5-HT1A receptors in the dorsal hippocampus mediate the anxiogenic effect induced by the stimulation of 5-HT neurons in the median raphe nucleus.

We evaluated the involvement of dorsal hippocampus (DH) 5-HT1A receptors in the mediation of the behavioral effects caused by the pharmacological manipulation of 5-HT neurons in the median raphe nucleus (MRN). To this end, we used the rat elevated T-maze test of anxiety. The results showed that intra-DH injection of the 5-HT1A/7 agonist 8-OH-DPAT facilitated inhibitory avoidance, an anxiogenic effect, without affecting escape. Microinjection of the 5-HT1A antagonist WAY-100635 was ineffective. In the elevated T-maze, inhibitory avoidance and escape have been related to generalized anxiety and panic disorders, respectively. Intra-MRN administration of the excitatory amino acid kainic acid, which non-selectively stimulates 5-HT neurons in this brain area facilitated inhibitory avoidance and impaired escape performance, but also affected locomotion. Intra-MRN injection of WAY-100635, which has a disinhibitory effect on the activity of 5-HT neurons in this midbrain area, only facilitated inhibitory avoidance. Pre-administration of WAY-100635 into the DH blocked the behavioral effect of intra-MRN injection of WAY-100635, but not of kainic acid. These results indicate that DH 5-HT1A receptors mediate the anxiogenic effect induced by the selective stimulation of 5-HT neurons in the MRN.     

Stimulation of 5-HT1A receptors in the dorsal raphe ameliorates the impairment of spatial learning caused by intrahippocampal 7-chloro-kynurenic acid in naive and pretrained rats

OBJECTIVE: The present study investigated the effect of stimulating 5-HT(1A) receptors in the dorsal raphe on the impairment of spatial learning caused by intrahippocampal 7-chloro-kynurenic acid (7-Cl-Kyn) in naive rats and in rats familiar with the general requirements of the task. METHODS: A week after implantation of cannulae to give access to the dorsal raphe (DR) and the CA1 region of the dorsal hippocampus, rats started their 5 days acquisition training on a two-platform spatial discrimination task in a water maze. On each acquisition day, WAY 100635 and 8-OH-DPAT alone or in combination were injected into the dorsal raphe (DR) 5 min before intrahippocampal injections of 7-Cl-Kyn which was given 10 min before the training session. Similar experiments were conducted in rats that had been familiarized with the general requirements of the task by pretraining them in the water maze in the absence of distal cues. RESULTS: 7-Cl-Kyn (3 microg/microl), injected bilaterally in the CA1 region of the dorsal hippocampus, impaired choice accuracy with no significant effect on choice latency. Rats treated with 7-Cl-Kyn tended to spend more time swimming close to the pool walls and made more errors of omission than controls in the first two sessions. Administered into the DR, the 5-HT1A receptor agonist 8-OH-DPAT (1 microg/0.5 microl) had no effect on any parameter of rats' performance but antagonized the impairment of choice accuracy caused by intrahippocampal 7-Cl-Kyn. Injected into the DR, 1 microg/0.5 microl WAY 100635, a 5-HT(1A) receptor antagonist, had no effect on rats' performance or on the impairment caused by intrahippocampal 7-Cl-Kyn, but antagonized the effect of 8-OH-DPAT on the 7-Cl-Kyn-induced deficit. The non-mnemonic behavioral disturbances shown by naive rats treated with 7-Cl-Kyn were greatly reduced in pretrained rats which, nevertheless, showed a marked impairment of choice accuracy similar to that of naive rats. As in previous experiments, administration of 1 microg/0.5 microl 8-OH-DPAT in the dorsal raphe antagonized the impairment of choice accuracy caused by intrahippocampal 7-Cl-Kyn without any effect on other parameters of rats' performance. CONCLUSIONS: The results show that stimulation of presynaptic 5-HT(1A) receptors in the dorsal raphe counteracts the deficit in spatial learning caused by a reduced NMDA-mediated excitatory input on pyramidal cells in the hippocampus. The possible mechanisms and the importance of these findings for the symptomatic treatment of memory disorders in man are discussed.     

