The absence of 5-HT<Subscript>1A</Subscript> receptors has minor effects on dopamine but not serotonin release evoked by MK-801 in mice prefrontal cortex

RATIONALE: Non-competitive NMDA receptor antagonists markedly increase neuronal activity in medial prefrontal cortex (mPFC), an effect which partly underlies their schizomimetic actions. Projection pyramidal neurons and local GABAergic interneurons in mPFC express 5-HT(1A) receptors, whose activation modulates dopaminergic (DA) and serotonergic (5-HT) activity in midbrain and the cortical release of both monoamines. OBJECTIVE: To examine whether the presence of 5-HT(1A) receptors can modulate the effect of NMDA receptor blockade with MK-801 (dizocilpine) on DA and 5-HT release in mouse mPFC. MATERIALS AND METHODS: Brain microdialysis and locomotor activity measures in wild-type and 5-HT(1A) receptor knockout mice. RESULTS: Systemic MK-801 administration (0.125, 0.25, 0.50, and 1 mg/kg i.p.) induced a dose-dependent increase in mPFC 5-HT output, which was independent of the genotype. MK-801 increased DA output in a dose-dependent manner with a significant effect of genotype on low doses (0.125, 0.25 mg/kg). These differences were not paralleled by differences in gross locomotor activity. Overall, MK-801 increased more markedly DA than 5-HT output in both genotypes. Finally, the local perfusion of MK-801 in mPFC (30, 100, 300 muM) by reverse dialysis did not elevate dialysate DA or 5-HT concentrations in mPFC. CONCLUSION: 5-HT(1A) receptors partly modulate the increase in mPFC DA (but not 5-HT) release produced by NMDA receptor blockade. The lack of effect observed after the local MK-801 application suggests that the change in cortical monoamines is mainly driven by subcortical NMDA receptor blockade, without a significant involvement of PFC 5-HT(1A) receptors.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

The non-competitive NMDA receptor antagonist (+)MK-801 counteracts the long-lasting attenuation of the hypothermic response induced by acute doses of 8-OH-DPAT in the rat

The effects of acute doses of 8-hydroxy 2-(di-n-dipropylamino)tetralin (8-OH-DPAT) on the hypothermic response, induced by a challenge dose of 8-OH-DPAT, were examined in rats. Acute doses of 8-OH-DPAT (1.0 or 0.5 mg/kg, s.c.) significantly attenuated the hypothermic response induced by 8-OH-DPAT (0.05 mg/kg, s.c.). The response to 8-OH-DPAT was almost abolished between 4 hr and 4 days and the attenuation of the response lasted for 21 days. On day 28 the response had returned to the control level. The non-competitive (N-methyl- -aspartate) (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo-(a,d)cyclohepten-5,10-imine [(+)MK-801], blocked this long-lasting attenuation of the 8-OH-DPAT-induced hypothermic response. Given on its own, (+)MK-801 did not reduce body temperature, at the doses used in the experiments but the drug did block the acute effects of 8-OH-DPAT, at the same doses which blocked the attenuation of the hypothermic response. The present data suggest that stimulation of glutamate NMDA receptors may underlie the long-lasting effect of acute injections of 8-OH-DPAT.     

Differential effects of 7-OH-DPAT and apomorphine on hyperactivity induced by MK-801 (dizocilpine) in rats

