Cardiovascular effects of intrathecal administration of substance P in the rat: interactions with serotonergic mechanisms

Summary Intrathecal (i.th.) administration of substance P (SP, 6.5nmol) at the Th 8–10 level in conscious rats increased blood pressure (carotid artery), heart rate and plasma catecholamine concentrations. The responses were antagonized by the intravenous (i.v.) but not i.th. pretreatment with the 5-HT₂-receptor antagonists ketanserin and ritanserin and intrathecally administered serotonin (5-HT, 10 g). The pressor response and the increase in plasma noradrenaline concentrations were also antagonized by i.v. or i.th. pretreatment with the 5-HT_1A-agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). In contrast the pressor response to SP was facilitated by the 5-HT_1A-antagonist 1-pindolol (i.v. or i.th). Pretreatment with SP (i.th) reduced the hypotensive response to i.v. 8-OH-DPAT. These results demonstrate functional interactions between SP and serotonergic mechanisms in the central system, but the precise location and nature were not elucidated.     

Effect of a 5-HT1A receptor agonist, flesinoxan, on the extracellular noradrenaline level in the hippocampus and on the locomotor activity of rats

We have studied effects of 5-hydroxytryptamine 1A (5-HT_1A) receptor-selective compounds on the extracellular noradrenaline (NA) level in the hippocampus of rats using microdialysis and on their locomotor activity. A selective 5-HT_1A receptor agonist, flesinoxan (5 mg/kg, i.p.) increased the extracellular NA level in the hippocampus, and increased the locomotor activity. Both responses were blocked by pretreatment with a 5-HT_1A receptor antagonist, WAY100635 (1 mg/kg, i.p.) and an α₂ adrenoceptor agonist, clonidine (50 μg/kg, i.p.). Bilateral intrahippocampal injection of flesinoxan (200 nmol in 2 μl, respectively) increased the locomotor activity of rats and the intrahippocampal perfusion of flesinoxan (1 mM, 2 μl/min) increased the extracellular NA level in the hippocampus. Bilateral intrahippocampal injections of a small amount of WAY100635 (0.1 nmol in 2 μl, respectively) blocked the flesinoxan (5 mg/kg, i.p.)-induced hyperactivity. Flesinoxan (5 mg/kg, i.p.) did not significantly influence the level of serotonin or its major metabolite in the hippocampus, or dopamine or its metabolites in the striatum. In conclusion, these behavioral as well as pharmacological results indicate that postsynaptic 5-HT_1A receptor activation by flesinoxan increase the extracellular NA level in the hippocampus, which may be the cause of the increase of the locomotor activity.     

Sleep effects following intrathecal administration of the 5-HT1A agonist 8-OH-DPAT and the NMDA antagonist AP-5 in rats

The modulating effect of an intrathecally (i.t.) administered 5-HT_1A agonist and an NMDA antagonist on sleep, waking and EEG power spectra was investigated in rats. The 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (38 nmol) increased total slow wave sleep (TSWS) and decreased waking over the 8 h recording period. The TSWS increase was mostly due to an increase in SWS1. Sleep latency to SWS1 was also reduced. The NMDA antagonist dl-2-amino 5-phosphonovaleric acid (AP-5) (31.5 nmol) reduced waking. SWS1 was increased, but TSWS was not changed. An increase in REM sleep was seen during the last part of the recording. Combined treatment with 8-OH-DPAT and AP-5 reduced waking and increasd TSWSS. No change in REM sleep was seen. There were no systematic changes in either waking, TSWS or REM fronto-frontal or fronto-parietal EEG power spectrum after any of the treatments. The results suggest that in the spinal cord stimulation of 5-HT_1A receptors have a dampening effect on transmission of sensory information, leading to deactivation and thereby increased possibilities for sleep induction. Blockade of the NMDA receptors may also lead to a small dampening of sensory transmission with similar consequences.     

Changes in rat cerebral blood volume due to modulation of the 5-HT1A receptor measured with susceptibility enhanced contrast MRI

Brain blood volume changes in the rat in response to 5-HT_1A agonist and antagonist administration were measured using susceptibility contrast enhanced magnetic resonance imaging (MRI). Administration of the 5-HT_1A agonist 8-OH-DPAT resulted in decreases in fractional brain blood volumes. Administration of the 5-HT_1A antagonist WAY-100635 following a dose of 8-OH-DPAT resulted in increases in fractional blood volumes greatest in hippocampus and cortex and smallest in thalamus and caudate-putamen. The magnitude of the regional increases in blood volumes paralleled the distribution of 5-HT_1A receptors in the rat brain. Administration of WAY-100635 alone resulted in decreases in cortical blood volume and increases in cerebellar blood volume.     

