The acute and chronic administration of the 5-HT(2B/2C) receptor antagonist SB-200646A significantly alters the activity of spontaneously active midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

This study examined the effect of the acute and chronic administration of the 5-HT(2B/2C) receptor antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride (SB-200646A) on the activity of spontaneously active DA cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using in vivo extracellular single cell recording. The i.v. administration of 4-16 mg/kg of SB-200646A significantly increased the firing rate and % events as bursts in spontaneously active VTA DA neurons and significantly increased the % events as burst in SNC DA neurons. The acute i.p. administration of 20 and 40 mg/kg of SB-200646A significantly increased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The acute administration of 10 mg/kg of SB-200646A significantly increased the coefficient of variation in spontaneously active SNC and DA neurons when compared with vehicle-treated controls. However, the acute i.p. administration of 20 mg/kg of SB-200646A significantly decreased the degree of bursting of VTA DA neurons. Similary, chronic i.p. administration of 10 mg/kg of SB-200646 did not significantly alter firing, whereas chronic administration of 20 mg/kg of SB-200646A or 20 mg/kg of clozapine significantly decreased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The SB-200646A-induced decrease in the number of spontaneously active VTA DA neurons was reversed by the i.v. administration of (+)-apomorphine or (-)-baclofen. The chronic i.p. administration of either 10 or 20 mg/kg of SB-200646A did not significantly alter the firing pattern of spontaneously active SNC DA neurons. However, the chronic administration of 20 mg/kg of SB-200646A significantly increased the degree of bursting in VTA DA neurons when compared with vehicle. Overall, the acute and chronic administration of SB-200646A produces in vivo electrophysiological effects, resembling that of atypical antipsychotic drugs.     

Effect of the acute and chronic administration of the selective 5-HT6 receptor antagonist SB-271046 on the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and repeated per os (p.o.) administration of the selective 5-HT(6) receptor antagonist SB-271046, on the number, as well as the firing pattern of spontaneously active dopamine (DA) neurons in the rat substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized male Sprague-Dawley rats. This was accomplished using the technique of extracellular in vivo electrophysiology. A single p.o. administration of either 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active SNC DA neurons per stereotaxic electrode tract compared to vehicle-treated animals. The acute administration of either 1 or 3 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons. In contrast, a significant decrease in the number of spontaneously active VTA DA neurons was observed after a single administration of 10 mg/kg of SB-271046 compared to vehicle-treated animals. The acute p.o. administration of SB-271046 significantly altered the firing pattern parameters of all (bursting + nonbursting DA neurons) DA neurons, particularly those in the VTA, compared to vehicle-treated animals. The repeated p.o. administration (once per day for 21 days) of 1, 3, or 10 mg/kg of SB-271046 did not significantly alter the number of spontaneously active VTA DA neurons compared to vehicle-treated animals. The repeated administration of 3 or 10 mg/kg of SB-271046 significantly increased the number of spontaneously active SNC DA neurons compared to vehicle controls. Overall, the repeated administration of SB-271046 had relatively little effect on the firing pattern of midbrain DA neurons. The results obtained following the chronic administration of SB-271046 show that this compound has a profile different from that of typical or atypical antipsychotic drugs in this model. Clinical studies are required to understand what role 5-HT(6) receptor blockade might eventually play in the treatment of schizophrenia.     

Acute and chronic administration of the selective 5-HT1A receptor antagonist WAY-405 significantly alters the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

