Differential effects of spinal 5-HT1A receptor activation and 5-HT2A/2C receptor desensitization by chronic haloperidol

The effects of 7- and 21-day haloperidol treatment on the spinal serotonergic system were examined in vivo in acutely spinalized adult rats. Intravenous administration of a selective 5-HT(2A/2C) receptor agonist, (+/-)-2,5-Dimethoxy-4-iodoamphetamine hydrochloride (0.1 mg/kg) significantly increased the excitability of spinal motoneurones as reflected by increased monosynaptic mass reflex amplitude. This was significantly reduced in rats treated with haloperidol (1 mg/kg/day, i.p.) for 7 and 21 days. Administration of a 5-HT(1A/7) receptor agonist, (+/-)-8-Hydroxy dipropylaminotetraline hydrobromide (0.1 mg/kg, i.v.) significantly inhibited the monosynaptic mass reflex. This inhibition was greatly prolonged in haloperidol treated animals. These results demonstrate that the effects of haloperidol on the activation and desensitization of 5-HT(1A) and 5-HT(2A/2C) receptors respectively, may be mediated via intracellular mechanisms shared by these receptors with dopamine D(2) receptors in the mammalian spinal cord. The above serotonergic mechanisms may be partly responsible for haloperidol-induced extrapyramidal motor dysfunction.     

Up-regulation of 5-HT2 receptors is involved in the increased H-reflex amplitude after contusive spinal cord injury

The amplitude of the H-reflex increases chronically after incomplete SCI and is associated with the development of exaggerated hindlimb reflexes. Although the mechanism for this increased H-reflex is not clear, previous studies have shown that pharmacological activation of the 5-HT2 receptors (5-HT2R) can potentiate the monosynaptic reflex. This study tested the hypothesis that increased expression of 5-HT2R on motoneurons is involved in increased H-reflex amplitude after a standardized clinically relevant contusive SCI. Adult female rats were subjected to contusion, complete surgical transection, or a T8 laminectomy only. At 4 weeks after surgery, H-reflex recordings from the hindpaw plantar muscles of contused rats showed twice the amplitude of that in laminectomy controls or transected rats. To probe the role of 5-HT2R in this increased amplitude, dose-response studies were done with the selective antagonists mianserin or LY53857 and the 5-HT2R agonist (+/-)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI). The drugs were intrathecally infused into the lumbar cord while recording the H-reflex. Mianserin did not have any significant effects on the H-reflex after transection, consistent with the loss of distal serotonergic innervation. After contusion, both 5-HT2R antagonists reduced the H-reflex reflex amplitude with a significantly higher ID50 compared to the uninjured controls. The 5-HT2R agonist DOI significantly increased reflex amplitude in contused but not control rats. Furthermore, while 5-HT immunoreactivity was similar, contused rats displayed increased 5-HT2AR immunoreactivity in plantar muscle motoneurons compared to uninjured controls. We conclude that increased expression of 5-HT2R is likely to be involved in the enhanced H-reflex that develops after contusive SCI.     

Modulation of neurotransmitter release induced by brain-derived neurotrophic factor in rat brain striatal slices in vitro

