A novel in vivo test for drugs affecting central serotonergic and adrenergic systems

In urethane-anaesthetized rats, myoclonic twitches of the anterior digastricus muscle were evoked by L-5-hydroxy-tryptophan (L-5-HTP, 50-100 mg/kg iv.), the serotonin (5-HT) receptor agonist, quipazine (1-8 mg/kg i.v.) and the 5-HT releaser, fenfluramine (4-8 mg/kg i.v.). The effect of L-5-HTP or quipazine on the frequency of twitches was inhibited by the 5-HT receptor antagonist cyproheptadine. Also L-DOPA (100 mg/kg i.p.) or the alpha 1-adrenoceptor agonist, cirazoline (0.3-3 mg/kg i.v.) evoked twitches of the muscle which were inhibited by the alpha 1-adrenoceptor antagonist, prazosin. In decerebrate, artificially respired rats, neither L-5-HTP nor L-DOPA evoked the twitches. The frequency of twitches evoked by fenfluramine but not by L-DOPA was increased by the alpha 2-adrenoceptor agonist, clonidine (0.2 and 0.4 mg/kg i.v.); clonidine's effect was abolished by the alpha 2-adrenoceptor antagonist, yohimbine. The beta 2-adrenoceptor agonist, salbutamol (0.01-1 mg/kg i.v.) had no effect on fenfluramine-induced twitches. It is concluded that (1) activation of 5-HT receptors or alpha 1-adrenoceptors in the brain of urethane-anaesthetized rats evokes twitches of the anterior digastricus muscle, and (2) this preparation can be utilized as a test to study the action of compounds on central 5-HT and adrenergic systems.     

Central antiserotonergic and antidopaminergic action of pirenperone, a putative 5-HT2 receptor antagonist

Pirenperone, an antagonist of 5-HT2 but not 5-HT1 receptors, has been studied for its central antiserotonergic and antidopaminergic activity. Pirenperone (0.00525-0.1 mg/kg) antagonized dose-dependently stimulation of the hind limb flexor reflex in spinal rats induced by LSD, quipazine or fenfluramine, and hyperthermia induced by serotonin (5-hydroxytryptamine; 5-HT)-like drugs (1-5-hydroxytryptophan, fenfluramine, p-chloroamphetamine, 1-/m-chlorophenyl/-piperazine, quipazine) in heat-adapted rats. Pirenperone also counteracted tryptamine-induced convulsions in rats (ID50 = 0.87 mg/kg); however, this action was weaker than that of metergoline (ID50 = 0.22 mg/kg). Pirenperone (0.1-1.6 mg/kg) produced sedation in mice and rats, and-in doses of 0.4-6.4 mg/kg-catalepsy in rats. Given in doses ranging from 0.1 to 1.6 mg/kg, pirenperone antagonized d-amphetamine-induced locomotor hyperactivity in mice and rats, the hyperactivity induced by apomorphine in rats, apomorphine- or d-amphetamine-induced stereotypy in rats and stimulation of the hind limb flexor reflex induced by the alpha-adrenoceptor agonist-clonidine. Pirenperone (6.4 mg/kg) significantly attenuated apomorphine (1 mg/kg)-induced hypothermia in mice. The results obtained indicate that pirenperone may be regarded as a relatively specific antagonist of the 5-HT2 receptor only when it is employed in very low doses (less than 0.1 mg/kg). Used in higher doses (greater than 0.1 mg/kg), it behaves like a typical neuroleptic, i.e. like a dopamine antagonist with antiserotonergic, antitryptaminergic and antiadrenergic properties.     

Serotonergic regulation of the brain and gut beta-endorphin and dynorphin content in the rat

A specific radioimmunoassay was used to measure immunoreactive dynorphin (ir-DYN) and beta-endorphin (ir-BE) in the brain, pituitary and gut, following a pharmacological manipulation of the serotonin system. Administration of the serotonin receptor agonist m-chlorophenylpiperazine (m-CPP, 2.5-5 mg/kg ip) or the serotonin releasing agent fenfluramine (20-40 mg/kg ip) induced a significant increase in the hypothalamic ir-BE content and a decrease in its anterior pituitary level. These effects were antagonized by cyproheptadine (1 mg/kg ip). Similar results were obtained after fluvoxamine (15 mg/kg ip), femoxetine (10 mg/kg ip) and 5-hydroxytryptophan (5-HTP 40-160 mg/kg ip). None of the above treatments altered significantly the ir-DYN content in the brain and pituitary. However, the gut ir-DYN level was dramatically decreased after m-CPP, fenfluramine, fluvoxamine, femoxetine and 5-HTP. The latter effect was antagonized by cyproheptadine. The obtained results suggest that serotonergic activation stimulates the release of beta-endorphin from the anterior pituitary and dynorphin from the gut, while the cerebral beta-endorphin system appears to be inhibited by activation of serotonin neurons.     