In this study, we examined the effect of the acute and chronic administration of WAY-405, a selective 5-HT(1A) receptor antagonist, on the number and firing pattern of spontaneously active substantia nigra pars compacta (A9) and ventral tegmental area (A10) dopamine (DA) neurons in anesthetized rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of WAY-405 (5-640 microg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active A9 and A10 DA neurons. A single injection of 10 microg/kg of WAY-405 decreased the number of spontaneously active A10 DA neurons and the 100 microg/kg dose significantly decreased the number of spontaneously active A9 and A10 DA neurons compared to vehicle-treated animals. A single injection of 1, 10, or 100 microg/kg of WAY-405 significantly decreased the degree of bursting of A10 DA neurons. In contrast, 1 microg/kg i.p. of WAY-405 significantly increased the percent of A9 DA neurons exhibiting a bursting pattern. The repeated administration of 10 or 100 microg/kg i.p. of WAY-405 (21 days) significantly decreased the number of spontaneously active DA neurons in both the A9 and A10 compared to vehicle-treated animals and this decrease was not reversed by i.v. (+)-apomorphine. The repeated administration of WAY-405 significantly altered the firing pattern of DA neurons, particularly those in the A10 area. Overall, these results indicate that the antagonism of the 5-HT(1A) receptor significantly alters the activity of midbrain DA neurons in anesthetized rats.     

Effect of the acute and chronic administration of the selective neurokinin2 receptor antagonist SR 48968 on midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

In this study, we examined the effect of the acute and chronic administration of the selective neurokinin₂ (NK₂) receptor antagonist SR 48968 on the activity of spontaneously active dopamine (DA) cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male rats. This was accomplished using the technique of in vivo, extracellular single cell recording. The intravenous (i.v.) administration of SR 48968 (10–1280 μg/kg) did not significantly alter the basal firing rate or pattern of either spontaneously active SNC or VTA DA neurons compared to control. However, the acute administration of 1 mg/kg, i.p., of SR 48968, but not its inactive enantiomer SR 48965, produced a significant increase in the number of spontaneously active DA cells in the SNC (48%) and VTA (28%) compared to vehicle controls. The i.p. administration of SR 48968 did not alter the basal firing pattern of either SNC or VTA DA neurons compared to vehicle controls. The pretreatment of animals with 1 mg/kg, i.p., of SR 48968 significantly potentiated the suppressant action of (+)-apomorphine on spontaneously active SNC and VTA DA cells. In contrast to its acute effects, the administration of 1 mg/kg, i.p., of SR 48968 once daily for 21 days produced a significant decrease in the number of spontaneously active DA cells in the SNC and VTA. The decrease in the number of spontaneously active VTA DA cells was not reversed by (+)-apomorphine administration; in fact, a further decrease in the number of VTA DA cells was observed. This suggests that the SR 48968-induced decrease in the number of spontaneously active DA neurons may not be the result of depolarization block. Overall, these results suggest that the acute and chronic administration of SR 48968 alters the number of spontaneously active midbrain DA neurons in anesthetized rats. Synapse 25:196–204, 1997. © 1997 Wiley-Liss, Inc.     

5-HT6 receptor antagonist SB-271046 enhances extracellular levels of monoamines in the rat medial prefrontal cortex

The present study investigated the neurochemical effects of the selective 5-HT(6) receptor antagonist SB-271046 in the rat medial prefrontal cortex (mPFC). The effect of SB-271046 on extracellular levels of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the mPFC was examined using in vivo microdialysis in the freely moving rat. SB-271046 (10 mg/kg, p.o.) produced a significant increase in extracellular levels of both DA and NE without altering 5-HT neurotransmission. These results further support the rationale for the use of 5-HT(6) receptor antagonists in the treatment of cognitive dysfunction associated with psychiatric diseases.     

Direct activation by dopamine of recombinant human 5-HT1A receptors: comparison with human 5-HT2C and 5-HT3 receptors