The atypical antipsychotic drugs (APDs) clozapine, olanzapine, risperidone, and ziprasidone preferentially increase dopamine (DA) release in rat medial prefrontal cortex (mPFC). These effects have been shown to depend upon potent 5-HT(2A) relative to weak D(2) antagonism, and 5-HT(1A) agonism as well. Atypical APDs also increase acetylcholine (ACh) release in the mPFC, but not the nucleus accumbens (NAC) or striatum (STR), whereas typical APDs such as haloperidol, S(-)-sulpiride and thioridazine do not produce either effect in the mPFC. This study examined the role of 5-HT(1A) agonism, 5-HT(2A) and D(2) antagonism, and the combination thereof, in the ability of clozapine to increase ACh release in rat mPFC. R(+)-8-OH-DPAT (0.2 mg/kg), a 5-HT(1A) agonist, WAY100635 (0.2-0.5 mg/kg), a 5-HT(1A) antagonist, and DOI (0.6-2.5 mg/kg), a 5-HT(2A/2C) agonist, increased ACh release in the mPFC, whereas M100907 (0.03-1 mg/kg), a 5-HT(2A) antagonist, did not. DOI (2.5 mg/kg) and M100907 (0.1 mg/kg) had no effect on ACh release in the NAC or STR. WAY100635 and M100907 inhibited the ability of R(+)-8-OH-DPAT and DOI, respectively, to increase ACh release in the mPFC. WAY100635, which inhibits clozapine-induced DA release in the mPFC, failed to inhibit clozapine (20 mg/kg)-induced ACh release in that region. Similarly, the combination of M100907 and haloperidol (0.1 mg/kg), which enhances DA release in the mPFC, failed to increase ACh release in that region. These results suggest that 5-HT(1A) agonism and 5-HT(2A) antagonism, as well as DA release, contribute minimally to the ability of clozapine, and perhaps other atypical APDs, to increase ACh release in the mPFC.     

The 5-HT1A receptor antagonist (S)-UH-301 blocks the (R)-8-OH-DPAT-induced inhibition of serotonergic dorsal raphe cell firing in the rat

Summary (S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin, 0.5–4.0 mg/kg i.V.] did not significantly alter the firing rate of 5-hydroxytryptamine (5-HT) containing neurons in the dorsal raphe nucleus (DRN) as a group, although some individual cells were activated whereas others were depressed. However, (S)-UH-301 (2.0mg/kg i.v.) consistently reversed the inhibition of DRN-5-HT cells produced by the selective 5-HT_1A receptor agonist (R)-8-OH-DPAT (0.5 g/kg i.v.) and the dose-response curve for this effect of (R)-8-OH-DPAT was markedly shifted to the right by pretreatment with (S)-UH-301 (1.0mg/kg i.v.). These results support the notion that (S)-UH-301 acts as an antagonist at central 5-HT_1A receptors.     

Selective heterologous regulation of 5-HT1A receptor-stimulated 35S GTPgammaS binding in the anterior cingulate cortex as a result of 5-HT2 receptor activation

Previous studies have shown that administration of the 5-HT(2) receptor agonist DOI to rats results in the heterologous desensitization of 5-HT(1A) receptor-mediated behavioral and neuroendocrine responses [Neuropsychopharmacology 19 (1998) 354; J. Neurosci. 21 (2001) 7919]. We hypothesized that the basis for these changes in 5-HT(1A) receptor function may involve changes in the capacity of the 5-HT(1A) receptor to activate G proteins. We examined the effect of chronic administration of DOI on the regulation of 5-HT(1A) receptor function at the level of receptor-G protein interaction using quantitative autoradiography of [(35)S]GTPgammaS binding stimulated by the 5-HT(1A) receptor agonist (+/-)8-OH-DPAT (1 microM). Repeated administration of DOI (1 mg/kg, s.c. once daily for 8 days) resulted in a marked down-regulation in 5-HT(2A) binding sites, as labeled by the antagonist radioligand [(3)H]ketanserin, throughout the cerebral cortex. Chronic DOI treatment also resulted in a significant and selective attenuation of 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in the anterior cingulate cortex (vehicle-treated: 74+/-7.7% above basal; DOI-treated: 43+/-4.6% above basal). Interestingly, 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding was not altered in the dorsal or median raphe, or in the limbic structures and other cortical regions examined. The decrease in 5-HT(1A) receptor-stimulated [(35)S]GTPgammaS binding in anterior cingulate cortex was not due to a decrease in 5-HT(1A) receptor number, indicating that the capacity of the 5-HT(1A) receptor to activate G proteins is attenuated in this cortical area following repeated DOI treatment. The heterologous regulation of 5-HT(1A) receptor function by chronic 5-HT(2) receptor activation in the anterior cingulate cortex raises interesting questions as to how the regulatory interaction between these serotonin receptor subtypes influences cognition, memory and emotion.     