Anxiogenic effects of nicotine in the dorsal hippocampus are mediated by 5-HT1A and not by muscarinic M1 receptors

After direct administration into the dorsal hippocampus nicotine decreased the time spent in social interaction, without changing locomotor activity, indicating an anxiogenic effect. The possibility that post-synaptic M1 muscarinic receptors mediated this effect was examined by determining whether dorsal hippocampal administration of a specific M1 receptor agonist (McN-A-343) had anxiogenic effects, and whether the anxiogenic effect of nicotine could be reversed by co-administration of the M1 receptor antagonist, pirenzepine. McN-A-343 (0.3, 1.6, 3.2, 15.8 nmol) was without effect on social interaction, and pirenzepine (0.7 and 2.4 nmol) injection into the dorsal hippocampus failed to reverse the decrease in social interaction caused by nicotine (6.3 nmol) injection into this area. However, the decrease in social interaction after nicotine (50 nmol) was completely reversed by the specific 5-HT1A receptor antagonist, WAY 100635 (0.4 nmol) after co-administration of both drugs into the dorsal hippocampus. Thus, the anxiogenic effect of nicotine in this brain region seems to be mediated by 5-HT1A, but not M1, receptors. In contrast to the effect of nicotine in naive animals, those retested after a second injection of 50 nmol did not show a significant anxiogenic effect. The theoretical implications of this are discussed and from a practical point of view this suggests caution in the retesting of animals after central injections.     

Potentiating effect of morphine on seizures induced by kainic acid in rats

Summary The effect of morphine pretreatment on kainic acid-induced seizures in rats was investigated by electroencephalographic recording. Seizure activity was quantified by counting the number of spikes in the EEG of freely-moving rats during 2 min periods at 30 min intervals after the intraperitoneal administration of 8, 10 or 12 mg/kg kainic acid. Pretreatment with morphine (1–10 mg/kg s.c.) 10 min before kainic acid administration significantly increased the number of spikes in the EEG in a dose-dependent manner. The potentiating effect of morphine on kainic acid-induced seizures was reduced considerably, but not abolished completely by pretreatment with naloxone (2–5 mg/kg s.c.). The results indicate that the potentiating action of morphine on kainic acid-induced seizures may be exerted in both a specific, naloxone-reversible manner and a non-specific, naloxone-resistant manner.     

Postsynaptic 5-HT1B receptors modulate electroshock-induced generalised seizures in rats

1. Although an important regulatory role for serotonin (5-HT) in seizure activation and propagation is well established, relatively little is known of the function of specific 5-HT receptor subtypes on seizure modulation. 2. The aim of the present study was to investigate the role of 5-HT(1A, 1B and 1D) receptors in modulating generalised seizures in the rat maximal electroshock seizure threshold (MEST) test. 3. The mixed 5-HT receptor agonists SKF 99101 (5-20 mg kg(-1) i.p.) and RU 24969 (1-5 mg kg(-1) i.p.), 0.5 h pretest, both produced marked dose-related increases in seizure threshold. These agents share high affinity for 5-HT(1A, 1B and 1D) receptors. 4. Antiseizure effects induced by submaximal doses of these agonists were maintained following p-chlorophenylalanine (150 mg kg(-1) i.p. x 3 days)-induced 5-HT depletion. 5. The anticonvulsant action of both SKF 99101 (15 mg kg(-1) i.p.) and RU 24969 (2.5 mg kg(-1) i.p.) was dose-dependently abolished by the selective 5-HT1B receptor antagonist SB-224289 (0.1-3 mg kg(-1) p.o., 3 h pretest) but was unaffected by the selective 5-HT1A receptor antagonist WAY 100635 (0.01-0.3 mg kg(-1) s.c., 1 h pretest). This indicates that 5-HT1B receptors are primarily involved in mediating the anticonvulsant properties of these agents. 6. In addition, the ability of the 5-HT(1B/1D) receptor antagonist GR 127935 (0.3-3 mg kg(-1) s.c., 60 min pretest) to dose-dependently inhibit SKF 99101-induced elevation of seizure threshold also suggests possible downstream involvement of 5-HT1D receptors in the action of this agonist, although confirmation awaits the identification of a selective 5-HT1D receptor antagonist. 7. Overall, these data demonstrate that stimulation of postsynaptic 5-HT1B receptors inhibits electroshock-induced seizure spread in rats.     