Sleep/waking effects following intrathecal administration of the 5-HT1A agonist 8-OH-DPAT alone and in combination with the putative 5-HT1A antagonist NAN-190 in rats

Sleep, waking, and EEG power spectra were investigated in rats after intrathecal (IT) administration of a 5-HT_1A agonist and a 5-HT_1A antagonist. Total slow wave sleep (TSWS) was increased and waking was decreased over the 8-h recording period after the 5-HT_1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (38 nmol). Within TSWS, SWS1 was unchanged while SWS-2 tended to be increased. The 5-HT_1A antagonist 1-[2-Methoxyphenyl)-4-(4-(2-phthalimido)-butyl]piperazine hydrobomide (NAN-190) did not change and sleep/waking stages. Combined treatment with 8-OH-DPAT and NAN-190 increased variance. Following the combination, sleep and waking were not significantly different from control. SWS-2 tended to be reduced compared to the effect of 8-OH-DPAT alone. There were no systematic changes in neither waking nor TSWS fronto-frontal or fronto-parietal EEG power spectrum after any of the treatments, indicating that sleep quality was not changed. The results confirm earlier data suggesting that in the spinal cord, stimulation of 5-HT1A receptors have a dampening effect on transmission of sensory information, leading to deactivation and thereby increased sleep tendency. The reason why the 8-OH-DPAT effect was not clearly antagonized by the putative 5-HT1A antagonist NAN-190, may be due to the generally weak antagonistic and also partial agonistic effect of NAN-190 as reported in the literature.     

Stimulation of spinal 5-HT(2A/2C) receptors potentiates the capsaicin-induced in vivo release of substance P-like immunoreactivity in the rat dorsal horn

Stimulation of spinal serotonin (5-HT)_2A/2C receptors has previously been reported to lead to either a pro-nociceptive or an anti-nociceptive response. Behavioral data have indicated that the pro-nociceptive effect is related to the release of substance P (SP). The aim of this in vivo microdialysis study was to investigate if stimulation of spinal 5-HT_2A/2C receptors by the selective agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) induces spontaneous or capsaicin-evoked increase in the release of SP-like immunoreactivity (SP-LI) in the rat dorsal horn. A dose of capsaicin (25 μM in the perfusion medium administered for 30 min), which did not lead to a significant release of SP-LI on its own, induced a significant increase of greater than 4-fold of the SP-LI level following spinal application of 50 nmol DOI. Higher (500 nmol) or lower (5 nmol) doses of DOI failed to induce a similar effect. In rats with a peripheral inflammation, induced by carrageenan, capsaicin (25 μM) induced a non-significant increase of SP-LI. A significant 8-fold increase of the SP-LI level was detected following administration of 50 nmol DOI in combination with capsaicin. The effect of DOI, which was completely prevented by co-administration of the 5-HT_2A receptor antagonist ketanserin in control animals without peripheral inflammation, was only partly blocked in animals with carrageenan induced peripheral inflammation. In conclusion, stimulation of 5-HT_2A/2C receptors facilitates the capsaicin-evoked release of SP-LI in the dorsal horn in both animals with and without carrageenan-induced unilateral inflammation. The observation that the highest dose of DOI failed to induce SP-LI release may be due to an inhibitory postsynaptic action at this dose.     

Melatonin reversal of DOI-induced hypophagia in rats; possible mechanism by suppressing 5-HT2A receptor-mediated activation of HPA axis