Functional effects of chronic electroconvulsive shock on serotonergic 5-HT(1A) and 5-HT(1B) receptor activity in rat hippocampus and hypothalamus

The aims of this work were to determine the influence of chronic electroconvulsive shock (ECS) on presynaptic 5-HT(1A) receptor function, postsynaptic 5-HT(1A) receptor function in hippocampus and hypothalamus, and presynaptic 5-HT(1B) receptor function in hippocampus and hypothalamus. This represents part of an on-going study of the effects of ECS on serotonergic receptor activity in selected brain areas which may be relevant to the effects of electroconvulsive therapy (ECT) in humans. Chronic ECS reduced the ability of the 5-HT(1A) receptor agonist 8-hydroxy-2(di-n-propylamino)tetraline (8-OH-DPAT) (0.2 mg/kg s.c.) to decrease 5-HT levels in hypothalamus as shown by in vivo microdialysis, indicative of a reduction in sensitivity of presynaptic 5-HT(1A) autoreceptors. The ability of the 5-HT(1B) receptor antagonist GR 127935 (5 mg/kg s.c.) to increase 5-HT levels in both hippocampus and hypothalamus was unaffected by chronic ECS. 8-OH-DPAT (0.2 mg/kg s.c.) increased cyclic AMP levels in hippocampus measured by in vivo microdialysis approximately 2-fold. The degree of stimulation of cyclic AMP formation was not altered by chronic ECS. However the cyclic AMP response to forskolin (50 micro M) administered via the microdialysis probe, which was approximately 4-fold of basal in sham-treated rats, was almost completely abolished in ECS-treated rats. Since this indicates that either adenylate cyclase catalytic unit activity or Gs protein activity is reduced in the hippocampus after chronic ECS, the lack of change in 8-OH-DPAT-induced cyclic AMP formation may be taken as possible evidence of an increase in sensitivity of postsynaptic 5-HT(1A) receptors in the hippocampus by chronic ECS. Chronic ECS increased basal plasma levels of corticosterone, ACTH and oxytocin. The ACTH response to s.c. injections of 0.2 mg/kg or 0.5 mg/kg 8-OH-DPAT was reduced by chronic ECS. Postsynaptic 5-HT(1A) receptor activity in the hypothalamus, in contrast to the hippocampus, thus appears to be desensitized after chronic ECS. We conclude that chronic ECS has regionally specific effects on both pre- and post-synaptic 5-HT(1A) receptors, but, in contrast to some antidepressant drugs, does not affect presynaptic 5-HT(1B) receptor activity.     

Chronic electroconvulsive shock and 5-HT autoreceptor activity in rat brain: an in vivo microdialysis study

Summary In vivo microdialysis was used to determine the effects of chronic electroconvulsive shock (ECS), given daily for 10 days, on basal 5-HT levels in rat frontal cortex and hippocampus and on the effect of systemic administration of the 5-HT-la receptor agonist, 8-OH-DPAT (0.2 mg/kg), to reduce 5-HT levels in these areas by activation of somatodendritic autoreceptors. Neither basal 5-HT levels nor the effects of 8-OH-DPAT on 5-HT levels were altered after chronic ECS. The effect of systemic administration of the 5-HT_1A and 5-HT_1B antagonist, (±)-pindolol (10mg/kg), to increase 5-HT levels in hippocampus, was also not affected by chronic ECS.     

5-HT 2A receptor stimulation by DOI,a 5-HT 2A/2C receptor agonist,potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens

(+/-)-([1-(2,5-Dimethoxy-4-iodophenyl)-aminopropane]-hydrochloride) (DOI) (2.5 mg/kg), a 5-HT(2A/2C) agonist, significantly potentiated D-amphetamine (AMPH) (1 mg/kg)-induced dopamine (DA) release in rat medial prefrontal cortex (mPFC) and nucleus accumbens (NAC). This effect of DOI was completely prevented by M100907 (1 mg/kg), a selective 5-HT(2A) antagonist, which by itself had no effect on basal and AMPH-induced DA release in either region. Thus, 5-HT(2A) receptor agonism potentiates AMPH-induced DA release in the mPFC and NAC.     