Regulation of conditioned and unconditioned fear in rats by 5-HT1A receptors in the dorsal periaqueductal gray

Studies on the involvement of 5-HT1-mediated mechanisms in the dorsal periaqueductal gray (dPAG) of animals with past stressful experiences have not been conducted so far. We investigated the role of 5-HT1 receptors in the dPAG of rats previously submitted to contextual fear conditioning. Defensive behaviors induced by activation of the dPAG were assessed by measuring the lowest electric current applied to this structure (threshold) able to produce freezing and escape responses during testing sessions of contextual fear conditioning, in which animals were placed in a context previously paired to footshocks. The 5-HT1A function of the dPAG was evaluated by local injections of 8-OH-DPAT (4 and 8 nmol/0.2 microL) and WAY-100635 (10 nmol/0.2 microL), selective agonist and antagonist of 5-HT1A receptors, respectively. In accordance with previous studies, 8-OH-DPAT increased aversive thresholds (antiaversive effects) but injections of WAY 100635 into the dPAG did not produce significant effects on the aversive thresholds in naive rats. However, the aversive thresholds of animals exhibiting contextual fear remained unchanged with both treatments. Moreover, 8-OH-DPAT and WAY 100635 did not change the dPAG post-stimulation freezing. The present results suggest that the stressful experience of being fear conditioned has an effect on the role of the 5-HT1A receptors in mediating unconditioned fear. Also, the reduction in the regulation of the defensive behaviors by 5-HT1A-mediated mechanisms in the dPAG of these animals may underlie the stress precipitated psychopathology associated with the neural substrates of aversion of the dPAG.     

Serotonin 5-HT1-like receptors mediate hyperactivity in rats induced by 3,4-methylenedioxymethamphetamine.

This study was designed to evaluate the role of different serotonin (5-HT) receptor subtypes in mediating the effects of 3,4-methylenedioxymethamphetamine (MDMA) on rat exploration of a novel environment. The active enantiomer of MDMA, S-MDMA increases forward locomotion and suppresses investigatory behaviors and local movements. Previous studies indicate that S-MDMA-induced hyperactivity depends upon drug-induced 5-HT release. Propranolol and pindolol, beta-noradrenergic antagonists with affinity for 5-HT1 receptors, antagonized the S-MDMA-induced locomotor hyperactivity. The antagonism by propranolol was stereoselective. In contrast, a beta-noradrenergic antagonist that is a weaker antagonist of 5-HT receptors, betaxolol, was much less effective at blocking the behavioral response to S-MDMA. Among nonselective 5-HT antagonists, methiothepin was effective and methysergide and cyproheptadine were ineffective as antagonists of S-MDMA-induced hypermotility. In other systems, methiothepin has been found to be a good antagonist at 5-HT1B receptors where methysergide and cyproheptadine are ineffective. The 5-HT2 antagonist ritanserin was ineffective in blocking S-MDMA-induced hypermotility. However, ritanserin, methysergide, and cyproheptadine partially reversed the S-MDMA-induced suppression of investigatory responding, suggesting a contribution of 5-HT2 receptor activation to this component of the behavioral response to S-MDMA. This study indicates that S-MDMA produces a characteristic form of locomotor hyperactivity in rats that depends upon activation of 5-HT1-like receptors, possibly of the 5-HT1B subtype.     

