduce 5-HT neurotransmission in these brain areas. The animals were tested for anxiety-like behavior on the elevated plus-maze and open field. An 82% depletion of 5-HT from the mPFC increased anxiety-like behavior, while no general motor effects were evident. In contrast, a 63% 5-HT-depletion of the EC or a 78% 5-HT-depletion of the OccC did not have any effects on emotional or exploratory behaviors. These findings are in line with a proposed role of 5-HT in the mPFC in the modulation of anxiety- and stress-mediated behavior and demonstrate a functional differentiation between different cortical 5-HT projections. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Methamphetamines pretreatment and the vulnerability of the striatum to methamphetamine neurotoxicity

Pretreatment with intermittent low-dose administrations of stimulants increases mesostriatal dopamine transmission upon administration of a challenge dose. This occurs without evidence of a long-term dopamine or serotonin depletion. The purpose was to examine whether pretreatment with low doses of methamphetamine enhances dopamine and/or glutamate efflux and the subsequent depletion of dopamine and serotonin produced by neurotoxic challenge doses of methamphetamine. Microdialysis was used to measure simultaneously extracellular concentrations of dopamine and glutamate in the striatum and prefrontal cortex of awake rats. Basal extracellular concentrations of dopamine and glutamate were unaltered following pretreatment with methamphetamine. The increase in methamphetamine-induced striatal dopamine efflux was not significantly different between methamphetamine and saline pretreated groups. In contrast, after high challenge doses of methamphetamine, dopamine efflux in prefrontal cortex was enhanced to a greater extent in methamphetamine pretreated rats as compared to saline pretreated controls. Acute methamphetamine did not enhance glutamate efflux in prefrontal cortex after pretreatment with saline or methamphetamine. The increase in striatal glutamate efflux was blunted in rats pretreated with methamphetamine. When measured 4 days later, dopamine and serotonin content in striatum was depleted in all rats acutely challenged with methamphetamine. However, these depletions were attenuated in rats pretreated with methamphetamine. An acute methamphetamine challenge did not affect dopamine tissue content in the prefrontal cortex of any rats. Serotonin content in cortex was depleted in all groups following the methamphetamine challenge administration, but these depletions were diminished in methamphetamine-pretreated rats. These results are the first evidence that an intermittent pretreatment regimen with low doses of methamphetamine, followed by a 1 week withdrawal, reduces the vulnerability of striatal dopamine and serotonin terminals and cortical serotonin terminals to methamphetamine neurotoxicity. These findings provide evidence for the mechanism leading to methamphetamine neurotoxicity.     

Serotonin 5-HT2C agonists selectively inhibit morphine-induced dopamine efflux in the nucleus accumbens

In vivo microdialysis was used to compare the effects of serotonergic drugs on morphine- and cocaine-induced increases in extracellular dopamine (DA) concentrations in the rat nucleus accumbens (NAc). Systemic administration of the 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg, s.c. ) prevented the increase in extracellular DA in the NAc produced by morphine (5 mg/kg, i.p.). In contrast, this dose of DOI had no effect on the ability of cocaine (10 mg/kg, i.p.) to increase extracellular DA concentrations in the NAc. A 5-HT2C selective agonist, 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212, 5 mg/kg, s.c.) also inhibited morphine-induced increases in extracellular DA concentrations in the NAc. Pretreatment of rats with the selective 5-HT2A antagonist, amperozide, had no effect on morphine-induced elevation of NAc DA concentrations. In order to determine if inhibition of the firing of 5-HT neurons contributes to the serotonin agonist-mediated inhibition of morphine-induced accumbens DA release, rats were pretreated with the 5-HT1A agonist, 8-OHDPAT. At a dose of 100 microg/kg (sc), 8-OHDPAT did not interfere with morphine's ability to increase DA concentrations in the NAc. These results suggest that the activation of 5-HT2C receptors selectively inhibits morphine-induced DA release in the NAc in a manner which is independent of the inhibition of 5-HT neurons.     