Serotonin type 2A (5-HT_2A) receptor-mediated neurotransmitter is known to activate hypothalamic–pituitary–adrenal (HPA) axis, regulate sleep–awake cycle, induce anorexia and hyperthermia. Interaction between melatonin and 5-HT_2A receptors in the regulation of the sleep–awake cycle and head-twitch response in rat have been reported. Previous studies have shown that melatonin has suppressant effect on HPA axis activation, decreases core body temperature and induces hyperphagia in animals. However, melatonin interaction with 5-HT_2A receptors in mediation of these actions is not yet reported. We have studied the acute effect of melatonin and its antagonist, luzindole on centrally administered (±)-1-(2,5-dimethoxy-4-iodophenyl) 2-amino propane (DOI; a 5-HT_2A/2C agonist)-induced activation of HPA axis, hypophagia and hyperthermia in 24-h food-deprived rats. Like ritanserin [(1 mg/kg, i.p.) 5-HT_2A/2C antagonist], peripherally administered melatonin (1.5 and 3 mg/kg, i.p.) did not affect the food intake, rectal temperature or basal adrenal ascorbic acid level. However, pretreatment of rats with it significantly reversed DOI (10 μg, intraventricular)-induced anorexia and activation of HPA axis. But the hyperthermia induced by DOI was not sensitive to reversal by melatonin. Mel₁ receptor subtype antagonist luzindole (5 μg, intraventricular) did not modulate the DOI effect but antagonized the melatonin (3 mg/kg, i.p.) reversal of 5-HT_2A agonist response. The present data suggest that melatonin reversal of DOI-induced hypophagia could be due to suppression of 5-HT_2A mediated activation of HPA axis.     

Implication of the 5-HT2A and 5-HT2C (but not 5HT1A) receptors located within the periaqueductal gray in the elevated plus-maze test–retest paradigm in mice

A single exposure to the elevated plus-maze test (EPM) increases open arms avoidance and reduces or abolishes the anxiolytic-like effect of benzodiazepines assessed during a second trial, a phenomenon defined as “one-trial tolerance” (OTT). It has been emphasized that the dorsal portion of the midbrain periaqueductal gray (dPAG) plays a role on this enhanced aversion phenomenon in maze-experienced rodents. Given that intra-dPAG injections of a wide range of serotonergic 5-HT_1A, 5-HT_2A and 5-HT_2C receptor agonists produce anxiolytic-like effects in maze-naïve rodents, the present study examined the effects of the 5-HT_1A receptor agonist 8-OH-DPAT (5.6 and 10.0 nmol in 0.15 µl) the preferential 5-HT_2A receptor agonist DOI (2.0 and 8.0 nmol in 0.1 µl) and the preferential 5-HT_2C receptor agonist MK-212 (21.2 and 63.6 nmol in 0.1 µl) microinjected into the dPAG prior to Trial 1 and Trial 2 on the behaviour of mice in the EPM. Test sessions were recorded and subsequently scored for anxiety-like behaviour (percentage of open arms entries and time) as well as general locomotor activity (closed arm entries). The results showed a lack of 8-OH-DPAT (5.6 and 10.0 nmol) effect on the behaviour of maze-naïve and maze-experienced mice, while intra-dPAG microinfusions of DOI (8 nmol) reduced anxiety-like behaviour only in maze-experienced mice that had received a similar treatment prior to Trial 1. Furthermore, intra-dPAG MK-212 (63.6 nmol) showed an anxiolytic-like effect on both Trial 1 and Trial 2. Importantly, these effects were observed in the absence of any significant change in closed arm entries, the parameter considered to be a valid index of locomotor activity in the plus-maze. These results support the dPAG as a crucial structure involved in the neurobiology of the OTT phenomenon as well as accounting the role of the 5-HT_2A and 5-HT_2C receptors located within this midbrain structure on the emotional state induced by EPM test and retest paradigm mice.     

Chronic administration of the 5-HT1A receptor agonist 8-OH-DPAT differentially desensitizes 5-HT1A autoreceptors of the dorsal and median raphe nuclei

The present study investigated alterations of the regulation of serotonin (5-hydroxytryptamine; 5-HT) release by 5-HT_1A autoreceptors following single and repeated treatment with the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT). Rats were pretreated with 8-OH-DPAT (1.0 mg/kg, s.c.) for 1, 7, or 14 days. The ability of an acute challenge administration of 8-OH-DPAT (1.0 mg/kg, i.p.) to decrease 5-HT release in the ventral striatum and the ventral hippocampus of rats maintained under chloral hydrate anesthesia was examined 24 h after the last pretreatment injection using in vivo microdialysis. The decrease of 5-HT release in the striatum produced by the challenge dose of the 5-HT_1A receptor agonist was diminished following 7 and 14 days of pretreatment, but not after 1 day of pretreatment, with 8-OH-DPAT. In contrast, decreases of 5-HT release in the hippocampus by the 8-OH-DPAT challenge were not altered after 1 or 7 days of pretreatment, and only a trend for attenuation appeared after pretreatment for 14 days. The results of the present study indicate that desensitization of 5-HT_1A autoreceptors regulating 5-HT release in different brain regions by repeated treatment with 8-OH-DPAT occurs at different rates. Synapse 25:107–116, 1997. © 1997 Wiley-Liss, Inc.     

