5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study.

In this study, we have identified and characterized 5-HT₃-like receptors in the rat medial prefrontal cortex (mPFc), an area with a moderate density of 5-HT₃ binding sites, using the techniques of single unit recording and microiontophoresis. The microiontophoresis of the 5-HT₃ receptor agonist 3-methylserotonin (2-Me-5HT), similar to the action of 5-HT), produced a current-dependent (10–80 nA) suppression of the firing rate of both spontaneously active and glutamate (GLU)-activated (quiescent) mPFc cells. Phenylbiguanide (PBG), another 5-HT₃ receptor agonist, suppressed the firing rate of mPFc cells but was less effective compared to 2-Me-5HT. The continuous iontophoresis (10–20 min) of 1 M magnesium chloride markedly attenuated the suppressant effect produced by electrical stimulation of the ascending 5-HT pathway, but did not alter 2-Me-5HT's action, suggesting that the action of 2-Me-5HT is a direct one. The suppressant action of 2-Me-5HT on mPFc cells was blocked by a number of structurally diverse and selective 5-HT₃ antagonists, with a rank order of effectiveness as follows: JCS 205930=(±)-zacopride>granisetron=ondansetron= LY 278584 >MDL72222. Furthermore, the intravenous administration of(±)-zacopride antagonized the action of 2-Me-5HT and PBG on mPFc cells. In contrast to the effects of the 5-HT₃ receptors antagonists, other receptor antagonists such as metergoline (5-HT_1A,1B,1C,2), (±)-pindolol (5-HT_1A,1B,β), SCH 23390 (5-HT_1C,2, D1), 1-sulpiride (D2) or SR 95103 (GABA_A) failed to block 2-Me-5HT's action. These results combined suggest that 2-Me-5HT's suppressive action on mPFc cells is mediated directly by 5-HT₃-like receptors.     

Electrophysiological evidence for a functional interaction between 5-HT1A and 5-HT2A receptors in the rat medial prefrontal cortex: An lontophoretic study

In this study, we examined the interaction of 5-HT_1A and 5-HT_2A receptors in the rat medial prefrontal cortex (mPFc) using the techniques of extracellular single unit recording and microiontophoresis. The iontophoresis of the selective 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced a current-dependent suppression (2.5-20 nA) of the basal firing rate of spontaneously active mPFc cells. The iontophoretic (5-10 nA) and systemic administration (0.1-0.5 mg/kg, i.v. ) of the 5-HT_2A/5-HT_2C receptor antagonist ritanserin and the selective 5 HT_2A receptor antagonist MDL 28727 significantly potentiated and prolonged 8-OHDPATs suppressant action. In addition, the systemic administration of another selective 5-HT_2A antagonist MDL 100907, but not its less active enantiomer MDL 100009, also potentiated and prolonged 8-OHDPATs action. The potentiating effect of the 5-HT_2A receptor antagonists on the action of 8-OHDPAT is specific in that neither the iontophoresis of ritanserin nor MDL 28727 altered the suppressant action produced by the iontophoresis of the 5-HT₃ receptor agonist 2-methylserotonin onto mPFc cells. Moreover, the suppressant action of 8-OHDPAT was not altered by the systemic administration of the selective 5-HT₃ receptor antagonist granisetron (0.1-0.5 mg/kg, i.v.). On the other hand, the iontophoresis of a low current (0.5 nA) of the 5-HT_2A,2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) potentiated the excitation induced by the iontophoresis of 1-glutamate on quiescent mPFc cells. The iontophoresis of 8-OHD-PAT at a current that had no effect on the firing rate of 1-glutamate activated when administered alone significantly attenuated the excitatory action produced by the iontophoresis of DOI. Overall these results confirm and extend the hypothesis that there is an interaction between 5-HT_1A and 5-HT_2A receptors in the mPFc at the neuronal level. © 1994 Wiley-Liss, Inc.     