Recent experiments from this laboratory demonstrated synergistic locomotor depressant effects of AMPA/kainate receptor blockade and D(2/3) dopamine (DA) receptor stimulation. This study explored functional interactions between DA and glutamate (Glu) systems using the NMDA receptor antagonist MK-801 and the DA receptor agonists 7-OH-DPAT and apomorphine. Using photocell locomotor activity boxes, systemic effects of MK-801 in combination with 7-OH-DPAT (0.03 mgkg(-1) SC, n=8) or a pre-synaptically effective dose of apomorphine (0.05 mgkg(-1) SC, n=6) were measured in male Sprague-Dawley rats. Effects of bilateral applications of MK-801 and 7-OH-DPAT into the nucleus accumbens (NAS) shell subregion were also investigated (n=7). When given alone, MK-801 (0.13 mgkg(-1) or 0.66 microg intra-NAS shell) increased horizontal locomotor activity, while 7-OH-DPAT (0.03 mgkg(-1)) or apomorphine (0.05 mgkg(-1)) decreased this measure. Co-administration of 7-OH-DPAT (systemically or into the NAS shell) completely blocked MK-801 induced hyperactivity. In contrast, MK-801 and apomorphine demonstrated additive effects. Stimulation of D(3) DA receptors may therefore block the hyperactivity induced by NMDA receptor antagonism, and the NAS shell is an important site for this interaction. The differential effects of the DA agonists on hyperactivity induced by NMDA receptor blockade support the proposal that 7-OH-DPAT may induce hypoactivity by stimulation of postsynaptic D(3) DA receptors.     

Cholesterol reduction attenuates 5-HT1A receptor-mediated signaling in human primary neuronal cultures

Lipid rafts regulate functions of various G protein-coupled receptors and signaling proteins. We show that human primary neuronal cultures contain high levels of 5-HT(1A) receptors. Stimulation with the 5-HT(1A/7) receptor agonist, 8-OH-DPAT, reduced P-T(185)/Y(187)-ERK2. This reduction could be blocked by the 5-HT(1A) receptor antagonist, WAY100635. Pretreatment with the cholesterol sequestering agent, methyl-beta-cyclodextrin, before adding 8-OH-DPAT, significantly counteracted the inhibitory influence of 8-OH-DPAT on P-T(185)/Y(187)-ERK2 and P-S(133)-CREB. These data indicate that reduction of cholesterol levels significantly influence signaling via 5-HT(1A) receptors in intact neurons.     

Differences in the effects of 5-HT1A receptor agonists on forced swimming behavior and brain 5-HT metabolism between low and high aggressive mice

Rationale Male wild house-mice genetically selected for long attack latency (LAL) and short attack latency (SAL) differ in structural and functional properties of postsynaptic serotonergic-1A (5-HT_1A) receptors. These mouse lines also show divergent behavioral responses in the forced swimming test (FST, i.e., higher immobility by LAL versus SAL mice).Objectives We investigated whether the line difference in 5-HT_1A receptors is associated with a difference in brain 5-HT metabolism, and whether acute administration of a 5-HT_1A receptor agonist could differentially affect the behavioral responses of LAL and SAL mice.Methods 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in homogenates of several brain regions using high-performance liquid chromatography. The behavioral effect of the full 5-HT_1A receptor agonist, 8-OH-DPAT, and of the somatodendritic 5-HT_1A autoreceptor agonist, S-15535, was examined in the FST. The effect of 8-OH-DPAT on forced swimming-induced 5-HT metabolism in brain homogenates was determined.Results In most brain regions, 5-HT and 5-HIAA levels and 5-HT turnover were not significantly different between LAL and SAL mice. 8-OH-DPAT abolished the behavioral line difference in the FST by reducing immobility in LAL mice and reducing climbing in SAL mice. S-15535 induced a similar behavioral effect to 8-OH-DPAT in SAL mice, but did not alter the behavior of LAL mice. Compared with LAL, forced swimming elicited in SAL mice a higher brain 5-HT turnover, which was potently attenuated by 8-OH-DPAT.Conclusions It is unlikely that the difference in 5-HT_1A properties between LAL and SAL mice is an adaptive compensatory reaction to changes in 5-HT metabolism. Although unspecific motor effects, at least in SAL mice, cannot be ruled out, it is suggested that the behavioral effects of 8-OH-DPAT and S-15535 may be mediated by predominant activation of postsynaptic 5-HT_1A receptors in LAL mice and by presynaptic 5-HT_1A receptors in SAL mice.     