Synaptic density of the prefrontal cortex regulated by dopamine instead of serotonin in rats

Recent findings indicate that monoamine contributes to synaptic plasticity. We examined the synaptic density of the prefrontal cortex and parietal cortex of rats using dopamine (DA) antagonists and agonists, as well as serotonin (5-HT) depleters and found a reduction in synaptic density in the prefrontal cortex lamina V-VI at a maximum of 20% with administration of a D1 antagonist (SCH23390) and at a maximum of 30% with a D2 antagonist (YM09151). Further, with the administration of D1+D2 antagonists there was a 27% decrease in synaptic density, which was a larger reduction than the total of the single dosages of each DA antagonist at equal levels. Increase in synaptic density was seen at a maximum of 8.5% with dosage of a D1 agonist (SKF38390) and 14.5% with dosage of a D2 agonist (PPHT). The dosage of D1+D2 agonists showed a 27.1% increase in synaptic density. There was no change in synaptic density of the parietal cortex with either DA antagonist or agonist administration. Administration of 5-HT depleter pCPA resulted in a 13.8% reduction of synaptic density in the parietal cortex, though there was no change identified in the synaptic density in the prefrontal cortex. Based on these results, it was suggested that the area of the brain with affected synaptic plasticity could differ, depending on the type of monoamine.     

A microdialysis study of the effects of the nicotinic agonist RJR-2403 on cortical release of acetylcholine and biogenic amines

Transcortical dialysis was employed to investigate the effects of subcutaneous (s.c.) injections of RJR-2403 (1.2-7.2 mumol/kg) on extracellular levels of acetylcholine (ACh), norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in rat. Systemic administration of RJR-2403 produced a 90% increase of cortical extracellular ACh levels that persisted for up to 90 minutes after injection. Norepinephrine and DA release were increased 124% and 131% above basal values, respectively. Serotonin (5-HT) levels in the dialysate were also significantly elevated by RJR-2403 (3.6 mumol/kg, s.c.) 70% above baseline at 90 minutes post-injection. Comparison of these responses to those of (-)nicotine from a previous study reveals little difference between the two compounds in their ability to influence cortical neurotransmitter release following systemic administration.     

Localization of bovine corneal protein 54K (BCP 54) in the prenatal mouse eye

Electrophysiological studies have suggested that a subpopulation of interneurons near the border of layer II and III in rat piriform cortex are excited by serotonin (5-hydroxytryptamine; 5-HT) via 5-HT2A (formerly 5-HT2) rather than 5-HT2C (formerly 5-HT1C) receptors. However, the pharmacological agents used in those studies were limited in specificity. In the present study, we tested a new, highly selective 5-HT2A receptor antagonist MDL 100,907 (R-(+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl-ethyl)]-4- piperidine-methanol, which has a 300-fold greater affinity for 5-HT2A than 5-HT1C receptors or alpha 1-adrenoceptors) on excitatory responses of interneurons to 5-HT in rat piriform cortex slices. We observed a parallel, reversible rightward shift in the 5-HT concentration-response curve in the presence of 1-10 nM concentrations of MDL 100,907. Schild regression analysis resulted in a slope of 1.13 and a Kd value of 1.17 which is close to the published Ki value of 0.36 for MDL 100,907. These data confirm that 5-HT2A rather than 5-HT2C receptors mediate excitation by 5-HT of interneurons in the piriform cortex. Because of its rapid equilibration and reversibility, MDL 100,907 appears to be an excellent tool for studies of 5-HT2A receptor function in the brain.     

Effect of repeated methamphetamine administrations on dopamine and glutamate efflux in rat prefrontal cortex

Pretreatment with psychostimulants such as methamphetamine (METH) results in augmented mesostriatal dopamine transmission upon a challenge administration of the drug. This effect can be blocked by dopamine antagonists and excitatory amino acid antagonists. However, no direct comparisons have been made with respect to the effects of a low-dose pretreatment regimen of METH on impulse and transporter-mediated dopamine release or to what extent glutamate release is altered by a pretreatment regimen with METH. The purpose of this study was to examine dopamine and glutamate efflux in the prefrontal cortex and striatum in rats pretreated with METH following either high potassium (80 microM) infusion or after a systemic injection of a low dose of METH. Extracellular dopamine and glutamate concentrations in the prefrontal cortex and striatum were measured in vivo by microdialysis. Potassium infusion increased extracellular dopamine and glutamate concentrations to a greater extent in the prefrontal cortex than in the striatum of METH-pretreated rats compared to saline-pretreated controls. A low dose METH challenge significantly increased extracellular dopamine but not glutamate concentrations in both prefrontal cortex and striatum of all animals. Moreover, the acute METH-induced increased in cortical dopamine efflux was significantly greater in rats pretreated with METH. Overall, these data are the first evidence that repeated METH administrations can enhance cortical glutamate efflux and indicate that a low dose pretreatment regimen of METH enhances dopamine transmission in the prefrontal cortex through both transporter and depolarization-induced mechanisms.     