Local infusion of the serotonin antagonists ritanserin or ICS 205,930 increases in vivo dopamine release in the rat medial prefrontal cortex

Previous research has indicated that atypical antipsychotic drugs like clozapine preferentially increase dopamine (DA) release from the mesocortical, relative to the nigrostriatal, system. While these drugs generally have weak affinity for the D2 receptor subtype, they are potent antagonists of the 5-hydroxytryptamine₂ (5-HT2) receptor. Research into neurotransmitter interactions indicates that 5-HT modulates DA release, but the nature of this interaction may depend upon the specific 5-HT receptor subtype and the neuronal location of that subtype. The present research tested the hypothesis that 5-HT2 receptors localized near mesocortical DA nerve terminals regulate DA release. This was accomplished by infusing the specific 5-HT2 antagonist ritanserin directly into the medial prefrontal cortex through reverse dialysis in vivo in the rat. Cortical extracellular fluid was then extracted by microdialysis and DA was subsequently assayed by HPLC with electrochemical detection. These results were compared to the systemic administration of ritanserin (1.0–5.0 mg/kg i.p.) and the local application of ICS 205,930, an antagonist at the 5-HT3/4 receptor subtypes. Both 5-HT antagonists increased cortical DA levels when infused locally at concentrations of 100 μM (12 nmoles/60 min), and these results were concentration-dependent. Systemically administered ritanserin also dose-dependently increased cortical DA efflux. These results indicate that atypical antipsychotic drugs may increase mesocortical DA release by antagonizing 5-HT receptors located in the prefrontal cortex. Furthermore, 5-HT may normally inhibit cortical DA release by actions at the 5-HT2 receptor subtype. © 1996 Wiley-Liss, Inc.     

Inhibition of NMDA-receptor mediated response in the rat medial prefrontal cortical pyramidal cells by the 5-HT3 receptor agonist SR 57227A and 5-HT: Intracellular studies

The techniques of intracellular recording and single-electrode voltage-clamp were used to study the effect of serotonin (5-HT) and the selective 5-HT₃ receptor agonist SR 57227A on N-methyl-D-aspartic acid (NMDA)-evoked responses in pyramidal cells of the rat medial prefrontal cortex (mPFC) in in vitro brain slice preparations. Bath application of 5-HT or SR 57227A produced a concentration-dependent inhibition of NMDA-induced membrane depolarization, action potentials, and inward current. The depressant action of 5-HT and SR 57227A had a slow onset and showed no signs of receptor desensitization. This action was markedly attenuated or completely blocked by the selective 5-HT₃ receptor antagonists granisetron and BRL 46470A, but not other receptor antagonists. In addition to inhibiting NMDA-evoked responses, SR 57227A also depressed significantly pharmacologically isolated, NMDA receptor-mediated, monosynaptic excitatory postsynaptic currents (EPSCs) elicited by electrical stimulation of the forceps minor; this inhibitory action was blocked by BRL 46470A but not other 5-HT receptor antagonists. Perfusion of Ca²⁺-free or low Ca²⁺ plus Cd²⁺ artificial cerebrospinal fluid prevented electrical stimulation-induced EPSCs, but did not affect the inhibitory action of 5-HT and SR 57227A. In conclusion, we demonstrate for the first time that 5-HT and SR 57227A interact with 5-HT₃-like receptors to produce a direct inhibitory action on NMDA receptor-mediated response in pyramidal cells of the mPFC. Synapse 29:257–268, 1998. © 1998 Wiley-Liss, Inc.     

Comparison of the effects of various typical and atypical antipsychotic drugs on the suppressant action of 2-methylserotonin on medial prefrontal cortical cells in the rat.

In this study, we report the effects of various typical and atypical antipsychotic drugs (APDs) on the suppressant action of microiontophoretically applied 2-methylserotonin (2-Me-5HT, a 5-HT3 agonist) on medial prefrontal cortical (mPFc) cells. The microiontophoresis of 2-Me-5HT (10-80 nA) produced a current-dependent suppression of mPFc cells' firing, and this effect was blocked by various 5-HT3 antagonists. The microiontophoresis of the atypical APDs clozapine and a structurally related compound, RMI 81,582, mimicked the action of the 5-HT3 antagonists. In addition, the intravenous administration of clozapine and RMI 81,582 antagonized the suppressant action produced by the iontophoretic application of 2-Me-5HT on mPFc cells. However, the suppressant action of 2-Me-5HT was not blocked by the typical APDs haloperidol and chlorpromazine. The putative atypical APDs risperidone, setoperone, CL 77328, SCH 23390, CGS 10746B, 1-sulpiride, and thioridazine were ineffective in antagonizing 2-Me-5HT's action. Overall, our results suggest that the majority of putative atypical APDs do not interact with 5-HT3 binding sites in the brain. Whether the interaction of clozapine and RMI 81,582 with 5-HT3 sites is correlated with their therapeutic efficacy or lower potential to induce neurological side effects remains to be determined.     