Long lasting attenuation of 8-OH-DPAT induced corticosterone secretion after a single injection of a 5-HT1A receptor agonist

Summary The effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and some other 5-hydroxytryptamine_1A (5-HT_1A) receptor agonists (buspirone, ipsapirone and flesinoxan) on corticosterone secretion in rats were studied. The 5-HT_1A receptors mediating the corticosterone secretion appear to be postsynaptic to the 5-HT neurons, since the response to 8-OH-DPAT was not decreased but potentiated by depletion of 5-HT with p-chlorophenylalanine pretreatment of the animals. Rapid attenuation of the response was developed after a single dose of a 5-HT_1A receptor agonist. Thus, 1 mg/kg s.c. of 8-OH-DPAT attenuated the response of a challenge dose (0.1 mg/kg s.c.) of this compound within 4 h lasting between 7 and 14 d. The development of the subsensitivity was antagonized by pretreatment of the rats with the 5-HT_1A receptor antagonist S-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((–)-UH 301). This compound also antagonized the acute effect of 8-OH-DPAT in increasing serum corticosterone. The subsensitivity development was specific for the 5-HT_1A receptor-mediated corticosterone secretion, since the increase in serum corticosterone produced by stimulation of other receptor systems, e.g. ₂-adrenoreceptors (clonidine) or 5-HT₂ receptors [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane, (DOI)] was not affected. Send offprint requests to S. B. Ross at the above address     

Behavioral and neurochemical effects of the serotonin (5-HT)1A receptor ligand spiroxatrine

The effects of spiroxatrine, a putative antagonist with selectivity for the serotonin (5-HT)_1A receptor, were compared with compounds believed to function as agonists at the 5-HT_1A receptor. Schedule-controlled responding of pigeons was maintained under a multiple 30-response fixed-ratio (FR), 3-min fixed-interval (FI) schedule or under a schedule in which responding was suppressed by electric shock (conflict procedure). Under the multiple schedule, spiroxatrine (0.3–1.0 mg/kg) decreased FR responding but did not affect FI responding; responding was decreased in both schedule components at 3.0 mg/kg. When administered alone, buspirone, a compound believed to produce its anxiolytic effects through 5-HT_1A agonist actions, produced effects similar to those of spiroxatrine; in combination, the two drugs produced greater effects than when either was administered alone. As with 5-HT_1A agonists such as buspirone and 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) in the pigeon, spiroxatrine (0.01–1.0 mg/kg) increased punished responding. Spiroxatrine and buspirone were potent inhibitors of [³H]8-OH-DPAT binding to pigeon cerebral membranes with IC₅₀ values in the nM range. Neurochemical analyses of metabolite changes produced by spiroxatrine in pigeon cerebrospinal fluid showed buspirone-like effects, with increases in MHPG, DOPAC and HVA at doses that decreased 5-HIAA levels. Spiroxatrine dose-dependently blocked the behavioral effects of the dopamine agonist piribedil indicating that, like buspirone, it also is a potent dopamine antagonist. Spiroxatrine most likely functions as an agonist at the 5-HT_1A receptor. As with buspirone, however, spiroxatrine has a prominent dopamine antagonist component.     

Influence of taste and food texture on the feeding responses induced by 8-OH-DPAT and gepirone

Previously it has been shown that 5-hydroxytryptamine (5-HT)_1A agonists such as 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and gepirone increase food intake in free-feeding rats. These experiments were conducted to examine the possible influence of taste and textural factors on the feeding responses induced by these two drugs. Separate groups of non-water-deprived rats were given access to one of a variety of different solutions of saccharin (0.02, 0.04, 0.20 and 2.0% w/v) or water for 2 h each day. Rats were then treated with different doses of 8-OH-DPAT (10, 60 or 100 µg/kg) or gepirone (1 or 2.5 mg/kg) in a repeated measures design. Under saline injection an inverted-U shaped concentration-response curve was obtained, with the highest level of intake occurring in rats drinking from the 0.20% saccharin solution. The highest doses of 8-OH-DPAT and gepirone suppressed drinking of saccharin, particularly over the first 30 min of the test period, leading to a flattening of the concentration response curve. At 2 h post-injection 60 µg/kg 8-OH-DPAT enhanced the consumption of the 0.04% saccharin solution only. In a second experiment, 8-OH-DPAT or gepirone was administered to rats eating either standard pelleted chow or the same food presented in powdered form. Both drugs stimulated feeding. However, interactions with food type were found. At 60 and 100 µg/kg 8-OH-DPAT increased eating of both food types equally, but with 500 µg/kg rats are significantly more of the pelleted food. Gepirone at 1 and 2.5 mg/kg also significantly increased pelleted food intake compared to powdered food intake. These results suggest that taste factors alone are unlikely to be a major determinant of 8-OH-DPAT's effects on food intake. On the other hand, food texture may play a significant role in the capacity to elicit feeding after high doses of both 8-OH-DPAT and gepirone.     