A new potent and selective non-peptide gastrin antagonist and brain cholecystokinin receptor (CCK-B) ligand: L-365,260

L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4- benzodiazepin-3-yl)-N'-(3-methylphenyl)urea), interacted in a stereoselective and competitive manner with guinea pig stomach gastrin and brain cholecystokinin (CCK) receptors. The affinity of L-365,260 for both gastrin (Ki = 1.9 nM) and brain CCK-B (Ki = 2.0 nM) receptors was greater than 2 orders of magnitude higher than its affinity for peripheral pancreatic CCK-A receptors or various other receptors. L-365,260 exhibited a similar high affinity for brain CCK-B receptors of rats, mice and man. A somewhat lower affinity for gastrin and brain CCK-B (IC50 = 20-40 nM) receptors was observed in dog tissues. In vivo, oral administration of L-365,260 antagonized gastrin-stimulated acid secretion in mice (ED50 = 0.03 mg/kg), rats (ED50 = 0.9 mg/kg) and guinea pigs (ED50 = 5.1 mg/kg). L-365,260 did not affect basal acid secretion and did not antagonize histamine- or carbachol-stimulated acid secretion in mice. L-365,260 represents a potentially powerful new tool for investigating gastrin and brain CCK-B receptors, and possibly their role in physiology and disease.     

Effects of CI-926 (3-[4-[4-(3-methylphenyl)-1-piperazinyl] butyl]-2,-4-imidazolidinedione), an antihypertensive agent, on rat brain catecholamine and serotonin turnover

The effects of the antihypertensive drug CI-926 on rat brain norepinephrine (NE), dopamine (DA), and serotonin (5-HT) turnover and its in vitro affinity for several receptors were investigated. CI-926 (3-30 mg/kg intraperitoneally, i.p.) caused a dose-dependent increase in the rate of brain stem NE synthesis and increased the decline in NE after inhibition of its synthesis by alpha-methyl-p-tyrosine. These findings indicated that CI-926 increased brain NE turnover, probably as a compensatory response to central adrenoceptor blockade based on its nanomolar affinity for alpha 1-adrenoceptors and micromolar affinity for alpha 2-adrenoceptors. CI-926 also increased the rate of DA synthesis and DA metabolite levels; this indicates an increase in DA turnover. The latter effect of CI-926 is attributed to a compensatory response to DA-2 receptor blockade because no affinity for DA-1 relative to DA-2 receptors was found and the effect was antagonized by the DA agonist pergolide. CI-926 decreased brain 5-HT turnover, as indicated by reduced concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid and a reduced rate of 5-HT synthesis, effects characteristic of centrally acting 5-HT agonists. Based on its affinity for 5-HT-1A receptors versus 5-HT-1B and 5-HT-2, the decrease in 5-HT synthesis and release is interpreted as evidence of 5-HT-1A receptor activation. These findings indicate that besides peripheral alpha 1-adrenergic blockade, an interference of CI-926 with central adrenergic and serotoninergic neurotransmission may contribute in part to an explanation of its antihypertensive properties.     

Central antiserotonin action of fluperlapine

The effect of fluperlapine--a new nonclassical neuroleptic--on the central serotoninergic system was studied. Fluperlapine antagonizes the head-twitch response induced by 5-hydroxytryptophan in mice and rats (the ED50 values are 0.3 mg/kg ip and 0.89 mg/kg ip respectively), counteracts forepaw clonic convulsions and tremor induced by tryptamine in rats (ED50 = 9.0 mg/kg ip and 7.5 mg/kg ip respectively), and abolishes hyperthermia induced by fenfluramine. In the flexor reflex preparation in spinal rats fluperlapine depresses the reflex only when given in higher doses. The drug given in low doses abolishes the stimulation of the flexor reflex evoked by quipazine and LSD (serotonin agonists) but not by clonidine (noradrenaline agonist). Higher doses of fluperlapine antagonise also the stimulatory effect of clonidine. Our findings demonstrate that fluperlapine shows potent central antiserotonin activity.     