5-HT1A and 5-HT1B receptors control the firing of serotoninergic neurons in the dorsal raphe nucleus of the mouse: studies in 5-HT1B knock-out mice

The characteristics of the spontaneous firing of serotoninergic neurons in the dorsal raphe nucleus and its control by serotonin (5-hydroxytryptamine, 5-HT) receptors were investigated in wild-type and 5-HT1B knock-out (5-HT1B-/-) mice of the 129/Sv strain, anaesthetized with chloral hydrate. In both groups of mice, 5-HT neurons exhibited a regular activity with an identical firing rate of 0.5-4.5 spikes/s. Intravenous administration of the 5-HT reuptake inhibitor citalopram or the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) induced a dose-dependent inhibition of 5-HT neuronal firing which could be reversed by the selective 5-HT1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xane carboxamide (WAY 100635). Both strains were equally sensitive to 8-OH-DPAT (ED50 approximately 6.3 microgram/kg i.v.), but the mutants were less sensitive than wild-type animals to citalopram (ED50 = 0.49 +/- 0.02 and 0.28 +/- 0.01 mg/kg i.v., respectively, P < 0.05). This difference could be reduced by pre-treatment of wild-type mice with the 5-HT1B/1D antagonist 2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carbox yli c acid [4-methoxy-3-(4-methyl-piperazine-1-yl)-phenyl]amide (GR 127935), and might be accounted for by the lack of 5-HT1B receptors and a higher density of 5-HT reuptake sites (specifically labelled by [3H]citalopram) in 5-HT1B-/- mice. In wild-type but not 5-HT1B-/- mice, the 5-HT1B agonists 3-(1,2,5, 6-tetrahydro-4-pyridyl)-5-propoxypyrrolo[3,2-b]pyridine (CP 94253, 3 mg/kg i.v.) and 5-methoxy-3-(1,2,3, 6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 0.6 mg/kg i.v.) increased the firing rate of 5-HT neurons (+22.4 +/- 2.8% and +13.7 +/- 6.0%, respectively, P < 0.05), and this effect could be prevented by the 5-HT1B antagonist GR 127935 (1 mg/kg i.v.). Altogether, these data indicate that in the mouse, the firing of 5-HT neurons in the dorsal raphe nucleus is under both an inhibitory control through 5-HT1A receptors and an excitatory influence through 5-HT1B receptors.     

Effects of 8-OH-DPAT, a 5-HT1A receptor agonist, and DOI, a 5-HT2A/2C agonist, on monosynaptic transmission in spinalized rats

We investigated the effect of the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and the 5-HT_2A/2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on monosynaptic transmission in spinalized rats. 8-OH-DPAT significantly inhibited the excitation of α-motoneurons evoked by monosynaptic transmission without a direct effect on α-motoneuron excitation. DOI potentiated the excitation of α-motoneurons by both direct stimulation and monosynaptic transmission. These results indicate that activation of 5-HT_1A receptors inhibits monosynaptic transmission, whereas activation of 5-HT_2A/2C receptors enhances it.     

5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy

The present study was conducted to investigate the role of 5-HT(2C) and 5-HT(1A) receptors in the generation of spike-wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG/Rij rats). We have determined the effects of the 5-HT(2C) receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT(2C) receptor antagonist SB-242084, the selective 5-HT(1A) receptor antagonist WAY-100635, two selective serotonin re-uptake inhibitors (SSRI, fluoxetine and citalopram) and their combinations in this model. The 5-HT(2C) agonist m-CPP caused marked, dose-dependent decreases in the cumulative duration and number of SWD administered either intraperitoneally (0.9 and 2.5 mg/kg) or intracerebroventricularly (0.05 and 0.1 mg/kg). Treatment with SB-242084 (0.2 mg/kg, ip) alone failed to cause any significant change in SWD compared to vehicle. Pretreatment with SB-242084 (0.2 mg/kg, ip) eliminated the effects of m-CPP on SWD. Fluoxetine (5.0 mg/kg, ip) alone caused moderate increase in SWD. After pretreatment with SB-242084, the effect of fluoxetine was significantly enhanced. The combination of SB-242084 and citalopram (2.5 mg/kg, ip) caused a similar effect, namely an increase in SWD. In contrast, pretreatment with WAY-100635 significantly attenuated the effect of fluoxetine. In conclusion, these results indicate that the increase in endogenous 5-HT produces a dual effect on SWD; the inhibition of epileptiform activity is mediated by 5-HT(2C), the activation by 5-HT(1A) receptors.     