Attenuation by the 5-HT1A receptor agonist osemozotan of the behavioral effects of single and repeated methamphetamine in mice

This study examined the effects of the selective 5-HT1A receptor agonist osemozotan on repeated methamphetamine (METH)-induced behavioral sensitization and single METH-induced locomotor stimulant effect in mice, and then the neurochemical mechanisms using in vivo microdialysis. Repeated administration of METH for 7 days enhanced METH challenge-induced locomotor activity, and this sensitization was observed even after its withdrawal for 7-14 days. Administration of osemozotan to METH-sensitized mice inhibited the maintenance of behavioral sensitization. This effect was blocked by a low dose of WAY100635, a selective 5-HT1A receptor antagonist. A METH challenge increased the extracellular levels of dopamine (DA), 5-HT, and noradrenaline in the prefrontal cortex, but only the increase in 5-HT release was enhanced by repeated METH administration. This augmented response of 5-HT release was attenuated by osemozotan in a WAY100635-sensitive way. A single administration of osemozotan to drug na?ve mice inhibited METH-induced locomotor stimulant effect and reduced METH-induced increase in prefrontal 5-HT, but not DA, release. These results suggest that prefrontal 5-HT release is involved at least partly in the effects of osemozotan on single and repeated METH-induced behavioral effects in mice, and imply that the 5-HT1A receptors may have a potential therapeutic value in the remission of schizophrenia.     

Relationship between development of cross-sensitization to MK-801 and delayed increases in glutamate levels in the nucleus accumbens induced by a high dose of methamphetamine

Rationale The present study hypothesized that delayed increases in extracellular glutamate (Glu) levels in the nucleus accumbens (NAC), induced by a high dose of methamphetamine (METH), can result in some functional changes of excitatory amino acid receptors, developing behavioral cross-sensitization to a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801.Objectives The present study aims to examine whether two different doses of METH (2.5 and 1.0 mg/kg) induce different effects on the development of cross-sensitization to MK-801. To clarify the mechanisms for development and expression of cross-sensitization to MK-801, we measured extracellular Glu and dopamine (DA) levels in the NAC at METH injections in a treatment period and at MK-801 injection after a 12-day withdrawal period.Materials and methods METH- or MK-801-induced changes in Glu and DA levels and in locomotion were measured using in vivo microdialysis and infrared sensor, respectively.Results METH, at only 2.5 mg/kg, produced delayed increases in Glu levels and developed behavioral cross-sensitization to MK-801 (0.2 mg/kg). MK-801 (0.2 mg/kg) induced delayed increases in Glu levels in the NAC, but this time course was not completely consistent with MK-801-induced enhanced hyperlocomotion. During this time course, MK-801 (0.2 mg/kg) did not induce any changes in DA levels.Conclusions These results suggest that METH-induced, at 2.5 mg/kg, delayed increases in Glu levels are necessary for development of behavioral cross-sensitization to MK-801, but not METH. The enhanced locomotion-inducing effect of MK-801 might be related to some functional changes in excitatory amino acid receptors such as NMDA and dl-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid in the NAC.     