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.     

Blockade of 5-HT(2) receptors in the periaqueductal grey matter (PAG) abolishes the anxiolytic-like effect of 5-HT(1A) receptor antagonism in the median raphe nucleus in mice

Several lines of evidence support the involvement of serotonergic (5-HT) neurons of the median raphe nucleus (MRN) in anxiety-like behaviour. In this context, it is known that blockade of 5-HT_1A somatodendritic autoreceptors in the midbrain raphe nuclei increases the firing rate of these neurons, disinhibiting 5-HT release in postsynaptic target areas such as amygdala, hippocampus and periaqueductal grey matter (PAG). However, while activation of 5-HT_1A or 5-HT₂ receptors in forebrain targets such as the amygdala or hippocampus enhances anxiety-like behaviours in rodents, stimulation of both receptor subtypes in the midbrain PAG markedly reduces anxiety-like behaviour. In view of these findings, the present study investigated whether the anti-anxiety effects induced by pharmacological disinhibition of 5-HT neurons in the MRN are attenuated by the blockade of 5-HT₂ receptors within the PAG. Mice received combined intra-PAG injection with ketanserin (10 nmol/0.1 μl), a 5-HT₂ receptor antagonist, followed by intra-MRN injection of WAY-100635 (5.6 nmol/0.1 μl), a highly selective 5-HT_1A receptor antagonist. They were then individually exposed to the elevated plus-maze (EPM), with the videotaped behavioural sessions subsequently scored for both conventional and ethological measures. The results confirmed that intra-MRN infusion of WAY100635 reduces behavioural indices of anxiety without significantly altering general activity measures, and further showed that this effect was completely blocked by intra-PAG pretreatment with an intrinsically-inactive dose of ketanserin. Together, these results suggest that 5HT₂ receptor populations located within the midbrain PAG play a significant role in the reduction of anxiety observed following disinhibition of 5-HT neurons in the MRN.     

5-HT1B and 5-HT1D receptors in the human trigeminal ganglion: co-localization with calcitonin gene-related peptide, substance P and nitric oxide synthase

5-Hydroxytryptamine (5-HT) is implicated in migraine and agonist directed aganist 5-HT_1B and 5-HT_1D receptors are commonly used as effective therapies. The antimigraine mechanisms involve the inhibition of intracranial sensory neuropeptide release. In order to determine which 5-HT₁ receptor subtypes are involved we have by immunocytochemistry examined the distribution of 5-HT_1B and 5-HT_1D receptors in the human trigeminal ganglia, and addressed which of them colocalize with calcitonin gene-related peptide (CGRP), substance P (SP) or nitric oxide synthase (NOS). We detected that 5-HT_1D receptor immunoreactivity (i.r.) was predominantly expressed in medium-sized cells (86% of positive cells, 30–60 μm). About 9% of the 5-HT_1D receptor i.r. cells were large in size (>60 μm) and 5% were small in size (<30 μm). In a similar pattern, 5-HT_1B receptor i.r. was mainly expressed in medium-sized cells (81% in 30–60 μm, 15% in >60 μm and 4% in <30 μm). Double immunostaining was used to determine whether the 5-HT_1B or 5-HT_1D receptor immunoreactive cells co-localized with either CGRP, SP or NOS. Thus, 89% of the CGRP i.r. cells expressed 5-HT_1D receptor i.r. and 65% of the CGRP positive cells were 5-HT_1B receptor positive. Most of the 5-HT_1D (95%) and the 5-HT_1B (94%) receptor i.r. cells showed SP immunostaining and 83% of 5-HT_1D receptor and 86% of 5-HT_1B receptor i.r. cells contained NOS. In conclusion, both 5-HT_1B and 5-HT_1D receptors are expressed in the human trigeminal ganglion and they are mainly localized in medium-sized cells and they seem to colocalize with CGRP, SP and NOS.     

