Terahertz electric-field-driven dynamical multiferroicity in SrTiO3.

The emergence of collective order in matter is among the most fundamental and intriguing phenomena in physics. In recent years, the dynamical control and creation of novel ordered states of matter not accessible in thermodynamic equilibrium is receiving much attention1-6. The theoretical concept of dynamical multiferroicity has been introduced to describe the emergence of magnetization due to time-dependent electric polarization in non-ferromagnetic materials7,8. In simple terms, the coherent rotating motion of the ions in a crystal induces a magnetic moment along the axis of rotation. Here we provide experimental evidence of room-temperature magnetization in the archetypal paraelectric perovskite SrTiO3 due to this mechanism. We resonantly drive the infrared-active soft phonon mode with an intense circularly polarized terahertz electric field and detect the time-resolved magneto-optical Kerr effect. A simple model, which includes two coupled nonlinear oscillators whose forces and couplings are derived with ab initio calculations using self-consistent phonon theory at a finite temperature9, reproduces qualitatively our experimental observations. A quantitatively correct magnitude was obtained for the effect by also considering the phonon analogue of the reciprocal of the Einstein-de Haas effect, which is also called the Barnett effect, in which the total angular momentum from the phonon order is transferred to the electronic one. Our findings show a new path for the control of magnetism, for example, for ultrafast magnetic switches, by coherently controlling the lattice vibrations with light.

Intrathecally administered spermine produces the scratching, biting and licking behaviour in mice.

Intrathecal (i.t.) administration of spermine (0.1-10000 fmol), an endogenous polyamine, produced the behavioural response mainly consisting of biting and/or licking of the hindpaw along with a slight hindlimb scratching directed toward the flank in mice, which peaked at 5-15 min and almost disappeared at 30 min after an injection. The behaviour induced by spermine (10 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.125-0.5 mg/kg). The characteristic behaviour was also inhibited dose-dependently by i.t. co-administration of ifenprodil (62.5-4000 pmol), a competitive antagonist of the polyamine recognition site on N-methyl-D-aspartate (NMDA) receptor ion-channel complex, and D(-)-2-amino-5-phosphonovaleric acid (D-APV) (0.5-2 nmol) and 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP) (7. 8-500 pmol), the competitive NMDA receptor antagonists, and (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,b]cycloheptene-5, 10-imine hydrogen maleate (MK-801) (0.5-4 nmol), an NMDA ion-channel blocker, but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a non-NMDA receptor antagonist. Both (2S, 3S)-[cis-2-(diphenylmethyl)-N-[(2-methoxyphenyl)-methyl]-1-azabicy clo [2.2.2]octane-3-amine] (CP-96,345), a non-peptidic neurokinin-1 (NK-1) receptor antagonist, and CP-96,344, its inactive 2R,3R enantiomer, inhibited spermine-induced behavioural response in a dose-dependent manner. However, [Tyr(6), D-Phe(7), D-His(9)]-substance P(6-11) (sendide) and [D-Phe(7), D-His(9)]-substance P(6-11), the selective antagonists for NK-1 receptors, were without affecting spermine-induced behaviour. These results indicate that spermine-induced behaviour is mediated through the polyamine recognition site on NMDA receptor ion-channel complex without the involvement of substance P system in the mouse spinal cord.

Involvement of alpha-adrenoceptors in para-hydroxyamphetamine-induced head-twitch response.

The effect of some drugs with a higher selectivity for either the alpha 1- or alpha 2-adrenoceptors on the head-twitches induced by intracerebroventricular administration of p-hydroxyamphetamine (p-OHA) in mice, have been studied. Pretreatment with yohimbine increased the number of head-twitches induced by p-OHA, whereas pretreatment with clonidine or prazosin reduced the number of responses. The decrease in head-twitches produced by clonidine was completely antagonized by pretreatment with yohimbine. Pretreatment with 6-hydroxydopamine prior to the combined treatment with clonidine and p-OHA, resulted in recovery of the reduced level head-twitches to the level induced by p-OHA alone. Pretreatment with 6-hydroxydopamine alone resulted in a marked increase in the number of p-OHA-induced head-twitches. These results clearly indicate that a noradrenaline system in the brain may, at least in part, be involved in the p-OHA-induced head-twitches in mouse, most probably by modulating a serotonergic system which is responsible for the head-twitch response.