Impulsive action induced by amphetamine, cocaine and MK801 is reduced by 5-HT(2C) receptor stimulation and 5-HT(2A) receptor blockade

Previous work has shown that 5-HT_2C receptor agonists and 5-HT_2A receptor antagonists reduce impulsive action, as well as the locomotor stimulant effect of psychomotor stimulants. Since psychomotor stimulants also increase impulsive action we examined the effects of the 5-HT_2C receptor agonist Ro60-0175, and the 5-HT_2A receptor antagonist M100907 on impulsive action induced by amphetamine, cocaine and the NMDA receptor antagonist MK801 (dizocilpine). Impulsive action was measured in adult male Long-Evans rats as premature responding in the 5-choice serial reaction time (5-CSRT) test. Initially, we determined that amphetamine (0.3 mg/kg), cocaine (15 mg/kg) and MK801 (0.03 mg/kg) induced comparable premature response rates of approximately 50-70 per session, compared to 10-15 responses under baseline conditions. Each drug and its vehicle were then tested in combination with Ro60-0175 (0.1 and 0.6 mg/kg) or its vehicle, or M100907 (0.5 mg/kg) or its vehicle. At 0.1 mg/kg Ro60-0175 did not modify the effects of amphetamine, cocaine or MK801. In contrast, the 0.6 mg/kg dose reduced premature responses induced by amphetamine, cocaine and MK801. M100907 also reduced premature responding induced by all three of these drugs. In general, treatment with Ro60-0175 or M100907 by itself did not consistently alter any of the other aspects of task performance in the 5-CSRT test including number of trials completed, and accuracy of responding. These data show that activation of 5-HT_2C receptors and blockade of 5-HT_2A receptors have seemingly similar functional effects on a measure of impulsive action.     

5HT1A agonist, 8-hydroxy-2-(DI-n-propylamino)tetralin (8-OH-DPAT), inhibits non-opioid analgesia in defeated mice: influence of route of administration

Recent studies have suggested that anxiety may be an important factor in the non-opioid analgesic response to defeat in muroid rodents. In the present study, we have examined the influence of the 5-HT_1A receptor agonist, 8-OH-DPAT, oin basal nociception and defeat analgesia in male DBA/2 mice. Our results show that, while devoid of intrinsic activity on the mouse tail-flick assay, 8-OH-DPAT blocks the analgetic consequences of defeat. A ten-fold potency differential was observed as a function of route of injection, with minimum effective doses of 0.1 and 1.0 mg/kg for subcutaneous and intraperitoneal administration, respectively. Although further studies are required, these preliminary data support 5-HT_1A receptor involvement in the mediation of this form of adaptive pain inhibition.     

Anxiolytic-like effect of a serotonergic ligand with high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors

S-(-)-2-[[4-(napht-1-yl)piperazin-1-yl]methyl]-1,4-dioxoperhydropyrrolo[1,2-alpha]-pyrazine (CSP-2503) is a serotonin (5-HT) receptor ligand with selectivity and high affinity for 5-HT1A, 5-HT2A and 5-HT3 receptors. CSP-2503 reduced rectal temperature and 5-HT neuronal hypothalamic activity in mice, decreased electrical activity of raphe nuclei cells in rats and blocked the enhancement of adenylate cyclase activity induced by forskolin in HeLa cells transfected with the human 5-HT1A receptor. This compound also blocked head-twitches induced by the 5-HT(2A/2C) receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). Contractions of guinea pig ileum induced by the 5-HT3 receptor agonist 2-methyl-5-HT were prevented by CSP-2503. Moreover, it reduced the bradycardia reflex induced by 2-methyl-5-HT in anaesthetized rats. In the light/dark box and social interaction tests, CSP-2503 presented anxiolytic activity, an action shared by 5-HT1 agonists and 5-HT3 antagonists. Taken together, these results suggest that CSP-2503 is a new 5-HT1 receptor agonist with 5-HT2A and 5-HT3)receptor antagonist activities that might be useful in a number of conditions associated with anxiety.     