Systemic PCP treatment elevates brain extracellular 5-HT: a microdialysis study in awake rats

THE NMDA receptor antagonist phencyclidine (PCP) has low micromolar affinity for the 5-HT reuptake site, but it is uncertain whether PCP blocks 5-HT reuptake when given systemically to rats in behaviourally stimulating doses. We here report for the first time that systemically administered PCP (5 mg/kg, s.c.) increases extracellular 5-HT levels in the rat medial prefrontal cortex (to 322%) and dorsal hippocampus (to 233%). Increases were found also when citalopram (1 microM) was included in the perfusion medium (to 184 and 180%, respectively). Extracellular 5-HIAA concentrations increased during both conditions, and extracellular GABA decreased in the dorsal hippocampus. It is concluded that systemic PCP treatment elevates extracellular 5-HT levels, probably through mechanisms other than a blockade of 5-HT reuptake.     

Amplification of tumor immunity by gene transfer of the co-stimulatory 4-1BB ligand: synergy with the CD28 co-stimulatory pathway

The superficial cells of the entorhinal cortex (EC), main input to the hippocampus, receive a serotonergic input from the raphe nuclei and express 5-hydroxytryptamine creatine sulfate complex (5-HT) receptors at high density. With the use of intracellular recordings, we investigated the effects of serotonin on synaptic inhibition of layer II and III neurons of the EC. Serotonin reduced both polysynaptic fast and slow inhibitory postsynaptic potentials (IPSPs) in projection neurons of the superficial EC. Polysynaptic fast and slow IPSPs were depressed by serotonin in a dose-dependent manner (0.1-100 microM). Serotonin in a concentration of 1 microM reduced the amplitudes of polysynaptic fast and slow IPSPs by approximately 40 and 50%, respectively. To identify the subtype of the 5-HT-receptor mediating the effects on polysynaptic IPSPs, we applied various 5-HT-receptor agonists and antagonists. Although the serotonin agonists for the 5-HT1B,2C,3 receptors were ineffective, the effects were mimicked by the 5-HT1A-receptor agonists (8-OH-DPAT, 5-CT) and prevented by the 5-HT1A-receptor antagonist NAN-190. To look at the direct effects of 5-HT on inhibitory interneurons, we elicited monosynaptic IPSPs in the absence of excitatory synaptic transmission. In contrast to the polysynaptic IPSPs, monosynaptic IPSPs were not significantly affected by serotonin. Recordings from putative inhibitory interneurons revealed that their excitatory postsynaptic potentials (EPSPs) were reversibly reduced by serotonin. We conclude that serotonin suppresses polysynaptic inhibition in projection neurons of layers II and III of the EC by depression of EPSPs on inhibitory interneurons via 5-HT1A receptors.     

Effect of acetylsalicylic acid on formalin test and on serotonin system in the rat brain

1. Acetylsalicylic acid (ASA; 400 mg/kg, i.p.) increased serotonin (5-HT) content in rat brain but did not modify the number or the affinity of 5-HT1A receptors in the pons and the cerebral cortex, whereas the number of cortical 5-HT2 receptors decreased significantly. 2. Pretreatment with parachlorophenylaline (100 mg/kg/day for 4 days) depleted 5-HT brain content but modified neither the serum levels of salicylates nor the 5-HT2 cortical receptor characteristics, and it abolished the antinociceptive effect of ASA, 400 mg/kg, in the first phase of the formalin test. 3. These data support the involvement of the central serotonergic system in the antinociceptive activity of ASA.     

Long-term alterations in regional brain serotonin metabolism following maternal polychlorinated biphenyl exposure in the rat

Pregnant Wistar WU rats were administered PCBs (0, 5 or 25 mg Aroclor 1254 per kg body weight) by gavage on day 10 to 16 of gestation. Levels of biogenic amines were measured in the lateral olfactory tract, prefrontal cortex, striatum, hippocampus and hypothalamus in male and female offspring 21 and 90 days after birth. 5-Hydroxyindole acetic acid (5-HIAA) concentrations and the ratio of 5-HIAA/5-hydroxytryptamine (5-HT, serotonin) were significantly increased in the lateral olfactory tract, prefrontal cortex and hippocampus on postnatal day 90 in male and female offspring following maternal PCB treatment. No effects were observed on regional brain levels of dopamine, 3,4-dihydroxyphenylacetic acid, norepinephrine and homovanillic acid. The results indicate that pre- and postnatal exposure to Aroclor 1254 results in regionally specific long-term alterations in the serotonergic system.