Inhibition of rat brain monoamine oxidase activity by cerebral anti-ischemic agent, ifenprodil.

Ifenprodil, which is clinically used as a cerebral vasodilator, inhibited rat brain type A (MAO-A) and type B (MAO-B) monoamine oxidase activity. It did not, however, affect rat lung semicarbazide-sensitive amine oxidase. The degree of inhibition of either form of MAO was not changed by 30 min preincubation of the enzyme preparations at 37 degrees C with ifenprodil. Modes of inhibition of MAO-A and MAO-B by ifenprodil were competitive towards oxidation of their respective substrates, 5-hydroxytryptamine and benzylamine, with Ki values of 75 microM for inhibition of MAO-A and 110 microM for inhibition of MAO-B.

alpha-Methylated tryptamine derivatives induce a 5-HT receptor-mediated head-twitch response in mice.

The two alpha-methylated tryptamine derivatives, 5- (5-FMT) and 6-fluoro-alpha-methyltryptamine (6-FMT), rapidly induced a head-twitch response (HTR) in mice. Two derivatives that lack the methyl group in their chemical structures, 5- (5-FT) and 6-fluorotryptamine (6-FT), did not induce the HTR. The induced HTR was depressed by pretreatment with cycloheptadine, p-chlorophenylalanine or fluoxetine, but was potentiated by 5,7-dihydroxytryptamine. Both 5- and 6-FMT increased brain 5-HT levels in hypothalamus, hippocampus, brainstem, striatum and cortex. 5-FMT decreased the levels of 5-hydroxyindoleacetic acid in those regions, but 6-FMT caused a significant decrease in only the hypothalamus and cortex. The two methylated derivatives inhibited mouse brain MAO-A activity more selectively than non-methylated derivatives. The results suggest that the HTR induced by 5- and 6-FMT may result from increased activity of central 5-HT neurons, probably due to increased 5-HT levels after MAO-A inhibition. This probably results in release of 5-HT with a concomitant increased interaction with postsynaptic 5-HT2 receptors. The present results also indicate the importance of the methyl group to selective MAO-A inhibition by the substrate-analogues tested, and the concomitantly induced animal behavior.

Inhibition of monoamine oxidase by two substrate-analogues, with different preferences for 5-hydroxytryptamine neurons.

Various intraperitoneal doses of 5-fluoro-alpha-methyltryptamine (5-FMT), given to mice, dose-dependently inhibited only MAOA activity, with similar degrees of inhibition in the striatum, hypothalamus and the rest of the forebrain. The activity inhibited in these regions, completely recovered to control levels within 24 hr after the injection. In contrast, p-chloro-beta-methylphenethylamine (p-CMP), selectively inhibited MAOB activity, with complete recovery within 45 min after the injection. Regardless of the differences in time interval and degree of inhibition of MAOA by 5-FMT or MAOB by p-CMP, both kinds of inhibition were competitive, with respect to oxidation of the respective substrate. 5-Fluoro-alpha-methyltryptamine markedly protected only MAOA against inhibition by phenelzine, without protecting MAOB. Also, 5-FMT greatly increased one kind of animal behaviour, the head-twitch and this behaviour was greatly reduced by treatment with fluoxetine, but increased by reserpine. The results indicate that p-CMP is a short-acting, probably reversible, MAOB-selective inhibitor and 5-FMT has the same characteristics of selectivity for MAOA in central serotonergic neurons.

Exploring the structural basis of neurotoxicity in C(17)-polyacetylenes isolated from water hemlock.

Water hemlock, Cicuta virosa, belonging to the Umbelliferae, is well-known as a toxic plant responsible for lethal poisonings in humans as well as animals, causing tonic and clonic convulsions and respiratory paralysis. Cicutoxin (1), being a major violent toxin of the plant, is a chemical in the class of C(17)-polyacetylenes bearing a long pi-bond conjugation system, a terminal hydroxyl, and an allylic hydroxyl in its structure, and a variety of its analogues have been isolated from the plant. In the present study, various derivatives of these toxins were synthesized through acetylation, methylation, and oxidation of cicutoxin (1) and virol A (3) and B (4). 1-Dehydroxyvirol A (28) was prepared through the coupling of (7S)-dodeca-3,5-dien-1-yn-7-ol and 1-iodopentyne under Sonogashira's conditions. A monoacetylenic compound (29) was also prepared through the coupling of (5S)-1-chlorodeca-1,3-dien-5-ol and 1-iodopentyn-5-ol. The structure-activity relationships involved in the acute toxicity of cicutoxin derivatives in mice were investigated, and the length and geometry of pi-bond conjugation and the O-functional groups were found to be important for activity. The potency in inhibition of the specific binding of the noncompetitive GABA antagonist, [(3)H]EBOB, to GABA-gated Cl(-) channels of GABA receptors in rat brain cortex was found to be correlated with acute toxicity, indicating that the ability to bind to these channels plays an important role in the acute toxicity of these compounds.