BIMT 17, a 5-HT1A receptor agonist/5-HT2A receptor antagonist,directly activates postsynaptic 5-HT inhibitory responses in the rat cerebral cortex

BIMT 17 (1-[2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] ethyl] benzimidazol- [1H]-2-one), a 5-HT_1A receptor agonist/5-HT_2A receptor antagonist (see Borsini et al., accompanying paper), in a dose range of 1–10 mg/kg i.v., dose-dependently inhibited the electrical activity of rat medial prefronto-cortical neurons, whereas buspirone, in a dose range of 0.1–1000 g/kg, increased it. 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and 1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphthyl)] piperazine (S 14671) presented biphasic patterns of response; they increased electrical activity at doses in the range of 0.1–10 g/kg and 0.1–3 g/kg i.v. respectively, and reduced it at higher doses, 30–300 g/kg and 10–30 g/kg i.v., respectively.The inhibitory effect of BIMT 17 on the firing rate of neurons in the frontal cortex was antagonized by the 5-HT_1A antagonists tertatolol and WAY 100135, and was still present after destruction of serotonin (5-HT) containing neuronal endings by the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT; 150 g/rat, given intraventricularly), which reduced the cortical 5-HT content by 85%. This destruction of 5-HT neurons, while suppressing the ability of 8-OH-DPAT to inhibit the firing rate at high doses, did not change the excitatory action of this compound at low doses. The addition of ritanserin, a 5-HT2A receptor antagonist, potentiated both the excitatory and inhibitory effects of 8-OHDPAT on neuronal electrical activity. Direct microiontophoretic application (100 nA/20 s) of 5-HT and BIMT 17, but not that of 8-OH-DPAT, onto medial prefronto-cortical neurons, decreased the firing rate of these neurons.These findings suggest that BIMT 17 directly inhibits the electrical activity of medial prefronto-cortical neurons through its dual mode of receptor interaction.     

Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline,as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181

1. Ejaculatory problems and anorgasmia are well-known side-effects of the SSRI antidepressants, and a pharmacologically induced increase in serotonergic neurotransmission inhibits ejaculatory behaviour in the rat. In the present study the role of 5-HT_1A and 5-HT_1B receptors in the mediation of male rat ejaculatory behaviour was examined by use of selective agonists and antagonists acting at these 5-HT receptor subtypes.
2. The 5-HT_1A receptor agonist 8-OH-DPAT (0.25–4.00 μmol kg⁻¹ s.c.) produced an expected facilitation of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the new selective 5-HT_1A receptor antagonist (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD-299) (1.0 μmol kg⁻¹ s.c.). NAD-299 by itself (0.75–3.00 μmol kg⁻¹ s.c.) did not affect the male rat ejaculatory behaviour.
3. The 5-HT_1B receptor agonist anpirtoline (0.25–4.00 μmol kg⁻¹ s.c.) produced a dose-dependent inhibition of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the 5-HT_1B receptor antagonist isamoltane (16 μmol kg⁻¹ s.c.) as well as by the new and selective antagonist (R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorpholino methansulphonate (NAS-181) (16 μmol kg⁻¹ s.c.). Isamoltane (1.0–16.0 μmol kg⁻¹ s.c.) and NAD-181 (1.0–16.0 μmol kg⁻¹ s.c.) had no, or weakly facilitatory effects on the male rat ejaculatory behaviour. The non-selective 5-HT₁ receptor antagonist (−)-pindolol (8 μmol kg⁻¹ s.c.), did not antagonize the inhibition produced by anpirtoline.
4. The present results demonstrate opposite effects, facilitation and inhibition, of male rat ejaculatory behaviour by stimulation of 5-HT_1A and 5-HT_1B receptors, respectively, suggesting that the SSRI-induced inhibition of male ejaculatory dysfunction is due to 5-HT_1B receptor stimulation.