In vivo modulation of 5-hydroxytryptamine release in mouse prefrontal cortex by local 5-HT(2A) receptors: effect of antipsychotic drugs

In the rat, postsynaptic 5-hydroxytryptamine2A receptors medial prefrontal cortex control the activity of the serotonergic system through changes in the activity of pyramidal neurons projecting to the dorsal raphe nucleus. Here we extend these observations to mouse brain. The prefrontal cortex expresses abundant 5- hydroxytryptamine2A receptors, as assessed by immunohistochemistry, Western blots and in situ hybridization procedures. The application of the 5-hydroxytryptamine2A/2C agonist DOI (100 microm) by reverse dialysis in the medial prefrontal cortex doubled the local release of 5-hydroxytryptamine. This effect was reversed by coperfusion of tetrodotoxin, and by the selective 5-hydroxytryptamine2A receptor antagonist M100907, but not by the 5-hydroxytryptamine2C antagonist SB-242084. The effect of DOI was also reversed by prazosin (alpha1-adrenoceptor antagonist), BAY x 3702 (5-hydroxytryptamine1A receptor agonist), NBQX (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate/kainic acid antagonist) and 1S,3S-ACPD (mGluR II/III agonist), but not by dizocilpine (N-methyl-d-aspartate antagonist). alpha-Amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate mimicked the 5-hydroxytryptamine elevation produced by DOI, an effect also reversed by BAY x 3702. Likewise, the coperfusion of classical (chlorpromazine, haloperidol) and atypical antipsychotic drugs (clozapine, olanzapine) fully reversed the 5-hydroxytryptamine elevation induced by DOI. These observations suggest that DOI increases 5-hydroxytryptamine release in the mouse medial prefrontal cortex through the activation of local 5-hydroxytryptamine2A receptors by an impulse-dependent mechanism that involves/requires the activation of local alpha-amino-3-hydroxy-5-methyl-4-isoxazole-4-propionate receptors. This effect is reversed by ligands of receptors present in the medial prefrontal cortex, possibly in pyramidal neurons, which are involved in the action of antipsychotic drugs. In particular, the reversal by classical antipsychotics may involve blockade of alpha1-adrenoceptors, whereas that of atypical antipsychotics may involve 5-hydroxytryptamine2A receptors and alpha1-adrenoceptors.     

Different regulation of serotonin receptors following adrenal hormone imbalance in the rat hippocampus and hypothalamus

Summary Adrenal influence on serotonin (5-HT) transmission in the hippocampal and hypothalamic areas was studied in adrenalectomized rats receiving or not corticosterone replacement. After adrenalectomy, the 5-HT presynaptic receptors were desensitized both in hippocampus and hypothalamus: a significant increase in 5-HT 1 and 5-HT 2 receptor binding numbers took place in membranes from the hippocampus, but not in hypothalamus, while no changes in affinity of receptors to radioligands were observed in either brain area. Corticosterone treatment restored the adrenalectomy-impaired 5-HT autoreceptor sensitivity in hippocampus and hypothalamus and 5-HT density receptor sites in the hippocampus. Serotonin autoreceptor down-regulation following adrenalectomy may increase 5-HT release to maintain the constancy of serotonergic transmission in the brain and 5-HT modulated CRH-ACTH release to compensate the plasma corticosteroid drop. Corticosterone seems to display a distinct tonic control on serotonin transmission in both hippocampus and hypothalamus, the diversity being due to the different roles played by the hormone in these brain regions.     

LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex

Both the phenethylamine hallucinogen (-)-1-2, 5-dimethoxy-4-bromophenyl-2-aminopropane (DOB), a selective serotonin 5-HT2A,2C receptor agonist, and the indoleamine hallucinogen D-lysergic acid diethylamide (LSD, which binds to 5-HT1A, 1B, 1D, 1E, 1F, 2A, 2C, 5, 6, 7, dopamine D1 and D2, and alpha1 and alpha2 adrenergic receptors), but not their non-hallucinogenic congeners, inhibited N-methyl-D-aspartate (NMDA)-induced inward current and NMDA receptor-mediated synaptic responses evoked by electrical stimulation of the forceps minor in pyramidal cells of the prefrontal cortical slices. The inhibitory effect of hallucinogens was mimicked by 5-HT in the presence of selective 5-HT1A and 5-HT3 receptor antagonists. The inhibitory action of DOB, LSD and 5-HT on the NMDA transmission was blocked by the 5-HT2A receptor antagonists R-(+)-alpha-(2, 3-dimethoxyphenil)-1-[4-fluorophenylethyl]-4-piperidineme thanol (M100907) and ketanserin. However, at low concentrations, when both LSD and DOB by themselves only partially depressed the NMDA response, they blocked the inhibitory effect of 5-HT, suggesting a partial agonist action. Whereas N-(4-aminobutyl)-5-chloro-2-naphthalenesulphonamide (W-7, a calmodulin antagonist) and N-[2-[[[3-(4'-chlorophenyl)- 2-propenyl]methylamino]methyl]phenyl]-N-(2-hydroxyethyl)-4'-methoxy-b enzenesulphonamide phosphate (KN-93, a Ca2+/CaM-KII inhibitor), but not the negative control 2-[N-4'methoxybenzenesulphonyl]amino-N-(4'-chlorophenyl)-2-propeny l-N -methylbenzylamine phosphate (KN-92), blocked the inhibitory action of LSD and DOB, the selective protein kinase C inhibitor chelerythrine was without any effect. We conclude that phenethylamine and indoleamine hallucinogens may exert their hallucinogenic effect by interacting with 5-HT2A receptors via a Ca2+/CaM-KII-dependent signal transduction pathway as partial agonists and modulating the NMDA receptors-mediated sensory, perceptual, affective and cognitive processes.     

Apparent absence of serotonin1B receptors in biopsied and post-mortem human brain

In order to determine if post-mortem delays could account for the apparent absence of 5-HT1B sites reported in human brain, 5-HT1B binding parameters were determined in fresh and fresh-frozen cortical biopsies and compared to results obtained in post-mortem tissues. Binding parameters and in vitro receptor autoradiography were performed by using two different ligands which have been shown to label 5-HT1B sites, namely [3H]5-HT, in presence of 100 nM 8-OH-DPAT, and [125I]cyanopindolol, in presence of 10 microM (-)isoproterenol. No specific binding was detected with [125I] cyanopindolol in either fresh cortical biopsies or post-mortem tissues, suggesting that the apparent absence of 5-HT1B receptor sites reported earlier was not related to long post-mortem delays. Some specific labelling was seen with [3H]5-HT, in presence of 8-OH-DPAT. This binding, which is unlikely to be to the 5-HT1B type, could represent labelling to the 5-HT1D or 5-HT1E sites.     

Quipazine exacerbation of a hyperkinetic syndrome: involvement of brain dopamine and serotonin

Quipazine (5-25 mg.kg-1, s.c.) was given to rats in which a hyperkinetic syndrome had been previously induced by administration of beta,beta'-iminodipropionitrile (IDPN). Quipazine produced a significant increase in the circling behavior and choreiform head and neck movements, characteristic of the syndrome. This response could be blocked by pretreatment with the serotonin antagonists, SQ10, 631 (25 mg.kg-1, i.p.) and methysergide (5.0 mg.kg-1, i.p.), as well as the dopamine receptor antagonist, haloperidol (0.5 mg.kg-1, i.p.). These observations are discussed with respect to the nature of the involvement of brain serotonergic and dopaminergic systems in quipazine action on these hyperkinetic disturbances.     