Enhancement of 5-hydroxytryptamine-induced head-twitch response after olfactory bulbectomy.

5-Hydroxytryptamine(2A) receptor agonists evoke the head-twitch response in mice. The head-twitch response in olfactory bulbectomized mice elicited by the administration of 5-hydroxytryptamine (40 microgram/mouse, i.c.v.) was increased about threefold as compared with controls on the 14th day after the operation. The injection of ketanserin (1 mg/kg, i.p.), a 5-hydroxytryptamine(2A) receptor antagonist, inhibited this enhancement of 5-hydroxytryptamine-induced head-twitch response after olfactory bulbectomized. On the 14th day, the number of head-twitch response induced by 5-hydroxytryptophan (40, 80 and 160 mg/kg, i.p.), a precursor of 5-hydroxytryptamine, did not differ between olfactory bulbectomized and control mice. Monoamine oxidase-B activity in the forebrain of olfactory bulbectomized mice was higher than that in controls while monoamine oxidase-A activities were unchanged. The 5-hydroxytryptamine uptake into synaptosomes in the forebrain homogenates of olfactory bulbectomized mice was lower than that in controls. These findings indicate that olfactory bulbectomized causes the enhancement of head-twitch response by a supersensitivity of 5-hydroxytryptamine(2A) receptors in cerebral cortex derived from degeneration of neurons projecting from the olfactory bulb.

Effect of kami-untan-to on the impairment of learning and memory induced by thiamine-deficient feeding in mice.

We have recently reported that thiamine deficient (TD) mice show an impairment of learning and memory on the 20th day after start of TD feeding. Interestingly, it has been reported that the kampo medicine, "kami-untan-to" (KUT) may be useful as a potential therapeutic agent in diseases associated with cholinergic deficit such as Alzheimer's disease. In the present study, we investigated the effects of KUT on the impairment of memory-related behavior concomitant with psychoneuronal symptoms after TD feeding in mice. Oral administration of KUT had no effect on the food intake, body weight or locomotor activity in TD mice, but the mortality rate in the KUT-treated TD group was significantly lower compared with that in the non-treated TD group. Daily administration of KUT from the 1st day of TD feeding protected against the impairment of memory-related behavior induced by TD. The intensity of the choline acetyltransferase fluorescence decreased in the field of CA1 and dentate gyrus in the hippocampus in TD mice compared with pair-fed mice as the control group, and KUT treatment inhibited this decrease. These results suggest that the effect of KUT on the impairment of memory-related behavior induced by TD feeding may be closely related to the activation of cholinergic neurons in the hippocampus.

Behavioural characterization and amounts of brain monoamines and their metabolites in mice lacking histamine H1 receptors.

Behavioural assessments were made of mutant mice lacking histamine H1 receptors to reveal the function of H1 receptors in the behaviour of mice. Exploratory behaviour of mice in a new environment was examined to discover whether the absence of H1 receptors in mice affects actions relating to their emotions. The H1 receptor-deficient mice showed a significant decrease in ambulation in an open field and on an activity wheel. Cognitive functions and anxiety were examined using passive avoidance response test and the elevated plus-maze test, respectively. The passive avoidance test did not show any change in latency. The elevated plus-maze test revealed that the transfer latency of the mutant mice was significantly prolonged, indicating that H1 receptors are partly associated with the control of anxiety. Aggressive behaviour was examined by a resident-intruder aggression test. When confronted with an intruder, the mutant mice attacked the intruder significantly slower and less frequently than did wild-type mice after a six-month isolation period. A formalin test and a forced swimming test were used to evaluate the nociceptive response and depressive or despairing state, respectively, of both groups. The mutant mice showed a significant decrease of nociceptive response in the late phase without affecting the early phase. There was no significant difference in the forced swimming test between the two groups. The brain content of monoamines and their metabolites was measured in the H1 receptor null and wild-type mice. The turnover rate of 5-hydroxytryptamine defined by the ratio of 5-hydroxyindoleacetic acid and 5-hydroxytryptamine was significantly increased in the cerebral cortex and hippocampus of H1 receptor null mice. These results support the previous pharmacological findings that histamine modulates various neurophysiological functions such as locomotor activity, emotion, memory and learning, nociception and aggressive behaviour through H1 receptors.