     

Circadian rhythm in the response of central 5-HT1A receptors to 8-OH-DPAT in rats

Circadian rhythm in the behavioral responsiveness to the selective 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied in rats. Rats were subcutaneously injected with 8-OH-DPAT at one of the following times of day: 0000, 0400, 0800, 1200, 1600, 2000 hours. The postsynaptic 5-HT_1A receptor behavioral syndrome, that is, forepaw treading, head weaving, and flat body posture, were measured after the administration of 8-OH-DPAT. Circadian rhythms were found in each of the behavioral responses to 8-OH-DPAT. Peak responses were observed in the mid-dark phase (1200 hours) while the weakest responses were observed in the midlight phase (0000 hours). In a subsequent experiment, 8-OH-DPAT was administered intracerebroventricularly during the mid-dark phase and the mid-light phase. The behavioral responses to the drug in the middark phase were significantly higher than those in the mid-light phase. These results suggest that the function of central postsynaptic 5-HT_1A receptor exhibits circadian rhythm.     

The behavioural responses to 8-OH-DPAT,ipsapirone and the novel 5-HT1A receptor agonist Bay Vq 7813 in the pig

Summary In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT_1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol-3(2H)one-1,1-dioxide), which act as partial agonists at 5-HT_1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg/kg i. m., ipsapirone, 2–5 mg/kg i.m., and Bay Vq 7813, 0.5–2 mg/kg i.m. or i.v., were head shakes. The potency of the three drugs to induce this behaviour correlated with their activity at 5-HT_1A receptors as determined by inhibition of forskolin-stimulated adenylate cyclase, substantiating that the head shake response has potential as a quantitative probe of in vivo receptor function. The 5-HT₂/5-HT_1C receptor antagonist ritanserin did not counteract the head shakes induced by ipsapirone, suggesting that neither 5-HT₂ nor 5-HT_1C receptors are involved in mediation of this response to this 5-HT_1A receptor agonist in pigs. Once daily administration of Bay Vq 7813 or ipsapirone for 3–5 days led to a reduction in the head shake response. 1-Pyrimidinylpiperazine (1-PP), a pharmacologically active metabolite shared by ipsapirone, Bay Vq 7813, and related pyrimidinylpiperazine derivatives, did not induce behavioural alterations in pigs. The data provide further evidence that marked species differences exist in functional responses to 5-HT receptor ligands. Send offprint requests to W. Löscher at the above address     

Chronic lithium treatment enhances the postsynaptic 5-HT1A receptor-mediated 5-HT behavioral syndrome induced by 8-OH-DPAT in rats via catecholaminergic systems

The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT_1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [³H]8-OH-DPAT binding to 5-HT_1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or -methyl-p-tyrosine, but not by 5-HT depletion withp-chlorophenylalanine. These data suggest that lithium enhances 5-HT_1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT_1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [³H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT_1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT_1A receptor down-regulation and unaltered 5-HT_1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment.     

The effect of zotepine, risperidone, clozapine and olanzapine on MK-801-disrupted sensorimotor gating

Dizocilpine (MK-801; 0.3 mg/kg i.p.)-induced disruption in prepulse inhibition of the acoustic startle response (PPI) can be preferentially restored by “atypical” antipsychotics. In contrast, some findings indicate that not all of the “atypical” antipsychotics, such as clozapine and risperidone, are effective in restoring the NMDA antagonist-induced deficits in PPI.

In our study, we evaluated the effect of four different “atypical” antipsychotic drugs on deficits in PPI induced by MK-801. Zotepine and risperidone have high affinities to D2-like and 5-HT_2A receptors, while clozapine and olanzapine have multipharmacological profiles with the highest affinities to serotonin 5-HT_1A,2A/2C receptors and muscarinic receptors.

Results have shown that MK-801 disrupted PPI and increased the ASR in rats. Our results showed no effect of zotepine (1 and 2 mg/kg) and risperidone (0.1 and 1 mg/kg) on disrupted PPI by MK-801. Administration of clozapine (5 and 10 mg/kg) and olanzapine (2.5 and 5 mg/kg) restored the deficits in PPI induced by MK-801. Additionally, we found a decrease of approximately 46% in PPI after administration of clozapine (5 mg/kg) and olanzapine (2.5 and 5 mg/kg) without MK-801 treatment.

In summary, the four “atypical” antipsychotics had different efficacies to restore the disrupted PPI by MK-801. Only clozapine and olanzapin restored the MK-801-induced deficits in PPI.