Differential effects of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in rat medial prefrontal cortex

Cognitive functions regulated by the prefrontal cortex are sensitive to changes in dopaminergic and serotoninergic transmission. The non-competitive N-methyl-

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-aspartate (NMDA) receptor antagonist ketamine influences dopaminergic transmission and induces psychotic symptoms in normal and schizophrenic individuals. This study examined the effect of single and repeated ketamine (25 mg/kg, i.p.) administration on extracellular levels of dopamine, GABA and the serotonin metabolite 5-hydroxyindoleacetic (5-HIAA) acid in the medial prefrontal cortex using in vivo microdialysis in conscious rat. In line with earlier studies, we observed a transient five-fold increase in dopamine release following single ketamine administration in drug naive animals. However, we also observed a two-fold increase in basal dopamine levels and an almost complete attenuation of the ketamine-induced increase in dopamine release in animals pre-treated with ketamine once daily for 7 days. Extracellular 5-HIAA levels were increased by ketamine in both drug naive and even more enhanced in ketamine-pre-treated animals but without a change in basal 5-HIAA levels. GABA levels were unaffected by either single or repeated ketamine administration. We demonstrate evidence for a differential effect of single and repeated ketamine administration on dopamine, serotonin and GABA transmission in the medial prefrontal cortex. We provide new evidence for a complex adaptation of neurotransmission following repeated NMDA receptor blockade whereby in the presence of increased basal dopamine levels the ketamine-induced increase in dopamine is attenuated and the increase in 5-HIAA is enhanced. It appears from our results that ketamine pre-treatment reduces the dynamics of dopaminergic transmission in the prefrontal cortex and may possibly alter the balance between dopamine and serotonin transmission.     

Electrophysiological evidence for convergence of inputs from the medial prefrontal cortex and lateral habenula on single neurons in the dorsal raphe nucleus

Neuronal projections to the dorsal raphe nucleus (DRN) from the medial prefrontal cortex (mPFC) and lateral habenula nucleus (LHb) provide the two key routes by which information processed by mood regulatory, cortico-limbic-striatal circuits input into the 5-HT system. These two projections may converge as it appears that both activate local GABAergic neurons to inhibit 5-HT neurons in the DRN. Here we have tested this hypothesis by measuring the effect of stimulation of the mPFC and LHb on the activity of 5-HT and non-5-HT, putative gamma-amino butyric acid (GABA) neurons in the DRN using extracellular recordings in anaesthetized rats. A total of 119 5-HT neurons (regular, slow firing, broad spike width) and 21 non-5-HT, putative GABA neurons (fast-firing, narrow spike width) were tested. Electrical stimulation of the mPFC or LHb caused a poststimulus inhibition (30 ms latency) of 101/119 5-HT neurons, of which 61 (60%) were inhibited by both the mPFC and LHb. Electrical stimulation of the mPFC or LHb also caused a short latency (12-20 ms) poststimulus facilitation of 10/21 non-5-HT neurons, of which 5 (50%) were activated by both the mPFC and LHb. These data indicate that a significant number of 5-HT neurons and non-5-HT neurons in the DRN are influenced by both the mPFC and LHb. Moreover, the data are compatible with the hypothesis and that there is a convergence of mPFC and LHb inputs on local circuit GABAergic neurons in the DRN which in turn inhibit the activity of 5-HT neurons.     

5-HT1 receptors in migraine pathophysiology and treatment

Migraine is a frequent paroxysmal headache disorder of unknown aetiology. Genetic factors may control attack frequency and possibly attack severity. Serotonin_1D (5-HT_1Dβ) receptors have a prominent position within the final common pathway of the mechanisms involved in the headache and associated symptoms. Stimulation of these receptors by selective 5-HT_1Dβ receptor agonists such as sumatriptan and newer compounds including MK-462 and 311C90, rapidly and fully blocks the symptoms of the headache phase. The efficacy depends on factors such as timing of administration during or before the headache, speed of initial rise of drug plasma levels, and possibly degree of brain penetration. All agonists at S-HT_1Dβ receptors share a short duration of action resulting in recurrence of the headache symptoms within 24 h in about one-third of attacks in clinical trials. The risk for headache recurrence seems patient dependent: about 10% of patients treating multiple attacks experience headache recurrence in every treated attack, whereas 40% never experience recurrence. These differences are not related to simple pharmacokinetic differences between patients or drugs. Increasing plasma half-life of the drug will most likely not reduce the risk of recurrence. “Breakthrough of peripheral suppressive effect” with an ongoing “central migraine generator”, rather than the occurrence of a new attack, seems to be the most likely underlying mechanism for headache recurrence. In a minority of, possibly predisposed, patients, use of sumatriptan may induce increase of attack frequency. Four mechanisms have been suggested for the antimigraine action of 5-HT_1Dβ receptor agonists: (1) vasoconstriction of cranial, most likely meningeal and dural blood vessels; (2) inhibition of release of vasoactive neuropeptides from perivascular trigeminal nerve terminals within dura mater and meninges; (3) blockade of trigeminal nerve terminal depolarization; and (4) central inhibition within the trigeminal nucleus caudatus in the brainstem. Which of these mechanisms is the most important, and whether or not vasoconstrictor action is necessary for antimigraine efficacy, is currently under extensive investigation. At this point all drugs with proven antimigraine efficacy share the ability to contract blood vessels and thus all feature also the potential risk of causing vasoconstriction of coronary vessels. In relation herewith, major efforts are put into the search for “the antimigraine receptor” and which receptor subtype mediates which action of sumatriptan-like drugs. At this point, the 5-HT_1Dβ receptor subtype is thought to mediate vasoconstriction. Some investigators feel that the 5-HT_1Dα receptor subtype mediates the neuronal effects of sumatriptan, while others are much less convinced about the physiological role of this subtype of receptor. Further research into receptor subtype specificity and affinity of compounds may promote the development of even better antimigraine drugs.     