The effects of dopamine (DA) on the function of human 5-HT1A receptors expressed in Xenopus oocytes and CHO-K1 cells were investigated. In addition, the effect of DA on the activation of three different types of human 5-HT receptors (5-HT1A, 5-HT2C, and 5-HT3) were studied comparatively in Xenopus oocyte expression system. Application of 5-HT or DA in oocytes coexpressing 5-HT1A receptors and G-protein-activated inwardly rectifying potassium channels (GIRK1) induced inward currents with respective EC50 values of 4.2 nM and 11.2 microM. Maximal responses induced by DA were 85 +/- 4% of maximal 5-HT currents and DA responses were blocked by the specific 5-HT1A antagonist, WAY-100635 (50 nM). In CHO-K1 cells expressing 5-HT1A receptors, 5-HT and DA inhibited the specific binding of selective antagonist [3H]-8-OH-DPAT with IC50 values of 10.2 nM and 1.4 microM, and both 5-HT and DA inhibited the forskolin-induced accumulation of cAMP. In oocytes expressing 5-HT2C receptors, 5-HT and DA induced inward currents with respective EC50 values of 6.2 nM and 67.7 microM. Magnitudes of maximal DA induced currents were 42 +/- 3% of maximal 5-HT responses and blocked by the 5-HT2 antagonist, piperazine (1 microM). In oocytes expressing 5-HT3 receptors, 5-HT and DA induced fast inward currents with respective EC50 values of 2.1 microM and 266.3 microM. Maximal DA induced currents were 37 +/- 3% of maximal 5-HT responses and blocked the specific 5-HT3 antagonist LY-278584 (0.1 microM). Comparison of the potencies and efficacies of 5-HT and DA indicated that the relative potency of DA increased in the order of 5-HT3 > 5-HT1A > 5-HT2C, and relative efficacy increased in the order of 5-HT1A > 5-HT2C > 5-HT3. These results suggest that although DA activates different subtypes of human 5-HT receptors directly, the potency and efficacy of the binding site varies significantly among different receptors.     

Acute and repeated administration of the selective 5-HT(2A) receptor antagonist M100907 significantly alters the activity of midbrain dopamine neurons: an in vivo electrophysiological study

We examined the effect of the acute and repeated administration of M100907 (formerly MDL 100907), a selective 5-HT(2A) receptor antagonist, on spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) of rats. This was accomplished using in vivo, extracellular single unit recording. The i.v. administration of M100907 (0.01-0.64 mg/kg) did not significantly alter the basal firing rate or pattern of spontaneously active SNC and VTA DA neurons. A single injection of either 0.01 or 0.03 mg/kg i.p. of M100907 did not significantly alter the number of spontaneously active DA neurons in either the SNC or VTA areas. However, 0.1 mg/kg i.p. of M100907 significantly increased the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. A single injection of all doses of M100907 significantly decreased the degree of bursting in VTA DA neurons, whereas the 0.1 mg/kg dose increased the degree of bursting in SNC DA neurons. The repeated administration (one injection per day for 21 days) of 0.03 and 0.1 mg/kg i.p. of M100907 produced a significant decrease in the number of spontaneously active SNC and VTA DA neurons compared to vehicle-treated animals. The repeated administration of M100907 did not significantly alter the firing pattern of VTA DA neurons but significantly altered the firing pattern of SNC DA neurons. The results of this study indicate that M100907 administration alters the activity of midbrain DA neurons in anesthetized rats.     

The effect of the acute and chronic administration of CP 96,345, a selective neurokinin1 receptor antagonist,on midbrain dopamine neurons in the rat: A single unit,extracellular recording study

In this study, we examined the effect of acute and chronic administration of the selective neurokinin₁ receptor antagonist CP 96,345 on the basal activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and the ventral tegmental area (VTA). This was accomplished using the technique of in vivo, extracellular single unit recording in anesthetized rats. The intravenous (i.v.) administration of CP 96,345 (0.01–1.28 mg/kg) did not significantly alter the firing rate of spontaneously active DA neurons in the SNC and VTA areas. The acute administration of 5 or 10 mg/kg, i.p., of CP 96,345 produced a significant decrease in the number of spontaneously active SNC and VTA dopamine cells compared to vehicle-treated rats. In contrast to its effect on the number of spontaneously active DA neurons, the administration of 5 mg/kg, i.p., of CP 96,345 did not significantly alter the basal firing pattern of either SNC or VTA DA neurons. The acute administration of CP 96,345 (10 mg/kg, i.p.) significantly potentiated the suppressant action of (+)-apomorphine on the basal firing rate of spontaneously active SNC and VTA DA cells. The chronic administration of CP 96,345 (5 or 10 mg/kg, i.p.) for 21 days also produced a significant decrease in the number of spontaneously active SNC and VTA DA cells compared to vehicle controls. This effect was not reversed by the systemic administration of (+)-apomorphine (50 μg/kg, i.v.), suggesting that the reduction in the number of spontaneously active DA cells produced by CP 96,345 is probably not the result of depolarization inactivation. Overall, our results indicate that the tonic activation of NK₁ receptors by substance P may be necessary to maintain the spontaneous activity of a proportion of midbrain DA neurons. © 1996 Wiley-Liss, Inc.     