The novel compound (+/-)-1-[10-((E)-3-Phenyl-allyl)-3,10-diaza-bicyclo[4.3.1]dec-3-yl]-propan-1-one (NS7051) attenuates nociceptive transmission in animal models of experimental pain; a pharmacological comparison with the combined mu-opioid receptor agonist and monoamine reuptake inhibitor tramadol

Tramadol is an atypical analgesic with a unique dual mechanism of action. It acts on monoamine transporters to inhibit reuptake of noradrenaline (NA) and serotonin (5-HT), and consequent upon metabolism, displays potent agonist activity at micro-opioid receptors. Here, we present data for the novel compound NS7051, which was shown to have sub-micromolar affinity (Ki=0.034microM) for micro-opioid receptors and inhibited reuptake of 5-HT, NA and DA (IC(50)=4.2, 3.3 and 3.5microM in cortex, hippocampus and striatum respectively). NS7051 (1-30mg/kg, s.c.) produced a dose-dependent naloxone-reversible increase in the hot plate withdrawal latency, and was also analgesic in the tail flick test. In models of persistent and chronic inflammatory nociception, NS7051 reversed flinching behaviours during interphase and second phase of the formalin test (ED(50)=1.7 and 1.8mg/kg, s.c.), and hindpaw weight-bearing deficits induced by complete Freund's adjuvant injection (ED50=1.2mg/kg, s.c.). In the chronic constriction injury model of neuropathic pain, mechanical allodynia and hyperalgesia were both reversed by NS7051 (ED50=6.7 and 4.9mg/kg, s.c.). Tramadol was also active in all pain models although at considerably higher doses (20-160mg/kg, s.c.). No ataxia was observed at antiallodynic doses giving therapeutic indices of 19 and 3 for NS7051 and tramadol. The combined opioid receptor agonism and monoamine reuptake inhibitory properties of NS7051 inferred from behavioural studies appear to contribute to its well tolerated antinociceptive profile in rats. However, unlike tramadol this did not correlate with the ability to increase hippocampal monoamine levels measured by microdialysis in anesthetised rats.     

Modulation of serotonergic function in rat brain by VN2222, a serotonin reuptake inhibitor and 5-HT1A receptor agonist.

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT(1A) receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT(ext)) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HT(ext). In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT(ext). Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED(50): 790, 14.9, and 0.8 microg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT(1A) receptors as assessed by microdialysis and single-unit recordings (ED(50) values for 8-OH-DPAT were 0.45 and 2.34 microg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT(1A) agonist that markedly desensitizes 5-HT(1A) autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.     

SLV313 (1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4- [5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride): a novel dopamine D2 receptor antagonist and 5-HT1A receptor agonist potential antipsychotic drug.

Combined dopamine D(2) receptor antagonism and serotonin (5-HT)(1A) receptor agonism may improve efficacy and alleviate some side effects associated with classical antipsychotics. The present study describes the in vitro and in vivo characterization of 1-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4-[5-(4-fluoro-phenyl)-pyridin-3-ylmethyl]-piperazine monohydrochloride (SLV313), a D(2/3) antagonist and 5-HT(1A) agonist. SLV313 possessed high affinity at human recombinant D(2), D(3), D(4), 5-HT(2B), and 5-HT(1A) receptors, moderate affinity at 5-HT(7) and weak affinity at 5-HT(2A) receptors, with little-no affinity at 5-HT(4), 5-HT(6), alpha(1), and alpha(2) (rat), H(1) (guinea pig), M(1), M(4), 5-HT(3) receptors, and the 5-HT transporter. SLV313 had full agonist activity at cloned h5-HT(1A) receptors (pEC(50)=9.0) and full antagonist activity at hD(2) (pA(2)=9.3) and hD(3) (pA(2)=8.9) receptors. In vivo, SLV313 antagonized apomorphine-induced climbing and induced 5-HT(1A) syndrome behaviors and hypothermia, the latter behaviors being antagonized by the 5-HT(1A) antagonist WAY100635. In a drug discrimination procedure SLV313 induced full generalization to the training drug flesinoxan and was also antagonized by WAY100635. In the nucleus accumbens SLV313 reduced extracellular 5-HT and increased dopamine levels in the same dose range. Acetylcholine and dopamine were elevated in the hippocampus and mPFCx, the latter antagonized by WAY100635, suggesting possible 5-HT(1A)-dependent efficacy for the treatment of cognitive and attentional processes. SLV313 did not possess cataleptogenic potential (up to 60 mg/kg p.o.). The number of spontaneously active dopamine cells in the ventral tegmental area was reduced by SLV313 and clozapine, while no such changes were seen in the substantia nigra zona compacta following chronic administration. These results suggest that SLV313 is a full 5-HT(1A) receptor agonist and full D(2/3) receptor antagonist possessing characteristics of an atypical antipsychotic, representing a potential novel treatment for schizophrenia.     