Evidence that spinal 5-HT1, 5-HT2 and 5-HT3 receptor subtypes modulate responses to noxious colorectal distension in the rat

This study examined whether the antinociception produced following the intrathecal (i.t.) administration of serotonin (5-hydroxytryptamine, 5-HT) and other 5-HT receptor agonists in a model of visceral pain that utilizes colorectal distension (CRD) as the noxious visceral stimulus is mediated through interaction with spinal 5-HT1, 5-HT2, or 5-HT3 receptor subtypes. CRD in conscious rats reliably elicits two pseudaffective reflexes: a vigorous pressor response and a visceromotor response. Antinociception is characterized by inhibition of both pseudaffective responses. The effects of 5-HT receptor agonists and antagonists on resting blood pressure were also examined. The i.t. administration of 5-HT resulted in a dose-dependent elevation of the visceromotor threshold and inhibition of the pressor response to CRD. The 5-HT1A receptor agonist 8-OH-DPAT, the 5-HT1B receptor agonist RU-24969, the 5-HT2 receptor agonists DOI, MK-212 and alpha-methyl-5-HT and the 5-HT3 agonist 2-methyl-5-HT all dose-dependently inhibited the pressor response and dose-dependently elevated the visceromotor threshold to noxious CRD. The rank order of potency of these agonists was the same for both pseudaffective responses to CRD: DOI greater than or equal to 8-OH-DPAT greater than or equal to MK-212 = RU-24969 greater than or equal to alpha-methyl-5-HT = 2-methyl-5-HT much greater than 5-HT. The antinociceptive effects of 5-HT, RU-24969, alpha-methyl-5-HT and DOI were antagonized by i.t. pretreatment with methysergide. Intrathecal pretreatment with ketanserin antagonized the antinociceptive effects of MK-212 and MDL-72222 antagonized the effects produced by 2-methyl-5-HT in response to CRD. The antinociceptive effects produced by 8-OH-DPAT were not antagonized by i.t. pretreatment with methysergide. These results demonstrate that 5-HT1, 5-HT2 and 5-HT3 receptors in the spinal cord mediate antinociception in response to noxious CRD in conscious rats.     

The role of spinal cord 5-HT1A and 5-HT1B receptors in the modulation of a spinal nociceptive reflex

The role of the 5-hydroxytryptamine (5-HT) receptor subtypes in the spinal cord in the regulation of nociception is unknown. This study examined whether administration of different 5-HT1 receptor agonists into the spinal subarachnoid space of mice modulates the nociceptive tail-flick reflex, and whether effects on the tail-flick reflex involve changes in tail skin temperature. The tail-flick latencies (the time needed to evoke the tail-flick reflex by noxious radiant heat) were significantly increased after intrathecal (i. th.) injection of 5-HT (10-20 micrograms), the 5-HT1A/5-HT1B receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 10-20 micrograms), the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 20 micrograms) and after i.th. injection of 1(m-chlorophenyl)piperazine (mCPP, 5-20 micrograms) and 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (RU 24969, 5-20 micrograms) which have high affinity for the 5-HT1B receptors. None of the 5-HT1 receptor agonists had the ability to change the tail skin temperature. The results show that in the mouse i.th. injection of both 5-HT1A and 5-HT1B receptor agonists has the ability to inhibit the tail-flick reflex without interfering with the tail skin temperature.     