Electrophysiology of 5-HT1A receptors in the rat hippocampus and cortex

Electrophysiological recordings from hippocampus and cortex have demonstrated that one of the most prominent effects of serotonin in these regions is a membrane hyperpolarization that effectively inhibits neuronal activity. The use of the in vitro brain slice preparation has allowed for detailed pharmacological and physiological studies of this response. Pharmacological analysis using agonists and antagonists indicates that these responses are mediated by activation of receptors of the 5-HT_1A subtype. Buspirone, ipsapirone and 8-OHDPAT are all partial agonists at this receptor with 8-OHDPAT exhibiting an intrinsic activity approximately one-fourth that of serotonin. The ability of 5-HT_1A receptor agonists to elicit a hyperpolarization is dependent on intracellular GTP, suggesting the involvement of a G protein in the transmembrane signalling mechanism. In agreement with this idea, injection of the stable GTP analog GTPγS renders the serotonin induced hyperpolarization irreversible, while GDPβS blunts its effects and pertussis toxin pretreatment blocks it. The 5-HT_1A receptor induced hyperpolarization is mediated by an increase in potassium conductance. While the identity of the potassium channel remains to be determined, its basic characteristics identify it as belonging to a general class of inwardly rectifying G protein activated potassium channels ubiquitously distributed in neuronal and cardiac muscle tissues. In the rat hippocampus and cortex, most pyramidal cells co-express 5-HT_1A with either 5-HT₄ or 5-HT₂ receptors, respectively, which in turn act to increase the ability of strong stimuli to excite these cells. As a result the net effect of serotonin on membrane excitability is dependent on the strength of incoming stimuli. Weak stimuli are depressed by the coactivation of these receptor subtypes while strong stimuli are enhanced. Thus the effects of selective 5-HT_1A ligands are likely to depend not only on their direct effect on membrane excitability but also on how they alter ongoing serotonergic neurotransmission. © 1992 Wiley-Liss, Inc.     

Stimulation of postsynaptic 5-HT1A receptors is responsible for the anticonflict effect of ipsapirone in rats.

Ipsapirone (1.25-10 mg kg-1), a non-benzodiazepine anxiolytic drug with high affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, increased dose-dependently the number of punished licks in the drinking conflict test (Vogel test) in rats. The anticonflict effect of the drug administered at a dose of 5 mg kg-1 was not modified in animals with lesions of 5-HT neurones, produced by p-chloroamphetamine (PCA, 2 x 10 mg kg-1). The anticonflict effect of ipsapirone in PCA-pretreated rats was antagonized by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist NAN-190 (1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)]butylpiperazine hydrobromide; 0.5-1 mg kg-1), but not by the selective alpha 1-adrenoceptor blocker prazosin (0.5 mg kg-1). Neither NAN-190 nor prazosin affected the punished response in PCA-pretreated rats. The present results indicate that the anticonflict effect of ipsapirone depends on stimulation of postsynaptic 5-HT1A receptors.     

Effects of fluoxetine and buspirone on the panicolytic-like response induced by the activation of 5-HT1A and 5-HT2A receptors in the rat dorsal periaqueductal gray

Rationale Administration of 5-hydroxytryptamine (5-HT)_1A and 5-HT_2A receptor agonists into the dorsal periaqueductal gray (DPAG) inhibits escape, a defensive behavior associated with panic attacks. Long-term treatment with the antipanic compound imipramine enhances the DPAG 5-HT_1A- and 5-HT_2A-receptor-mediated inhibition of escape, implicating these receptors in the mode of action of panicolytic drugs. Objectives In the present study, we investigated whether the inhibitory effect on escape elicited by the intra-DPAG injection of 5-HT_1A and 5-HT_2A receptor agonists is also enhanced after treatment with fluoxetine, another widely used antipanic drug. The effects of fluoxetine were compared to those of buspirone, an anxiolytic drug without major effect on panic disorder. Methods Male Wistar rats, subchronically (3–6 days) or chronically (21–24 days) treated with fluoxetine (10 mg/kg i.p.) or chronically treated with buspirone (0.3 mg/kg i.p.), were intra-DPAG injected with 5-HT (20 nmol), the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 8 nmol) or the preferential 5-HT_2A receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl) piperazine dihydrochloride (DOI; 16 nmol). The intensity of electrical current that applied to the DPAG-evoked escape behavior was measured before and after the microinjection of these agonists. Results The electrical current necessary to produce escape was increased after the microinjection of the three 5-HT receptor agonists in all groups of animals tested. However, this panicolytic-like effect was significantly higher in animals receiving long-term treatment with fluoxetine. Conclusions The results suggest that facilitation of the 5-HT_1A- and 5-HT_2A-receptor-mediated inhibition of DPAG neuronal activity is implicated in the beneficial effect of antidepressants in panic disorder.     