8-Hydroxy-2-(di-n-propylamino) tetralin, a selective serotonin1A receptor agonist, blocks haloperidol-induced catalepsy by an action on raphe nuclei medianus and dorsalis

The selective serotonin1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was studied for its ability to reverse haloperidol-induced catalepsy in rats. Given subcutaneously 8-OH-DPAT (0.06-0.5 mg/kg), dose-dependently antagonized the catalepsy induced by 1 mg/kg of haloperidol. Intraventricular injection of the serotonin (5-HT) neurotoxin 5,7-dihydroxytryptamine (5,7-DHT), which caused marked depletion of 5-HT in brain, did not change haloperidol-induced catalepsy per se, but completely antagonized the anticataleptic effect of subcutaneously administered 8-OH-DPAT. When injected directly into the median or dorsal raphe nucleus, 8-OH-DPAT, in doses ranging from 0.2 to 5 micrograms/0.5 microliter, reduced the catalepsy induced by haloperidol. The results suggest that the activation of 5-HT1A receptors, probably those located presynaptically on 5-HT-containing cell bodies, reduces the catalepsy induced by haloperidol.     

Pharmacological studies of the acute effects of (+)-3,4-methylenedioxymethamphetamine on locomotor activity: role of 5-HT(1B/1D) and 5-HT(2) receptors.

The role of serotonin 5-HT(2) receptors (5-HT(2)R) in the hyperactivity induced by (+)-3,4-methylenedioxy-methamphetamine ((+)-MDMA; 3 mg/kg) was investigated. Hyperactivity induced by (+)-MDMA was robustly potentiated by the 5-HT(2B/2C)R antagonist SB 206553 (1.0, 2.0, and 4.0 mg/kg). Administration of the 5-HT(1B/1D)R antagonist GR 127935 (2.5 mg/kg) or the 5-HT(2A)R antagonist M100907 (1.0 mg/kg) partially suppressed the potentiated hyperactivity seen following SB 206553 plus (+)-MDMA; a blockade to activity levels seen with (+)-MDMA alone was observed following the combination of GR 127935 plus M100907. A modest potentiative interaction was seen when SB 206553 was combined with the DA releaser amphetamine (0.5 mg/kg) or amphetamine plus the 5-HT releaser fenfluramine (4.0 mg/kg). SB 206553 (1-4 mg/kg), GR 127935 (2.5 mg/kg) and M100907 (1 mg/kg) did not alter spontaneous activity upon administration singly or in combination. These data suggest that activation of 5-HT(2C)R exerts a strong inhibitory influence on the hyperactivity induced by (+)-MDMA, and that 5-HT(2C)R blockade unmasks hyperactivity mediated through several mechanisms.     