Serotonin release in human cerebral cortex and its modulation via serotonin receptors

Human cerebral cortex slices were prepared from brain tissue which had to be removed in order to gain access to deep-seated tumours. Subsequent to incubation with [3H]serotonin, the slices were superfused with physiological salt solution containing paroxetine, and 3H overflow was evoked by electrical field stimulation. The evoked tritium overflow (86% of which was accounted for by unmetabolized [3H]serotonin) was abolished by tetrodotoxin or omission of calcium from the superfusion fluid. Unlabelled serotonin decreased, and the serotonin receptor antagonist metitepin increased, the evoked overflow. The inhibition produced by serotonin was antagonized by metitepin. It is concluded that serotonin release in human cerebral cortex is modulated by inhibitory serotonin receptors, which may be localized presynaptically on the serotoninergic nerve fibers themselves. There are marked similarities between human and rat brain cortex with respect to action potential-induced, Ca2+-dependent serotonin release and its modulation via serotonin receptors.     

Differential involvement of rat medial prefrontal cortex dopamine receptors in modulation of hypothalamic-pituitary-adrenal axis responses to different stressors

Recent investigations have implicated the medial prefrontal cortex (mPFC) in modulation of subcortical pathways that contribute to the generation of behavioural, autonomic and endocrine responses to stress. However, little is known of the mechanisms involved. One of the key neurotransmitters involved in mPFC function is dopamine, and we therefore aimed, in this investigation, to examine the role of mPFC dopamine in response to stress in Wistar rats. In this regard, we infused dopamine antagonists SCH23390 or sulpiride into the mPFC via retrodialysis. We then examined changes in numbers of cells expressing the c-fos immediate-early gene protein product, Fos, in subcortical neuronal populations associated with regulation of hypothalamic-pituitary-adrenal (HPA) axis stress responses in response to either of two stressors; systemic injection of interleukin-1 beta, or air puff. The D1 antagonist, SCH23390, and the D2 antagonist, sulpiride, both attenuated expression of Fos in the medial parvocellular hypothalamic paraventricular nucleus (mpPVN) corticotropin-releasing factor cells at the apex of the HPA axis, as well as in most extra-hypothalamic brain regions examined in response to interleukin-1 beta. By contrast, SCH23390 failed to affect Fos expression in response to air puff in any brain region examined, while sulpiride resulted in an attenuation of the air puff-induced response in only the mpPVN and the bed nucleus of the stria terminalis. These results indicate that the mPFC differentially processes the response to different stressors and that the two types of dopamine receptor may have different roles.     

Dopamine and 5-HT turnover are increased by the mGlu2/3 receptor agonist LY379268 in rat medial prefrontal cortex, nucleus accumbens and striatum