Serotonin 5-HT1A and 5-HT2/1C receptors in the midbrain periaqueductal gray differentially modulate defensive rage behavior elicited from the medial hypothalamus of the cat

Recent studies have established that the expression of defensive rage behavior in the cat is mediated over a descending pathway from the medial hypothalamus to the dorsolateral quadrant of the midbrain periaqueductal gray matter (PAG). The present study was designed to determine the roles played by 5-HT_1A and 5-HT_2/1C receptors in this region of PAG in modulating defensive rage behavior elicited from the cat's medial hypothalamus. Monopolar stimulating electrodes were implanted into the medial hypothalamus from which defensive rage behavior could be elicited by electrical stimulation. During the course of the study, the `hissing' component of the defensive rage response was used as a measure of defensive rage behavior. Cannula-electrodes were implanted into sites within the PAG from which defensive rage could also be elicited by electrical stimulation in order that 5-HT compounds could be microinjected into behaviorally identifiable regions of the PAG at a later time. Microinjections of the selective 5-HT_1A agonist, (+)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OHDPAT) (50 pmol, 2.0 and 3.0 nmol), into the PAG suppressed the hissing response in a dose-dependent manner. Administration of the selective 5-HT_1A antagonist, 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl] ethyl]-N-2-pyridinyl-benzamide hydrochloride (p-MPPI) (1.5 and 3.0 nmol), blocked the suppressive effects of 8-OHDPAT upon hissing. In contrast, microinjections of the 5-HT_2/1C receptor agonist (+)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride ((+)-DOI hydrochloride) (0.01, 1.0 and 1.5 nmol) facilitated the occurrence of hissing elicited from the medial hypothalamus in a dose-dependent manner. Immunohistochemical analysis revealed the presence of 5-HT axons and preterminals throughout the PAG, and in particular, in its dorsolateral aspect which receives major inputs from the medial hypothalamus in association with defensive rage behavior. The overall findings of the study provide evidence that activation of 5-HT_1A and 5-HT_2/1C receptors within the midbrain PAG differentially modulate the expression of defensive rage behavior elicited from the medial hypothalamus of the cat.     

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.     

Stimulation of 5-HT2A receptors in the paraventricular hypothalamus attenuates neuropeptide Y-induced hyperphagia through activation of corticotropin releasing factor

The effect of 5-HT₁ and 5-HT₂ receptor agonists administered into the paraventricular hypothalamus was studied on the hyperphagia caused by neuropeptide Y (NPY) injected into the same area. The 5-HT_2A/2C receptor agonist DOI (10–20 nmol/0.5 μl) significantly reduced NPY overeating while the 5-HT_1A/1B receptor agonist RU 24969 (3.5–14 nmol/0.5 μl) and the 5-HT_1B/2C receptor agonist mCPP (5–20 nmol/0.5 μl) had no such effect. The 5-HT_2A receptor antagonist spiperone (5 μg/0.5 μl) and the corticotropin releasing factor antagonist α-helical-CRF^9–41 (0.5–1 μg/0.5 μl completely antagonized the effect of 10 nmol DOI.     

Effects of the 5-HT3 receptor agonist 1-(m-chlorophenyl)-biguanide in the rat kindling model of epilepsy

The present study was conducted to identify serotonin (5-HT) receptor subtypes involved in the development of amygdala (AM) kindling. We used 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT_1A agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT₂ agonist, both of which were injected subcutaneously 15 min prior to each daily electrical stimulation to the rat AM. Treatment with 8-OH-DPAT (1 mg/kg) slightly suppressed behavioral and electrographic seizure development during the course of kindling. In contrast, DOI (1 mg/kg) strongly facilitated kindling development and reduced the number of stimulations needed to produce generalized seizures. These facilitatory effects of DOI were completely blocked by pretreatment with a 5-HT₂ antagonist ketanserin. The present results suggest that the activation of 5-HT_1A receptors can retard the development of AM kindling, whereas 5-HT₂ receptors play a facilitatory role in this developmental seizure process.     

Regulation of GABA release via NMDA and 5-HT1A receptors in guinea pig dentate gyrus

The regulation by N-methyl-d-aspartate (NMDA) and 5-HT_1A receptors of the endogenous γ-aminobutyric acid (GABA) release was investigated in slices of the guinea pig dentate gyrus. The release of GABA was increased in a concentration-dependent fashion by NMDA. The release of GABA evoked by NMDA was Ca²⁺-dependent, tetrodotoxin-resistant, Mg²⁺-sensitive and inhibited by MK-801, a selective non-competitive NMDA receptor antagonist. These results suggest that the NMDA receptor present on GABAergic neurons is involved in the stimulatory regulation of GABA release. The release of GABA was increased concentration-dependently by NAN-190, a 5-HT_1A receptor antagonist, but was not affected by 8-OH-DPAT, a 5-HT_1A receptor agonist. The release of GABA evoked by NAN-190 was Ca²⁺-dependent, tetrodotoxin-resistant and inhibited by 8-OH-DPAT. These results suggest that the 5-HT_1A receptor present on GABAergic neurons is involved in the inhibitory regulation of GABA release. The release of GABA evoked by NMDA from the dentate gyrus was inhibited by pretreatment with 8-OH-DPAT. The release of GABA evoked by NAN-190 was inhibited by pretreatment with MK-801. The release of GABA evoked by NMDA from the dentate gyrus was augmented by the concurrent application of NAN-190. Taken together, the results indicate that the NMDA receptor and the 5-HT_1A receptor, which are both located on GABAergic neurons in the guinea pig dentate gyrus, exert stimulatory and inhibitory regulation of neuronal GABA release, respectively.     