Antimyoclonic properties of S2 serotonin receptor antagonists in the rat

The capacity of the putative S2 serotonin receptor antagonists, pirenperone, pipamperone, ketanserin and cinanserin, to block the myoclonic syndrome produced by 30 mg/kg of L-5-hydroxytryptophan (5-HTP) [after lesioning 5-hydroxytryptamine (serotonin, 5-HT)-containing neurons with 5,7-dihydroxytryptamine (DHT)] or 15 mg/kg of fenfluramine (FF) or p-chloroamphetamine (PCA) was tested in adult male Sprague-Dawley rats. S2 antagonists inhibited limb (arrhythmic and asynchronous) and axial (truncal) myoclonus in a dose-dependent manner in the rank order of potency: pirenperone greater than pipamperone greater than ketanserin = cinanserin. Abnormal movements (myoclonus, lateral head weaving) of the myoclonic syndromes were better antagonized than postural abnormalities (hindlimb abduction, hunching of back). Centrally acting drugs, selective for S2 receptors (pirenperone, pipamperone), exhibited greater antimyoclonic properties than the non-selective 5-HT antagonist methysergide, which was as effective as ketanserin and cinanserin. Significant non-specific reduction in myoclonus without the improvement of other behavioral responses followed treatment with sedative/neuroleptic drugs, such as haloperidol (but not the non-neuroleptic dopamine antagonist sulpiride), clonazepam and diazepam. The anticonvulsants valproic acid (100 and 300 mg/kg), adrenocorticotrophic hormone (ACTH; 100 and 300 U/kg), diphenylhydantoin (15 mg/kg), and phenobarbital (20 mg/kg) and drugs which do not act principally at S2 receptors were ineffective in these models. These data support the hypothesis that myoclonus in behavioral models induced by 5-HT is S2 receptor mediated. S2 antagonists could have a role in the treatment of human myoclonus.     

Antidepressant-like activity of VN2222, a serotonin reuptake inhibitor with high affinity at 5-HT1A receptors

It has been suggested that drugs combining serotonin (5-hydroxytryptamine, 5-HT) transporter blockade and 5-HT1A autoreceptor antagonism could be a novel strategy for a shorter onset of action and higher therapeutic efficacy of antidepressants. The present study was aimed at characterizing the pharmacology of 1-(3-benzo[b]tiophenyl)-3-[4-(2-methoxyphenyl)-1-piperazinyl]-1-propanol (VN2222) a new synthetic compound with high affinity at both the 5-HT transporter and 5-HT1A receptors and devoid of high affinity at other receptors studied, with the only exception of alpha1-adrenoceptors. In keeping with the binding affinity at the 5-HT transporter, VN2222 inhibited 5-HT uptake in vitro both in rat cortical synaptosomes and in mesencephalic cultures and also in vivo when administered locally into the rat ventral hippocampus. After systemic administration, VN2222 exhibited an inverted U-shape effect so the inhibition of [3H]5-HT uptake ex vivo and the increase in 5-HT extracellular levels in microdialysis experiments was observed at low doses of 0.01-0.1 mg/kg whereas higher doses were ineffective. In studies related to 5-HT1A receptor function, 0.01-0.1 microM VN2222 produced a partial inhibition of forskolin-stimulated cAMP formation behaving as a weak agonist of 5-HT1A receptors. In body temperature studies, 5 mg/kg VN2222 produced a mild hypothermic effect in mice, suggesting a weak agonist activity at presynaptic 5-HT1A receptors; much lower doses (0.01-0.5 mg/kg) partially antagonized the hypothermia induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) possibly through 5-HT transporter blockade. In the learned helplessness test in rats, an animal model for antidepressants, 1-5 mg/kg VN2222 reduced significantly the number of escape failures. Consequently, VN2222 is a new compound with a dual effect on the serotonergic system, as 5-HT uptake blocker and 5-HT1A receptor partial agonist, and with a remarkable activity in an animal model of depression with high predictive validity.     

The selective 5-HT2 receptor antagonist amperozide attenuates 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane-induced inhibition of male rat sexual behavior.

This study was aimed at exploring the role of 5-HT2/5-HT1C neurotransmission in male rat sexual behavior. The administration of the 5-HT2/5-HT1C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (1 mg/kg), suppressed sexual activity in most of the animals. The suppressive effect of DOI was antagonized by treatment with amperozide, a selective 5-HT2 receptor antagonist, in doses which did not by themselves affect sexual activity. In addition, several other serotonin antagonists were tested with varying affinity profiles for 5-HT2/5-HT1C receptors, including ketanserin, ritanserin, and mesulergine. All these compounds antagonized the suppressive action of DOI. In contrast, no antagonizing effect was obtained by treatment with (-)-alprenolol, a 5-HT1A antagonist. The present findings suggest that 5-HT2/5-HT1C receptors might be involved in the neural control of male rat sexual behavior, presumably by exerting an inhibitory influence on the behavior.     

Behavioural pharmacology of polygalasaponins indicates potential antipsychotic efficacy.