The acute and chronic administration of (+/-)-8-hydroxy-2-(Di-n-propylamino)tetralin significantly alters the activity of spontaneously active midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and chronic systemic administration of (+/-)-8-Hydroxy-2-(Di-n-propylamino)Tetralin(8-OH-DPAT) on the number and firing pattern of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA or A10) and substantia nigra pars compacta (SNC or A9) in anesthetized male rats. These parameters were measured using extracellular in vivo electrophysiology. A single s.c. injection of 0.01, 0.1, or 1 mg/kg of 8-OH-DPAT did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals (controls). The acute administration of 0.01 or 0.1 mg/kg of 8-OH-DPAT did not significantly alter, whereas the 1 mg/kg dose significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The acute administration of 8-OH-DPAT significantly increased the percentage of VTA DA neurons firing in a bursting pattern. In contrast, there was a significant decrease in the percentage of SNC DA neurons firing in a bursting pattern following the acute administration of 8-OH-DPAT. The number of spontaneously active SNC DA neurons was not significantly altered by the chronic s.c. administration of 8-OH-DPAT (0.01, 0.1, or 1 mg/kg s.c.) as compared to controls. However, the chronic s.c. administration of all doses of 8-OH-DPAT significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The i.v. administration of (+)-apomorphine (50 microg/kg) did not reverse the 8-OH-DPAT-induced decrease in the number of spontaneously active VTA DA neurons, suggesting that this effect is unlikely due to depolarization blockade. The percentage of VTA DA neurons exhibiting burst firing was significantly increased by 0.01 and 0.1 mg/kg, but significantly decreased by 1 mg/kg of 8-OH-DPAT. Overall, the systemic administration of 8-OH-DPAT preferentially affects the activity of spontaneously active A10 DA neurons in rats.     

Dopamine neurotransmission is involved in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute methamphetamine-induced locomotor hyperactivity in mice

We have previously shown that 5-HT3 receptors are involved in the development and expression of methamphetamine (MAP)-induced locomotor sensitization in mice. In the present study, we further examined whether the dopaminergic system is involved in the attenuating effects of MDL 72222, a 5-HT3 receptor antagonist, on acute MAP-induced locomotor hyperactivity. For this, we examined alterations of dopamine (DA) in the form of D1 receptor, D2 receptor, and dopamine transporter (DAT) binding labeled with [3H]SCH23390 for D1, [3H]raclopride for D2, and [3H]mazindol for DAT binding in the mouse brains with acute MAP exposure or pretreatment of MDL 72222 with MAP. No significant differences were detected in the D1 receptor, D2 receptor, or DAT binding between any of the groups studied. Interestingly, we found increased DA levels in the striatum following acute MAP exposure; these increased levels were reversed by pretreatment with MDL 72222, but did not affect 5-HT levels in the dorsal raphe. Overall, our results suggest that dopamine neurotransmission plays an important role in the attenuating effects of 5-HT3 receptor antagonist MDL 72222 on acute MAP-induced locomotor hyperactivity in mice.     