Effect of gamma-mangostin through the inhibition of 5-hydroxy-tryptamine2A receptors in 5-fluoro-alpha-methyltryptamine-induced head-twitch responses of mice.

1. Intracerebronventricular (i.c.v.) injection of gamma-mangostin (10-40 nmol/mouse), a major compound of the fruit hull of Garcinia mangostana Lin., like ketanserin (10, 20 nmol/mouse, i.c.v.) inhibited 5-fluoro-alpha-methyltryptamine (5-FMT) (45 mg kg(-1), i.p.)-induced head-twitch response in mice in the presence or absence of citalopram (a 5-hydroxytryptamine (5-HT)-uptake inhibitor). 2. Neither the 5-FMT- nor the 8-hydroxy-2-(di-n-propylamino)tetralin (5-HT1A-agonist)-induced 5-HT syndrome (head weaving and hindlimb abduction) was affected by gamma-mangostin or ketanserin. 3. The locomotor activity stimulated by 5-FMT through the activation of alpha1-adrenoceptors did not alter in the presence of gamma-mangostin. 4. 5-HT-induced inositol phosphates accumulation in mouse brain slices was abolished by ketanserin. Gamma-mangostin caused a concentration-dependent inhibition of the inositol phosphates accumulation. 5. Gamma-mangostin caused a concentration-dependent inhibition of the binding of [3H]-spiperone, a specific 5-HT2A receptor antagonist, to mouse brain membranes. 6. Kinetic analysis of the [3H]-spiperone binding revealed that gamma-mangostin increased the Kd value without affecting the Bmax value, indicating the mode of the competitive nature of the inhibition by gamma-mangostin. 7. These results suggest that gamma-mangostin inhibits 5-FMT-induced head-twitch response in mice by blocking 5-HT2A receptors not by blocking the release of 5-HT from the central neurone. Gamma-mangostin is a promising 5-HT2A receptor antagonist in the central nervous system.

Effects of transient global ischemia and a monoamine oxidase inhibitor ifenprodil on rat brain monoamine metabolism.

Ifenprodil, a cerebral vasodilator and non-competitive glutamate antagonist, is also an anti-ischaemic agent; it has been shown to inhibit both forms of MAO in rat brain and lung (with slightly greater potency towards MAO-A), but it does not inhibit SSAO. The effects of ifenprodil on rat brain regional levels of monoamines and their principal metabolites following transient global ischaemia have been investigated 1 h after reperfusion. Among the three most ischaemically vulnerable brain regions (striatum, hippocampus and cortex), striatal DA, DOPAC, HVA, 5-HT and 5-HIAA levels were the most markedly increased. Simultaneous treatment with ifenprodil during reperfusion reversed the increases in the striatum, except for HVA, to the level similar to those of sham-operated controls. In contrast to the striatum, ifenprodil failed to reverse the increases seen in the cortex and hippocampus.

Selective inhibition of MAO-A in serotonergic synaptosomes by two amphetamine metabolites, p-hydroxyamphetamine and p-hydroxynorephedrine.

The present study was carried out mainly to clarify whether the two amphetamine metabolites, p-hydroxyamphetamine (P-OHA) and p-hydroxynorephedrine (p-OHN) are taken up by mouse brain 5-hydroxytryptamine (5-HT) nerve terminals to inhibit type A monoamine oxidase (MAO-A) and then potentiate the abnormal behavior, head-twitch. Of the two metabolites, only intracerebroventricular p-OHA, at 80 ?g/mouse, sufficient to cause a head-twitch response (HTR), appreciably inhibited MAO-A activity without affecting MAO-B activity in homogenates of the mouse striatum, hypothalamus and the rest of the forebrain; and p-OHN did not inhibit either type of MAO at the dose tested. Estimation of intra- and extrasynaptosomal MAO-A activity showed that both metabolites significantly inhibited only the intrasynaptosomal deamination of 5-HT by MAO-A with p-OHA being more potent. Taken together with our previous findings, these present results clearly indicate that p-OHA may accumulate in the 5-HT nerve terminals through the uptake system, and concomitantly inhibit MAO-A activity. These actions of p-OHA may increase intraneuronal 5-HT levels and then potentiate 5-HT release to cause interaction with the post-synaptic 5-HT receptors.