Central administration of 5-HT activates 5-HT1A receptors to cause sympathoexcitation and 5-HT2/5-HT1C receptors to release vasopressin in anaesthetized rats.

1. The effects of intracerebroventricular injections to the right lateral ventricle (i.c.v.) of 5-hydroxytryptamine (5-HT, 40 and 120 nmol kg-1), N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT; 3 nmol kg-1), 5-carboxamidotryptamine (5-CT; 3 nmol kg-1), 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT; 3, 40 and 120 nmol kg-1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 40 and 120 nmol kg-1) on renal sympathetic nerve activity, blood pressure, heart rate and phrenic nerve activity were investigated in normotensive rats anaesthetized with alpha-chloralose. 2. 5-HT caused a long lasting pressor response which was associated with an initial bradycardia and renal sympathoinhibition followed by a tachycardia and renal sympathoexcitation. Pretreatment with the 5-HT2/5-HT1C receptor antagonists, cinanserin (300 nmol kg-1, i.c.v.) or LY 53857 (300 nmol kg-1, i.c.v.) reversed the initial bradycardia and sympathoinhibition to tachycardia and sympathoexcitation. Combined pretreatment with LY 53857 (300 nmol kg-1, i.c.v.) and the 5-HT1A antagonist, spiroxatrine (300 nmol kg-1, i.c.v.), blocked the effects of 5-HT on all the above variables. 3. Pretreatment with the vasopressin V1-receptor antagonist, beta-mercapto-beta,beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8-vasopressin [(d(CH2)5Tyr(Me)AVP, 10 micrograms kg-1, i.v.] did not affect the magnitude but reduced the duration of the pressor response produced by i.c.v. 5-HT and reversed the initial bradycardia and renal sympathoinhibition to tachycardia and sympathoexcitation. 4. 1-(2,5-Di-methoxy-4-iodophenyl)-2-aminopropane (DOI) caused a pressor effect which was associated with a bradycardia and sympathoinhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endogenous 5-HT tonically inhibits spontaneous firing activity of dorsal hippocampus CA1 pyramidal neurons through stimulation of 5-HT(1A) receptors in quiet awake rats: in vivo electrophysiological evidence.

The present study was performed to examine an overall effect of endogenous serotonin (5-HT) on the spontaneous firing activity of the dorsal hippocampus CA1 pyramidal neurons in quiet awake rats. A selective 5-HT(1A) antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohe xanecarboxamide (WAY-100635: 0.03-0.2 mg/kg, s.c.) significantly increased the firing activity. A depletion of 5-HT with parachlorophenylalanine (PCPA: 500 mg/kg/day x 3 days) completely abolished this increasing effect of WAY-100635. The baseline spike frequency of the PCPA-treated rats (3.90 +/- 0.39 Hz) was significantly higher than that of the vehicle-treated rats (2.09 +/- 0.19 Hz). A 5-HT(2A) antagonist ritanserin (1 mg/kg, i.p.) and a 5-HT(3/4) antagonist 2-methoxy-4-amino-5-chloro benzoic acid 2-(diethylamino) ethyl ester (SDZ-205557: 3 mg/kg, s.c.) did not modify the firing activity and the increasing effect of WAY-100635. These results suggest that, in quiet awake rats, endogenous 5-HT would tonically inhibit the spontaneous firing activity of the CA1 pyramidal neurons mainly through stimulating 5-HT(1A) receptors.     

Chronic treatment with fluvoxamine by osmotic minipumps fails to induce persistent functional changes in central 5-HT1A and 5-HT1B receptors,as measured by in vivo microdialysis in dorsal hippocampus of conscious rats