Acute and repeated administration of fluoxetine, citalopram, and paroxetine significantly alters the activity of midbrain dopamine neurons in rats: an in vivo electrophysiological study

We examined the effect of the administration of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, citalopram, and paroxetine on the activity of spontaneously active dopamine (DA) neurons in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized adult male Sprague-Dawley rats. This was accomplished using the technique of in vivo extracellular recording. A single injection of 2.5 mg/kg (i.p.) of fluoxetine significantly increased the number of spontaneously active SNC and VTA DA neurons. In contrast, a single injection of either 1 mg/kg (i.p.) of paroxetine or 5 mg/kg of fluoxetine significantly increased the number of spontaneously active VTA DA neurons. The repeated administration (one injection per day for 21 days) of all of the SSRIs produced a significant increase in the number of spontaneously active VTA DA neurons. Overall, our results indicate that the systemic administration of SSRI alters the activity of midbrain DA neurons with differential effects on VTA compared with SNC DA neurons.     

Depression of mGluR-mediated IPSCs by 5-HT in dopamine neurons of the rat substantia nigra pars compacta

Dopamine neurons of the substantia nigra pars compacta receive a prominent serotonin (5-HT) projection from the dorsal raphe nucleus and important functional interactions between the serotonergic and the dopaminergic system have been postulated. In the present report we examined the role of 5-HT in the modulation of the metabotropic glutamate receptor-mediated inhibitory postsynaptic current (mGluR-IPSC) in midbrain dopamine neurons, and we found a reversible depression of this synaptic response at concentrations of 5-HT ranging from 100 nm to 30 microm (EC50 1.06 microm). This resulted in a shift towards excitation of the overall dopamine neuron response to glutamatergic synaptic input. This effect was not because of a direct modulation of the Ca2+-sensitive K+ conductances underlying the mGluR-IPSC, but was associated with a decrease in the intracellular calcium signal triggered by mGluR stimulation. Similar results were obtained with alpha-methyl-5-hydroxytryptamine and 5-methoxytryptamine, but not with 5-carboxamidotryptamine or 1-(3-chlorophenyl) piperazine. No significant depression of the mGluR-IPSC by 5-HT was observed in the presence of the 5-HT2 antagonist cinanserin or the 5-HT4 receptor antagonist RS 23597-190, whereas the 5-HT2C antagonist RS 102221 was ineffective. Our results demonstrate a powerful inhibition of the mGluR-IPSC by 5-HT in midbrain dopamine neurons, most probably through stimulation of 5-HT2A and 5-HT4 receptors.     

The effect of a 5-HT1A receptor agonist on striatal dopamine release

5-HT1A receptor agonists consistently reduce neuroleptic induced catalepsy in rats. A serotonin-dopamine interaction has been proposed to underlie this effect. Specifically, 5-HT1A receptor agonists may reduce the activity of serotonergic projections that inhibit dopaminergic nigrostriatal neurones, therefore increasing dorsal striatal dopamine levels and partially overcoming the neuroleptic blockade of D2 receptors. We tested the hypothesis that 5-HT1A receptor agonists increase striatal dopamine release in man using PET scanning with the selective D2 receptor radioligand [11C]raclopride, which is sensitive to endogenous dopamine levels. Six healthy volunteers received two PET scans, one after placebo, the other after 1 mg flesinoxan, a selective 5-HT1A receptor agonist. Binding potential values for striatal subdivisions were determined using a simplified reference tissue model. We did not find any difference in striatal [11C]raclopride binding between conditions, even though flesinoxan lead to typical 5-HT1A receptor agonist side effects and produced elevation of growth hormone in five of the six subjects. Our results suggest that the anticataleptic effect of 5-HT1A receptor agonists is not mediated by striatal dopamine release, and indicates a need for further research with other suitable 5-HT1A receptor agonists.     