Inhibitory effect of intracerebroventricularly-administered [D-Arg(2), beta-Ala(4)]-dermorphin (1-4) on gastrointestinal transit.

The inhibitory effect of intracerebroventricularly-administered [D-Arg(2), beta-Ala(4)]-dermorphin (1-4) (TAPA), a highly selective mu(1)-opioid receptor agonist, on mouse gastrointestinal transit was compared with that of morphine and [D-Ala(2), N-methyl-Phe(4), Gly(5)-ol]-enkephalin (DAMGO). When administered intracerebroventricularly 5 min before the oral injection of charcoal meal, TAPA (10-100 pmol), morphine (0.25-4 nmol), and DAMGO (20-80 pmol) dose-dependently inhibited gastrointestinal transit of charcoal. The inhibitory effect of each mu-opioid receptor agonist was completely antagonized by naloxone, a nonselective opioid receptor antagonist. The inhibitory effects of morphine and DAMGO were significantly antagonized by both beta-funaltrexamine, a selective mu-opioid receptor antagonist, and naloxonazine, a selective mu(1)-opioid receptor antagonist. In contrast, the inhibitory effect of TAPA was not affected at all by beta-funaltrexamine, naloxonazine, nor-binaltorphimine (a selective kappa-opioid receptor antagonist), or naltrindole (a selective delta-opioid receptor antagonist). These results suggest that the inhibitory effect of TAPA on gastrointestinal transit may be mediated through an opioid receptor mechanism different from that of morphine and DAMGO.

Intrathecal administration of p-hydroxymercuribenzoate or phosphoramidon/bestatin-combined induces antinociceptive effects through different opioid mechanisms.

The antinociceptive effect of intrathecally (i.t.) administered protease inhibitors was tested against capsaicin (800 ng) injected into the dorsal surface of a hindpaw. Both p-hydroxymercuribenzoate (2-8 nmol), a cysteine protease inhibitor, and phosphoramidon (1-4 nmol), an endopeptidase 24.11 inhibitor in the presence of bestatin (0.25 nmol) an aminopeptidase inhibitor, administered i.t. 60 min prior to the injection of capsaicin produced a dose-dependent reduction of the capsaicin-induced paw licking and biting response. p-Hydroxymercuribenzoate (4 nmol)-induced antinociception was significantly antagonized by nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-opioid receptor antagonist. On the other hand, phosphoramidon (4 nmol) /bestatin-induced antinociception was significantly antagonized by naltrindole, but not by nor-binaltorphimine. The results indicate that the antinociceptive effect of p-hydroxymercuribenzoate may be due to the inhibition of a cysteine protease degrading endogenous dynorphins whereas phosphoramidon in the presence of bestatin blocks the degradation of enkephalins.

Antinociceptive effect produced by intracerebroventricularly administered dynorphin A is potentiated by p-hydroxymercuribenzoate or phosphoramidon in the mouse formalin test.

The antinociceptive effects of intracerebroventricularly (i.c.v.) administered dynorphin A, an endogenous agonist for kappa-opioid receptors, in combination with various protease inhibitors were examined using the mouse formalin test in order to clarify the nature of the proteases involved in the degradation of dynorphin A in the mouse brain. When administered i.c.v. 15 min before the injection of 2% formalin solution into the dorsal surface of a hindpaw, 1-4 nmol dynorphin A produced a dose-dependent reduction of the nociceptive behavioral response consisting of licking and biting of the injected paw during both the first (0-5 min) and second (10-30 min) phases. When co-administered with p-hydroxymercuribenzoate (PHMB), a cysteine protease inhibitor, dynorphin A at the subthreshold dose of 0.5 nmol significantly produced an antinociceptive effect during the second phase. This effect was significantly antagonized by nor-binaltorphimine, a selective kappa-opioid receptor antagonist, but not by naltrindole, a selective delta-opioid receptor antagonist. At the same dose of 0.5 nmol, dynorphin A in combination with phosphoramidon, an endopeptidase 24.11 inhibitor, produced a significant antinociceptive effect during both phases. The antinociceptive effect was significantly antagonized by naltrindole, but not by nor-binaltorphimine. Phenylmethanesulfonyl fluoride (PMSF), a serine protease inhibitor, bestatin, a general aminopeptidase inhibitor, and captopril, an angiotensin-converting enzyme inhibitor, were all inactive. The degradation of dynorphin A by mouse brain extracts in vitro was significantly inhibited only by the cysteine protease inhibitors PHMB and N-ethylmaleimide, but not by PMSF, phosphoramidon, bestatin or captopril. The present results indicate that cysteine proteases as well as endopeptidase 24.11 are involved in two steps in the degradation of dynorphin A in the mouse brain, and that phosphoramidon inhibits the degradation of intermediary delta-opioid receptor active fragments enkephalins which are formed from dynorphin A.