We have shown, using in vivo microdialysis sampling, that systemic administration of the selective group II metabotropic (mGlu) receptor agonist LY379268, like the atypical antipsychotic clozapine, increased extracellular levels of dopamine, dopamine metabolites DOPAC and HVA, and the major 5-HT metabolite 5-HIAA, in rat medial prefrontal cortex (mPFC). Here, we have compared the effects of LY379268 with clozapine as well as risperidone on ex vivo tissue levels of dopamine, DOPAC, HVA, 5-HT and 5-HIAA in multiple brain regions. One to two hours following administration of LY379268, mPFC tissue levels of DOPAC, HVA and 5-HIAA were increased in a dose-dependent manner. Increases evoked by LY379268 (10 mg/kg s.c.) at the 2 h point were 189, 245 and 139% of basal levels, respectively. These effects were reversed within 4 h of administration. Clozapine (10 mg/kg s.c.) and risperidone (1 mg/kg s. c.) also increased levels of the dopamine metabolites to a similar extent but were without significant effect on tissue levels of 5-HIAA. LY379268 (10 mg/kg s.c.) also increased tissue levels of DOPAC, HVA and 5-HIAA by 169, 221 and 134% of basal levels in nucleus accumbens, respectively, and by 131, 179 and 132% of basal levels in striatum, respectively. These data show that activation of mGlu2/3 receptors can increase the turnover of dopamine and 5-HT in the areas of the brain implicated in the actions of atypical antipsychotics.     

Regional studies of serotonin and dopamine metabolism and quantification of serotonin uptake sites in human cerebral cortex

Summary An increasing number of studies have indicated that neuronal metabolism of serotonin (5-HT) and other monoamines may be altered in patients with affective disorders and in completed suicides. However, studies have yielded discordant results. The purpose of this study was to determine the regional variation of 5-hydroxyindolacetic acid (5-HIAA), homovanillic acid (HVA), (5-HT) and 5-HT uptake sites within the human cerebral cortex.Our sample consisted of 19 patients who died suddenly and accidently. Cortical concentrations of 5-HIAA, HVA and 5-HT were measured in six regions using an HPLC. 5-HT uptake sites in cortex were examined using [³H] Paroxetine.5-HT values within each brain were fairly constant in cortical regions studied except for the posterior parietal areas. By contrast, 5-HIAA values showed a trend towards a rostro-caudal increase, with peak values seen at sections corresponding to the post-central gyrus and the occipital pole. Using the ratio of 5-HIAA/5-HT as a crude index of 5-HT turnover, there was a progressive rostro-caudal increase of values which achieved statistical significance: the posterior superior parietal area and the occipital pole displayed a greater ratio than the other four cortical regions. HVA values were highest in the pre-central region and decreased both rostrally and caudally. 5-HIAA and HVA values were correlated positively in 5 of 6 cortical areas, while 5-HIAA and 5-HT were correlated in areas 4 and 5. Results obtaining using [³H]-Paroxetine suggest that 5-HT uptake sites in the human cortex are distributed rather uniformally and are not correlated with 5-HT levels.     

Regulation of corticosteroid receptors in the rat brain: the role of serotonin and stress

It has been suggested that physiological resistance to repeated stress is associated with increased 5-hydroxytryptamine (5-HT) release in the dorsal hippocampus and that dysregulation of this neuroadaptation may be implicated in the psychopathology of depression. This study used 5,7-dihydroxytryptamine lesions to investigate the role of 5-HT projections to the hippocampus in physiological responses to repeated stress and putative changes in corticosteroid receptor immunoreactivity in the brain. Repeated exposure to elevated open platform stress (1 h/day) caused regionally selective changes in glucocorticoid and mineralocorticoid receptor immunoreactivity in the dorsal hippocampus that were not observed in ventral hippocampus, frontal cortex, hypothalamus or parietal cortex. Glucocorticoid receptor immunoreactivity in the dorsal hippocampus was decreased after 5 days but increased after 20 days of stress. Mineralocorticoid receptor immunoreactivity was increased after 5 or 10 days of stress. The increases in glucocorticoid and mineralocorticoid receptor immunoreactivity, evoked by repeated stress, were abolished by lesions of the principal 5-HT projections to the hippocampus. The lesions abolished the increased defecation observed in stressed animals, but had no effects on the plasma corticosterone response to the stressor or the habituation of this response observed following repeated stress. The experiments have revealed a dissociation in the regulation of corticosteroid receptor expression in the dorsal and ventral hippocampus by repeated stress and 5-HT. The data suggest that adaptation to inescapable stress is associated with regionally selective changes in corticosteroid receptor expression in dorsal hippocampus that are largely 5-HT-dependent, although these changes do not mediate habituation of the pituitary adrenocortical response to the stressor.