The acute administration of the selective dopamine D(3) receptor antagonist SB-277011A reverses conditioned place aversion produced by naloxone precipitated withdrawal from acute morphine administration in rats

We examined the effect of SB-277011A, a selective D(3) receptor antagonist, on the conditioned place aversion (CPA) response associated with naloxone-induced withdrawal from acute morphine administration in male Sprague-Dawley rats. Morphine (5.6 mg/kg i.p.) was given, followed 4 hrs later by naloxone (0.3 mg/kg i.p.) and prior to placing the animals in one specific chamber of the test apparatus. All animals were subjected to 2 of these trials. A significant CPA occurred in animals that received an i.p. injection of vehicle 30 minutes prior to the measurement of chamber preference. The pretreatment of animals (30 minutes prior to testing) with 3 mg/kg i.p. of SB-277011A did not significantly alter the CPA compared to animals treated with vehicle (1 ml/kg i.p. of deionized distilled water). In contrast, the acute pretreatment of animals with 6, 12 or 24 mg/kg i.p. of SB-277011A significantly decreased the CPA compared to vehicle-treated animals. In fact, the 12 and 24 mg/kg doses of SB-277011A significantly increased the time spent in the chamber where animals were paired with morphine and naloxone. These results suggest that the selective antagonism of D(3) receptors attenuates the CPA produced by a model of naloxone-induced withdrawal from acute morphine dependence.     

Intrastriatal serotonin 5-HT2 receptors mediate dopamine D1-induced hyperlocomotion in 6-hydroxydopamine-lesioned rats

Striatal dopamine (DA) and serotonin (5-HT) functions are altered following DA denervation. Previous research indicates that intrastriatal coadministration of D1 and 5-HT2 receptor agonists synergistically increase locomotor behavior in DA-depleted rats. In the present study, we examined whether striatal 5-HT2 mechanisms also account for supersensitive D1-mediated locomotor behavior following DA denervation. Adult male Sprague-Dawley rats were subjected to bilateral striatal cannulation and then received either intracerebroventricular (i.c.v.) or intrastriatal 6-hydroxydopamine (6-OHDA; 200 microg or 20 microg/side, respectively). After at least 3 weeks, i.c.v.-lesioned rats received intrastriatal infusions of the 5-HT2 receptor antagonist ritanserin (2.0 microg/side) or its vehicle (DMSO) followed by systemic SKF 82958, a D1 agonist (1.0 mg/kg, i.p.) and locomotor activity was monitored. In another experiment, intrastriatal sham and 6-OHDA-lesioned rats received bilateral intrastriatal infusions of ritanserin (2.0 microg/side) or its vehicle (DMSO) followed by intrastriatal infusions of SKF 82958 (5.0 microg/side) or vehicle (0.9% saline). Rats with DA loss demonstrated supersensitive locomotor responses to both systemic and intrastriatal SKF 82958. Ritanserin pretreatment blunted systemic SKF 82958-induced hyperlocomotion and returned intrastriatal D1-mediated hyperactivity to sham lesion levels. The results of this study suggest that striatal 5-HT2 receptors contribute to D1-mediated hyperkinesias resulting from DA loss and suggest a pharmacological target for the alleviation of dyskinesia that can develop with continued DA replacement therapy.     

Effect of ritanserin, a 5HT2A/2C antagonist, on negative symptoms of schizophrenia: a double-blind randomized placebo-controlled study

It was reported that ritanserin, a 5HT2A/2C antagonist, improves negative symptoms when added to neuroleptics in inpatients with predominantly negative symptoms. Nevertheless, the results of published studies are contradictory so far. This study was designed to investigate the effect of ritanserin added to risperidone as augmentation therapy in patients with chronic schizophrenia and prominent negative symptoms in a double blind and randomized clinical trial. Eligible participants in this study were 40 patients with chronic schizophrenia. All patients were inpatients and were in the active phase of the illness, and met DSM-IV-TR criteria for schizophrenia. Patients were allocated in a random fashion, 20 to risperidone 6 mg/day plus ritanserin 12 mg/day (6 mg bid) and 20 to risperidone 6 mg/day plus placebo. The principal measure of the outcome was Positive and Negative Syndrome Scale (PANSS). Although both protocols significantly decreased the score of the positive, negative and general psychopathological symptoms over the trial period, the combination of risperidone and ritanserin showed a significant superiority over risperidone alone in decreasing negative symptoms and PANSS total scores. The present study indicates ritanserin as a potential adjunctive treatment strategy for the negative symptoms of schizophrenia. Nevertheless, results of larger controlled trials are needed, before recommendation for a broad clinical application can be made.     