Polygalasaponins were extracted from a plant (Polygala tenuifolia Willdenow) that has been prescribed for hundreds of years to treat psychotic illnesses in Korean traditional medicine. Previous in vitro binding studies suggested a potential mechanism for its antipsychotic action, as polygalasaponin was shown to have an affinity for both dopamine and serotonin receptors [Psychopharmacol. Bull. 31 (1995) 139.]. In the present study we have investigated the functional in vivo actions of this material in tests that are predictive of dopamine and serotonin antagonist activities. Polygalasaponin (25-500 mg/kg) was shown to produce a dose-related reduction in the apomorphine-induced climbing behaviour (minimum effective dose [ED(min)] 25 mg/kg ip, 250 mg/kg sc and po), the 5-hydroxytryptamine (5-HTP)-induced serotonin syndrome (ED(min) 50 mg/kg ip) and the MK-801-induced hyperactivity (ED(min) 25 mg/kg ip) in mice. This compound also reduced the cocaine-induced hyperactivity (ED(min) 25 mg/kg ip) in rats. These results demonstrated that polygalasaponin has dopamine and serotonin receptor antagonist properties in vivo. This might suggest its possible utility as an antipsychotic agent.     

Ipsapirone, a new anxiolytic drug, stimulates catecholamine turnover in various regions of the rat brain

Ipsapirone, a new anxiolytic drug with a high affinity to 5-HT1A receptors, given in a dose of 10 mg/kg ip markedly accelerated noradrenaline disappearance after inhibition of tyrosine hydroxylase with alpha-methyl-p-tyrosine (250 mg/kg ip) in the cortex, hippocampus and hypothalamus of male Wistar rats. It also increased disappearance of dopamine and the level of 3,4-dihydroxyphenylacetic acid and homovanillic acid in the striatum. At the same time, the level of 5-hydroxyindoleacetic acid was decreased in the cortex, striatum, hypothalamus, but not changed in the hippocampus. 8-OH-DPAT, a selective agonist of 5-HT1A receptors, used in a dose of 5 mg/kg sc was less effective, having accelerated noradrenaline disappearance in the cortex and hypothalamus, and having increased only the level of homovanillic acid in the striatum. The effect of ipsapirone on catecholamine turnover might be secondary in relation to inhibition of the serotonin neurons. A direct interaction between ipsapirone and its metabolite 1-PP with alpha 1- and alpha 2-adrenoceptors is very likely, too.     

Drug-induced penile erections in rats: indications of serotonin1B receptor mediation

The induction of penile erections by a variety of compounds with a direct or indirect effect on serotonin (5HT) receptors was investigated in rats. L-5-Hydroxy-tryptophan (L-5HTP) induced penile erections when co-administered with nialamide and the peripheral decarboxylase inhibitor benserazide, indicating that the site of action for inducing penile erections is within the central nervous system. Penile erections were also induced by the 5HT uptake inhibitors zimelidine, fluoxetine, citalopram, Org 6997, by the 5HT-releasing agent fenfluramine and by the putative 5-HT1B receptor agonist 1-(3'-chlorophenyl)-piperazine (mCPP). The 5HT1A-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) did not induce penile erections. The less selective 5HT receptor agonists 5-methoxy-N,N-dimethyl-tryptamine (5MeODMT), 5-methoxytryptamine (5MeOT), dl-lysergic acid diethylamide (LSD) and Ru 24969 were also ineffective. Induction of penile erections by quipazine appeared only when this compound was co-administered with the 5HT2 receptor antagonist pirenperone. Receptor antagonists were tested against penile erections induced by Org 6997. The beta-adrenoceptor antagonists that also have 5HT1 antagonistic properties, (S)-pindolol and dl-propranolol, antagonized Org 6997-induced penile erections but butoxamine and metoprolol did not. Spiperone and pirenperone in doses selective for 5HT1A and 5HT2 receptors respectively were also inactive. Haloperidol, 0.46 mg/kg, partially attenuated penile erections induction. The data are discussed in the light of the hypothesis that penile erections induction by serotonin-mimetic compounds is mediated by 5HT1B receptors in the striatum.     