Synergism Between a Serotonin 5-HT2A Receptor (5-HT2AR) Antagonist and 5-HT2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction

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5-HT2 receptor regulation of acetylcholine release induced by dopaminergic stimulation in rat striatal slices

The role of 5-hydroxytryptamine (5-HT) receptor subtypes in acetylcholine (ACh) release induced by dopamine or neurokinin receptor stimulation was studied in rat striatal slices. The dopamine D₁ receptor agonist SKF 38393 potentiated in a tetrodotoxin-sensitive manner the K⁺-evoked [³H]ACh release while SCH 23390, a dopamine D₁ receptor antagonist, had no effect. [³H]ACh release was decreased by the dopamine D₂ receptor agonist LY 171555 (quinpirole) and slightly potentiated by the dopamine D₂ receptor antagonist haloperidol. The selective neurokinin NK₁ receptor agonist [Sar⁹, met(O₂)¹¹]SP also potentiated K⁺-evoked release of [³H]ACh. GR 82334, a NK₁ receptor antagonist, blocked not only the effect of [Sar⁹, met(O₂)¹¹]SP but also the release of ACh induced by the D₁ receptor agonist SKF 38393. Among the 5-HT agents studied, only the 5-HT_2A receptor antagonists ketanserin and ritanserin were able to reduce the ACh release induced by dopamine D₁ receptor stimulation. Mesulergine, a more selective 5-HT_2C antagonist, showed an intrinsic releasing effect but did not affect K⁺-evoked ACh release induced by SKF 38393. Methysergide and methiothepin, mixed 5-HT_1/2 antagonists, as well as ondansetron, a 5-HT₃ receptor antagonist, showed an intrinsic effect on ACh release, their effects being additive to that of SKF 38393. 5-HT₂ receptor agonists were ineffective. However, the 5-HT₂ agonist DOI was able to prevent the antagonism by ketanserin of the increased [³H]ACh efflux elicited by SKF 38393, suggesting a permissive role of 5-HT_2A receptors. None of the above indicated 5-HT agents was able to reduce the ACh release induced by the selective NK₁ agonist. The results suggest that 5-HT₂ receptors, probably of the 5-HT_2A subtype, modulate the release of ACh observed in slices from the rat striatum after stimulation of dopamine D₁ receptors. It seems that this serotonergic control is exerted on the interposed collaterals of substance P-containing neurons which promote ACh efflux through activation of NK₁ receptors located on cholinergic interneurons.     

5-HT(2A) receptor activation in the dorsolateral septum facilitates inhibitory avoidance in the elevated T-maze

Serotonin in the lateral septum has been implicated in the modulation of defense and hence in anxiety. However, it deserves investigation how changes in 5-HT-mechanisms in this area modulate defensive responses associated with specific subtypes of anxiety disorders. We evaluated the effects of intra-dorsolateral septum (DLS) injections of the preferential 5-HT_2A receptor agonist DOI (8 and 16 nmol), the 5-HT_2C selective agonist MK-212 (0.1 and 1 nmol) and the preferential 5-HT_2A antagonist ketanserin (10 and 20 nmol) in rats exposed to the elevated T-maze (ETM), a model which allows the measurement of two defensive responses: inhibitory avoidance and escape. These responses have been respectively related to generalized anxiety and panic disorder. All animals were tested in an open-field after the ETM for locomotor activity assessments. Results showed that intra-DLS DOI increased avoidance latencies, an anxiogenic effect. MK and ketanserin were without effect. Also, none of the drugs administered affected the escape performance. Ketanserin blocked the anxiogenic effect caused by DOI. No changes to locomotion were observed. The data suggests that DLS 5-HT_2A receptors are involved in the control of inhibitory avoidance and that a failure in this mechanism may be of importance to the physiopathology of generalized anxiety.