Pre- and postsynaptic localization of the 5-HT7 receptor in rat dorsal spinal cord: immunocytochemical evidence

Several lines of evidence indicate that 5-HT7 receptors are involved in pain control at the level of the spinal cord, although their mechanism of action is poorly understood. To provide a morphological basis for understanding the action of 5-HT on this receptor, we performed an immunocytochemical study of 5-HT7 receptor distribution at the lumbar level. 5-HT7 immunolabelling is localized mainly in the two superficial laminae of the dorsal horn and in small and medium-sized dorsal root ganglion cells, which is consistent with a predominant role in nociception. In addition, moderate labelling is found in the lumbar dorsolateral nucleus (Onuf's nucleus), suggesting involvement in the control of pelvic floor muscles. Electron microscopic examination of the dorsal horn revealed three main localizations: 1) a postsynaptic localization on peptidergic cell bodies in laminae I-III and in numerous dendrites; 2) a presynaptic localization on unmyelinated and thin myelinated peptidergic fibers (two types of axon terminals are observed, large ones, presumably of primary afferent origin, and smaller ones partially from intrinsic cells; this presynaptic labelling represents 60% and 22% of total labelling in laminae I and II, respectively); and 3) 16.9% of labelling in lamina I and 19.8% in lamina II are observed in astrocytes. Labeled astrocytes are either intermingled with neuronal elements or make astrocytic "feet" on blood vessels. In dendrites, the labelling is localized on synaptic differentiations, suggesting that 5-HT may act synaptically on the 5-HT7 receptor. This localization is compared with other 5-HT receptor localizations, and their physiological consequences are discussed.     

Desensitization of 5-HT2A receptor function by chronic administration of selective serotonin reuptake inhibitors

We have previously shown that chronic treatment with selective serotonin reuptake inhibitors (SSRIs), fluvoxamine and paroxetine, attenuated m-chlorophenylpiperazine (mCPP)-induced hypolocomotion in rats. The effect of these SSRIs on the response to mCPP is thought to be caused by the desensitization of 5-HT2C receptor function. In the present study, we investigated whether chronic administration of SSRI could reduce another pharmacological response to mCPP in rats, i.e., the induction of the secretion of corticosterone. The mCPP-induced increase in the serum concentration of corticosterone was not blocked by the 5-HT2C antagonist SB242084, but was blocked by the 5-HT2A antagonist ketanserin. Chronic treatment with fluvoxamine and paroxetine attenuated the response to mCPP, while these SSRIs had no effects in control rats. These results suggest that the desensitization of 5-HT2A receptor function occurs in the same way as that of 5-HT2C receptor function through chronic treatment with either fluvoxamine or paroxetine as a consequence of prolonged exposure to elevated levels of serotonin. The hypersensitivity of 5-HT2A receptors is observed in depressed patients, and chronic treatment with many antidepressants such as tricyclic antidepressants have been reported to reduce 5-HT2A receptor density and/or efficacy. The desensitization of 5-HT2A receptor function might contribute to the therapeutic mechanism of action of these SSRIs, as seen with other classes of antidepressants.     

5-HT2C受体在癫患者脑组织的表达

目的研究5-羟色胺2C受体(5-HT2C受体)在癫患者脑组织的表达,探索其临床意义。方法用免疫组化方法检测46例癫患者术后脑组织5-HT2C受体的表达,研究比较不同部位不同病程脑组织表达。结果癫患者额叶脑组织5-HT2C受体的含量较颞叶海马明显增高,长病程组表达低于短病程组。结论 5-HT2C受体可能参与了癫的发病机制,改变5-HT2C受体的表达有望成为癫新的治疗靶点。