A neuropharmacological analysis of the discriminative stimulus properties of fenfluramine

Rats were trained to discriminate fenfluramine (1.0 mg/kg) from saline in a two-lever drug discrimination task. The dose-response curve for this discrimination was orderly with an ED₅₀ of about one-half of the training dose (0.52 mg/kg). In substitution tests, indirect (p-chloroamphetamine) and direct (quipazine, MK-212, lisuride) serotonin (5-HT) agonists substituted for fenfluramine. Since none of these compounds have been reported to be hallucinogenic and the potent hallucinogen LSD did not substitute completely, it was suggested that the discriminative stimulus properties of fenfluramine are not related to its ability to produce hallucinations in humans. The fenfluramine cue, like the quipazine cue, was antagonized by the 5-HT antagonists cyproheptadine and methiothepin. Unlike quipazine, fenfluramine was also partially antagonized by the 5-HT uptake inhibitor, fluoxetine, and the 5-HT synthesis inhibitor, p-chlorophenylalanine. Thus, the fenfluramine cue differs from that of quipazine in that it is mediated via indirect actions on 5-HT receptors. Since the indirect dopamine (DA) agonist d-amphetamine failed to substitute and the DA antagonist haloperidol failed to block the fenfluramine cue, a mediating role for DA was not indicated. Another indirect DA agonist, cocaine, substituted partially for fenfluramine, a result which paralleled that seen with fluoxetine. Both of these partial substututions were reduced by cyproheptadine; therefore, it was concluded that these effects may be due to the common ability of cocaine, fluoxetine, and fenfluramine to inhibit 5-HT uptake.Portions of this research were presented at the Ninth Annual Meeting of the Society for Neuroscience Atlanta, Georgia, November 2–6, 1979     

Action mechanism of anticonvulsant and anti-immobility (forced swim) effects of 3', 4'-dihydro-N, N-dimethylspiro-[9H-fluorene-9, 2' (5'H) furane]-3'-methanamine (AE37F)

AE37F, a new aminotetrahydrofuranic derivative, exhibited, at 10-30 mg/Kg (po) or 1-10 mg/Kg (ip), antagonism of tonic convulsions, induced by pentetrazole (130 mg/Kg, ip), and of forced swin immobility, in mice. At these doses AE37F induced a considerable (100-250%) increase of serotonin (5-HT) and its main metabolite, 5-hydroxyindolacetic acid (5-HIAA), in the rat nucleus reticularis pontis oralis (NRPO), antagonized by amantadine, which also increased 5-HT and 5-HIAA levels in the NRPO. It is suggested: a) that the anti-immobility effect of AE37F is related to its antimuscarinic properties, b) that the rate of 5-HT release in the NRPO, calculated here by a new approach (from the 5-HT and 5-HIAA brain levels) is increased by AE37F and decreased by amantadine, in the NRPO, c) that the anti-convulsant action, observed with AE37F, could be related to a NMDA-sigma mediated stimulation of serotoninergic, GABAergic and glycinergic brain neurones, antagonized by the NMDA-sigma inhibition induced by amantadine.     

Cardiovascular effects of irindalone, a new S2-serotonergic antagonist, in the rat

Irindalone is a new antihypertensive agent with affinity to serotonin (5-HT2) receptors and at higher concentrations also to alpha 1-adrenoceptors. The present study was designed to evaluate the relative importance of the antagonism of central and peripheral alpha 1- and 5-HT2-receptors in the blood pressure lowering properties or irindalone after acute administration. In conscious Sprague-Dawley rats intravenous irindalone (0.05-1.5 mg/kg) dose-dependently reduced the blood pressure. In the same dose-range irindalone antagonized pressor responses to phenylephrine and electrical stimulation of the spinal sympathetic outflow (SNS) in the pithed rats, indicating that the acute blood pressure lowering effect is primarily related to the blockade of alpha 1-adrenoceptors. However, the concomitant 5-HT2-receptor blockade may contribute since irindalone in a dose (0.15 mg/kg) where it had no alpha-adrenoceptor blocking properties enhanced the hypotensive response to selective alpha 1-adrenoceptor blockade by prazosin (1 micrograms/kg). We found no evidence that central mechanisms contributed to the blood pressure lowering effect of irindalone. In anaesthetized rats irindalone (1 mg/kg) did not reduce the directly recorded sympathetic nerve activity. Intracerebroventricular administration of irindalone in conscious rats (10-100 micrograms) had no consistent effects on the blood pressure and did not enhance the hypotensive response to intracerebroventricularly administered prazosin (10 micrograms). Finally, the hypotensive response to irindalone was not influenced by depletion of central serotonin stores (by PCPA). It is concluded that the blood pressure lowering effect of irindalone following acute administration is related primarily to blockade of peripheral alpha-adrenoceptors but that the concomitant blockade of 5-HT2-receptors may contribute.