Distribution of various calcium channel alpha(1) subunits in murine DRG neurons and antinociceptive effect of omega-conotoxin SVIB in mice.

Immunohistological study revealed the differential localization of subtypes of voltage-dependent calcium channels in the dorsal root ganglion neurons. Intrathecal injection of omega-conotoxin SVIB, an analogue of omega-conotoxin GVIA, which acts on N-type voltage-dependent calcium channels, significantly shortened the licking time in the late phase of a formalin test.

Immunohistochemical determination of rat spinal cord substance P, and antinociceptive effect during development of thiamine deficiency.

During 30 days of thiamine deficiency (TD) feeding, the rat antinociceptive effect (pain threshold) to noxious heat stimulation was significantly increased in proportion to the decrease substance P (SP) fluorescent intensity in the spinal cord. Only a single injection of thiamine HCl (0.5 mg/kg, s.c.) on the early treatment day during TD feeding effectively reversed the analgesic effect to the pair-fed control level. Whereas this reversal effect by thiamine treatment was not found if this treatment was done on the relatively late day. However, either treatment day, except muricide, complete disappearance of various animal behaviours induced by TD was found. These results indicate that, after certain degree of TD development, TD-induced behavioral effects might be reversible, but the afferent nerve fibers might be irreversibly damaged, probably by the similar mechanism as found for an excitotoxin(s) mediated injury in the certain brain region(s). The results also suggest a possibility that SP and an excitotoxin, glutamate, in the dorsal part of the spinal cord greatly contribute to the pain transmission induced by noxious heat stimulation.

Antinociceptive effect of cilnidipine, a novel N-type calcium channel antagonist.

We investigated the antinociceptic effects of cilnidipine, a dihydropyridine derivative which acts on both L- and N-type voltage-dependent calcium channels, in mice. Intrathecally injected cilnidipine showed significant analgesic effect in formalin test. Cilnidipine significantly suppressed N-type currents in dorsal root ganglion (DRG) cells. Our findings apparently support the idea that cilnidipine attenuates synaptic neurotransmission by inhibiting N-type calcium channels in DRG neurons.

Pharmacological studies of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., in the central nervous system.

The pharmacological properties of geissoschizine methyl ether, isolated from Uncaria sinensis Oliv., were analyzed in vitro and in vivo using mice central serotonin neurons. In the in vitro experiment, geissoschizine methyl ether inhibited [3H]8-hydroxy-2-(di-n-propylamino)tetralin) ([3H]8-OH-DPAT) (K(i)=0.8 microM), [3H]mesulergine (K(i)=0.9 microM) and [3H]ketanserin (K(i)=1.4 microM), but had less affinity toward [3H]prazosin (K(i) > 10 microM) and [3H]spiperone (K(i) >15 microM) binding to mouse brain membranes. The in vivo studies showed that geissoschizine methyl ether dose-dependently reduced 5-hydroxy-L-tryptophan (I-5-HTP) plus clorgyline-induced head twitch response without inhibiting the I-5-HTP plus clorgyline and 8-OH-DPAT-induced head weaving. On the other hand, geissoschizine methyl ether also decreased the rectal temperature of mice (hypothermic response) in a dose-dependent manner. These results suggest that geissoschizine methyl ether possesses mixed 5-HT(1A) receptor agonist/5-HT(2A/2C) receptor antagonist activities and inhibits the head twitch response by blocking the 5-HT(2A) receptors, and possibly, at least in part, by stimulating the 5-HT(1A) receptors in the central nervous system.