This study investigated the alterations of the 5-HT_1A and 5-HT_1B autoreceptor function following chronic treatment with fluvoxamine using osmotic minipumps. The 5-HT_1A and 5-HT_1B autoreceptor function were studied using microdialysis in the dorsal hippocampus. The effect of the 5-HT_1A receptor agonist 8-OH-DPAT (0.3 mg/kg, SC) and the 5-HT_1B receptor agonist RU-24969 (100 nM through the dialysis probe for 30 min) on 5-HT release was compared with rats chronically treated with saline. 8-OH-DPAT decreased 5-HT release to 55% and 60% of baseline, while RU-24969 decreased 5-HT release to 66% and 70% of baseline value in the saline and fluvoxamine group, respectively. In both cases, differences between the saline and fluvoxamine groups were not statistically significant. Plasma levels of fluvoxamine after 21 days of treatment ranged from 3 to 5 ng/ml. Fluvoxamine concentration in rat brain during treatment was estimated between 100 and 200 nM, which approximates to the IC₅₀ value of fluvoxamine on the 5-HT transporter in synaptosomes and is 50 times higher than the K_d value for the 5-HT reuptake site. In conclusion, no evidence was found for changes in 5-HT_1A,B receptor function using 8-OH-DPAT and RU-24969 as probes after continuous treatment with fluvoxamine by means of osmotic minipumps.     

Peripheral 5-HT1B and 5-HT2A receptors mediate the nociceptive response induced by 5-hydroxytryptamine in mice

While the role of 5-hydroxytryptamine (5-HT, serotonin) in the nociceptive processing has been widely investigated in the central nervous system, information regarding its role in peripheral tissues is still lacking. Noteworthy, 5-HT induces phenotypic changes of nociceptors and peripheral injection induces pain in humans and nociceptive response in rodents. However, local receptors involved in 5-HT effects are not well characterized. Thus, we aimed to investigate the role of 5-HT and some of its receptors in the peripheral nociceptive processing in mice. Intraplantar injection of 5-HT (10, 20 or 40 μg) into the hind-paw of mice induced paw licking behavior, which was inhibited by previous intraplantar treatment with cyproheptadine (5-HT₁ and 5-HT₂ antagonist; 0.5 or 5 μg), mianserin (5-HT₂ and 5-HT₆ antagonist; 0.1 μg), isamoltane (5-HT_1B antagonist; 0.5 or 5 μg) and ketanserin (5-HT_2A antagonist; 0.1 or 1 μg), but not by BRL 15572 (5-HT_1D antagonist; 1 or 10 μg), ondansetron (5-HT₃ antagonist; 1, 5, 10 or 20 μg) and SB 269970 (5-HT₇ antagonist; 2.5 and 25 μg). Altogether, these results indicate the local involvement of 5-HT₁, 5-HT₂ and 5-HT₆, especially 5-HT_1B and 5-HT_2A, in the nociceptive response induced by 5-HT in mice, thus contributing to a better understanding of 5-HT role in the peripheral nociceptive processing. In addition, they also point to important species differences and the need of a wide evaluation of the peripheral nociceptive processing in mice as these animals have been increasingly used in studies investigating the cellular and molecular mechanisms mediating the nociceptive response.     

The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats

Rationale The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm.Objectives A series of interaction studies using the serotonin (5-HT)_1A antagonist WAY-100635 (1.0 mg/kg), the 5-HT_2A antagonist M100907 (1.0 mg/kg), and the 5-HT_2C antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms.Results 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT.Conclusions While the prevailing view was that the activation of 5-HT₂ receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT_1A receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.     

Opposing roles for 5-HT1B and 5-HT3 receptors in the control of 5-HT release in rat hippocampus in vivo.

1. Intracerebral microdialysis was used to determine whether 5-hydroxytryptamine (5-HT) release in the ventral hippocampus of rats anaesthetized with chloral hydrate was modulated by 5-HT3 receptors. 2. It was confirmed that 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969), a selective 5-HT1B receptor agonist, decreased 5-HT release in a dose- and concentration-related manner when administered i.p. (1 and 5 mg kg-1) or via the dialysis probe (0.1 and 1 microM) respectively. The effect of RU 24969 infusion (1 microM) was attenuated by concurrent infusion of metitepine (10 microM) into the hippocampus. 3. When infused into the hippocampus for 15 min, the selective 5-HT3 receptor agonist, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT; 0.1- 10 microM) increased dialysate 5-HT levels in a concentration-related manner; an effect which was abolished by concurrent infusion of 3-tropanyl-3,5-dichlorobenzoate (1 microM, MDL 72222), a selective 5-HT3 antagonist. 4. MDL 72222 had no effects on hippocampal 5-HT release when administered via the dialysis probe (1 or 10 microM). 5. The data show that 5-HT3 and 5-HT1B receptors have opposing roles in the control of 5-HT release in the hippocampus, with 5-HT3 receptors facilitating and 5-HT1B receptors inhibiting 5-HT efflux, respectively. They also indicate that the facilitatory 5-HT3 receptors are not tonically activated.     