Effects of serotonergic 5-HT1A and 5-HT1B ligands on ventral pallidal neuronal activity

To clarify the role of the 5-HT system in limbic outputs, the present study compared the effects of the 5-HT1A agonist 8-OH-DPAT and the 5-HT1B agonist CP-94253 with the non-selective 5-HT agonist TFMPP on the firing rate of ventral pallidal (VP) neurons recorded in chloral hydrate-anesthetized rats. 8-OH-DPAT (0.25-256 microg/kg i.v.) dose-dependently enhanced (9/26 neurons) or suppressed (8/26) activity, and the 5-HT1A antagonist (+)WAY-100135 often attenuated these responses. TFMPP (0.011-1.453 mg/kg i.v.) dose-dependently reduced the firing rate of 7/8 VP neurons tested. In contrast, CP-94253 (0.013-12.8 mg/kg i.v.) had little or no effect. In sum, these data suggest that the 5-HT1A receptor appears to be particularly important in influencing limbic outputs mediated via the VP.     

DOI, a 5-HT2A/2C receptor agonist, attenuates clozapine-induced cortical dopamine release

(±)-1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI, 1.25, 2.5 and 5 mg/kg), a serotonin (5-HT)_2A/2C agonist, produced an inverted U-shaped increase in DA release in rat medial prefrontal cortex (mPFC) with a significant effect only at 2.5 mg/kg. This effect was completely abolished by M100907 (0.1 mg/kg), a 5-HT_2A antagonist, and WAY100635 (0.2 mg/kg), a 5-HT_1A antagonist, neither of which when given alone affected dopamine release. DOI (2.5 mg/kg), but not the 5-HT_2C agonist Ro 60-0175 (3 mg/kg), attenuated clozapine (20 mg/kg)-induced mPFC dopamine release. These results suggest that 5-HT_2A receptor stimulation increases basal cortical dopamine release via 5-HT_1A receptor stimulation, and inhibits clozapine-induced cortical dopamine release by diminishing 5-HT_2A receptor blockade.     

Differential responsiveness of the rat dorsal and median raphe 5-HT systems to 5-HT1 receptor agonists and p-chloroamphetamine

The dorsal and median raphe 5-HT neurons give rise to projections that differ in axon morphology and in vulnerability to certain amphetamine derivatives. The present study was undertaken to determine if these two 5-HT systems possess different functional properties. To this end, we studied the effects of selective 5-HT1A or 5-HT1A/5-HT1B receptor agonists and of p-chloroamphetamine on extracellular levels of indoleamines, as measured by differential pulse voltammetry with extracellular levels of indoleamines, as measured by differential pulse voltammetry with electrochemically pretreated carbon fiber electrodes, in cell body and nerve terminal regions of these subsets of 5-HT neurons in the rat brain. The selective 5-HT1A agonist 8-OH-DPAT produced a gradual decrease in the height of the 300 mV oxidation peak in the dorsal raphe and in the frontal cortex, reaching a maximum of 60% 3 h after the i.v. injection of 30 micrograms/kg. However, the same dose of 8-OH-DPAT was ineffective in the median raphe and in the dentate gyrus that receives its 5-HT innervation exclusively from the median raphe. A higher dose of 8-OH-DPAT (150 micrograms/kg, i.v.) produced a 60% decrease in the height of the 300 mV oxidation peak in the median raphe, whereas only a 20% decrease was obtained in the dentate gyrus. In contrast, the non-selective 5-HT1 agonist RU 24,969 (10 mg/kg, i.p.) caused a 70% reduction of the 300 mV peak height in both the dorsal and median raphe and a 50% decrease in both the frontal cortex and the dentate gyrus. Moreover, although a high dose of 8-OH-DPAT (150 micrograms/kg, i.v.) given alone reduced by 20% the amplitude of the oxidative peak in the dentate gyrus, subsequent administration of RU 24,969 (10 mg/kg, i.p.) caused a further 30% diminution of the oxidative peak height. The greater responsiveness of dorsal as compared to median raphe 5-HT systems to 5-HT1A receptor agonists was confirmed in two further series of experiments. First, the microiontophoretic application of 8-OH-DPAT directly onto 5-HT neurons was three times more potent in suppressing the firing rate of dorsal raphe 5-HT neurons than that of their median raphe congeners. Second, 8-OH-DPAT and buspirone were ten and four times, respectively, more potent in decreasing 5-HT synthesis in the frontal cortex than in the hippocampus.(ABSTRACT TRUNCATED AT 400 WORDS)     

Presynaptic dopaminergic inhibition of the spinal reflex in rats.