5-HT1A receptor agonist affects fear conditioning through stimulations of the postsynaptic 5-HT1A receptors in the hippocampus and amygdala

Evidence from preclinical and clinical studies has shown that 5-HT(1A) receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT(1A) receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT(1A) receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT(1A) receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats. These results reveal that both intrahippocampal and intraamygdala injections of flesinoxan decreased the expression of conditioned freezing, while injections into the medial prefrontal cortex did not. In addition, intraamygdala injection of flesinoxan attenuated the increased defecation induced by conditioned fear, but injections into the hippocampus and medial prefrontal cortex failed. These results suggest that flesinoxan exerts its anxiolytic actions in the fear conditioning through stimulations of the postsynaptic 5-HT(1A) receptors in the hippocampus and amygdala.     

Cholinergic terminals in rat hippocampus possess 5-HT1B receptors mediating inhibition of acetylcholine release

The effects of 5-hydroxytryptamine (5-HT) on the release of [3H]acetylcholine ([3H]ACh) from rat hippocampal nerve endings were investigated using synaptosomes labelled with [3H]choline and depolarized in superfusion with 15 mM KCl. The release of [3H]ACh was concentration dependently inhibited by exogenous 5-HT. The concentration-response curve of 5-HT was shifted to the right in a parallel way by methiothepin. The 5-HT2 antagonists ketanserin or methysergide did not antagonize the effect of 5-HT. The 5-HT1 agonist 5-methoxy-3-[1,2,3,6-tetrahydropyridin-4-yl]-1H-indole (RU 24969) mimicked 5-HT, whereas the 5-HT1A selective agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was ineffective. When used as a 5-HT1A/5-HT1B antagonist, (-)propranolol antagonized 5-HT whereas spiperone (a 5-HT1A displacer) did not. The 5-HT1C selective antagonist mesulergine was also ineffective towards 5-HT. It can be concluded that hippocampal cholinergic terminals are endowed with inhibitory 5-HT receptors which appear to belong to the 5-HT1B subtype.     

Stimulation of 5-HT1A and 5-HT1B receptors in brain regions and its effects on male rat sexual behaviour.

In the present series of experiments we compared the effect of injecting serotonin (40 micrograms/cannula), the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (5.0 micrograms/cannula), and the 5-HT1B/C agonist, trifluoromethyl-phenyl-piperazine (TFMPP) (1.0 micrograms/cannula), into the preoptic area, the nucleus accumbens and the nucleus raphe dorsalis. The dose injected was selected on the basis of dose-response curves. Injection of serotonin and TFMPP into the medial preoptic area and nucleus accumbens resulted in an inhibition of male sexual behaviour, as evidenced by an increase in the number of mounts and a prolongation of the ejaculation latency. Injection of 8-OH-DPAT into these brain areas facilitated copulatory behaviour as evidenced by a reduction in the number of mounts, intromissions and ejaculation latency. Administration of these compounds into the nucleus raphe dorsalis produced no effect, except for a prolongation of the intromission latency after serotonin. These results would suggest that at least some of the 5-HT1A receptors involved in the facilitation of male sexual behaviour are located postsynaptically in limbic brain areas that regulate male sexual behaviour. On the basis of the similarities between the inhibitory effects of serotonin and TFMPP, the present results further support the idea that endogenous serotonin acts via the stimulation of 5-HT1B receptors to inhibit male sexual behaviour.     

3，4－二氯苯丙烯酰另丁胺对卡英酸致惊作用的影响

３，４－二氯苯丙烯酰另丁胺对卡英酸致惊作用的影响刘福君，陶成（北京医科大学药理教研室，北京１０００８３）卡英酸（ｋａｉｎｉｃａｃｉｄ，ＫＡ）是一种外源性氨基酸，对哺乳动物的中枢神经系统具有很强的兴奋作用及神经毒性，可造成特定的神经元退变性组织学改变和...