Dopaminergic influence on spinal monosynaptic transmission was examined in rats. Monosynaptic mass reflex (MMR) was recorded from the ventral root L6 following supramaximal stimulation (0.2 Hz; 0.1 ms) to the ipsilateral dorsal root L6 in spinalized rat under pentobarbitone sodium (40 mg/kg, i.p.) anaesthesia. MMR was inhibited by intravenous administration of the dopaminergic agonist, apomorphine (50-200 ug/kg) in a dose-dependent manner. The attenuatory effect of apomorphine (200 ug/kg i.v.) on the reflex could be reversed by the dopaminergic antagonist haloperidol (0.5 mg/kg, i.v.). Under tetanic stimulation (200 Hz; 15s), the pretetanic relative inhibition induced by apomorphine (200 ug/kg, i.v.) was increased only for a short period immediately after the cessation of tetanic stimulation. The results indicate existence of presynaptic dopamine receptors on the afferent terminals converging on the motoneurone which may functionally modulate the spinal motor output.     

Neuromodulatory role of 5-hydroxytryptamine type 1A receptors on the excitability of Renshaw cells in the rat spinal cord

Serotonin modulates neurotransmission at synapses between various spinal neurons and, thus, may either facilitate or depress the information processed in the circuits and ultimately modulate the final motor output. A possible neuromodulatory role of 5-hydroxytryptamine type 1A (5-HT1A) receptors on the excitability of lumbar spinal Renshaw cells was explored in anesthetized rats spinalized at T4 level. Intravenous administration of the specific 5-HT1A agonist (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT) (0.1 mg/kg) decreased the Renshaw cell burst response by 20-45%. This effect was completely antagonized by the specific 5-HT1A antagonist (S)-N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide dihydrochloride [(S)-WAY 100135] (0.1 mg/kg, intravenous), although this drug per se had no effect on the Renshaw cell burst response. These results suggest that 8-OH-DPAT-induced decrease in Renshaw cell burst firing was mediated by 5-HT1A receptors located either presynaptically or postsynaptically.     

Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors

A selective 5-HT reuptake inhibitor, fluvoxamine (10 and 30 mg/kg, i.p.) suppressed long-term potentiation (LTP) in the hippocampal CA1 field of anesthetized rats. Fluvoxamine (30 mg/kg, i.p.)-induced suppression of LTP was completely reversed by the 5-HT(1A) receptor antagonist NAN-190 (0.5 mg/kg, i.p), but not by the 5-HT(4) receptor antagonist GR 113808 (20 microg/rat, i.c.v.) and the 5-HT(7) receptor antagonist DR 4004 (10 microg/rat, i.c.v.). These data suggest that the inhibitory effect of fluvoxamine on LTP induction is mediated via 5-HT(1A) receptors.     

5-HT(1B) receptor knockout mice show no adaptive changes in 5-HT(1A) receptor function as measured telemetrically on body temperature and heart rate responses

Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT(1A) and 5-HT(1B) receptor. The present study focuses on putative adaptive changes in the 5-HT(1A) receptor system in mice that lack 5-HT(1B) receptors (5-HT(1B) KO). 5-HT(1A) receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT(1A) receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT(1A) receptor activation by flesinoxan (0.1-3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT(1B) KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT(1A) receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT(1B) KO mice showed no shift in 5-HT(1A) receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT(1A) receptor function in 5-HT(1B) KO mice as measured telemetrically on body temperature and heart rate responses.