A comparison of the behavioral effects of oral versus intravenous mCPP administration in OCD patients and the effect of metergoline prior to i.v. mCPP.

In prior studies form three centers, an exacerbation of obsessive-compulsive disorder (OCD) symptoms was reported in some (55%-83%) patients with OCD receiving the serotonergic agonist m-chlorophenylpiperazine (m-CPP) orally, whereas intravenously administered mCPP produced anxiety but no OCD symptom exacerbation. In the present replication attempt, 27 OCD patients were given mCPP either orally (n = 17) or intravenously (n = 10) under double-blind conditions, using identical behavioral rating measures. OCD symptoms were significantly increased after intravenous mCPP (0.1 mg/kg), but not after oral mCPP (0.5 mg/kg). Anxiety and other ratings were markedly elevated after intravenous mCPP administration. After oral mCPP administration, anxiety and most other self-ratings were only slightly elevated in comparison to placebo administration, and behavioral rating increases were no different for the OCD patients compared to age-matched healthy controls. Pretreatment with the potent serotonin (5-HT) antagonist, metergoline, prior to intravenous mCPP was associated with essentially complete blockade of the exacerbation in OCD symptoms and the other behavioral responses in the OCD patients. These results suggest that the behavioral response of OCD patients to mCPP are variable and depend on the route and dose of mCPP. In addition, the ability of metergoline to antagonize the behavioral effects of intravenous mCPP suggests that these responses are mediated by 5-HT1/5-HT2 receptors.

Clozapine treatment and its effect on neuroendocrine responses induced by the serotonin agonist, m-chlorophenylpiperazine.

The effects of clozapine treatment on neuroendocrine responses induced by the serotonin agonist, m-chlorophenylpiperazine (mCPP) were examined. mCPP and placebo were administered after a 2-week drug-free period and again after 5 weeks of clozapine treatment in nine schizophrenic inpatients. Adrenocorticotropic hormone (ACTH), prolactin, and mCPP levels were measured. Clozapine treatment completely blocked mCPP-induced ACTH and prolactin release suggesting that clozapine blocks serotonin receptors that mediate these hormone responses.

5-HT1B receptors mediate potent contractile responses to 5-HT in rat caudal artery.

5-Hydroxytryptamine (5-HT) evoked potent contractile responses in phenoxybenzamine-treated ring segments of rat caudal artery, partially contracted with U46619. Responses were mimicked by 5-HT1-selective agonists with the potency order: RU24969 > 5-carboxamidotryptamine > 5-HT = CP-93,129 >> sumatriptan. 8-Hydroxy-N,N-dipropylaminotetralin was virtually inactive. Responses were unaffected by spiperone (0.1 microM) and mesulergine (1.0 microM), but were antagonized competitively by (+/-)-cyanopindolol affording agonist-independent pKB estimates of 8.4 to 8.9. The pharmacological profile of this receptor is consistent with that of the 5-HT1B subtype. Since the 5-HT1B receptor is the rodent homologue of the 5-HT1D beta subtype, it might be anticipated that 5-HT1D beta receptors will be found to mediate vasoconstrictor responses in non-rodent species.

Effects of FG 5893, a new compound with 5-HT1A receptor agonistic and 5-HT2 receptor antagonistic properties, on male rat sexual behavior.

In the present study male rat sexual behavior was used to explore the functional properties of FG 5893, a newly developed diphenylbutylpiperazinepyridyl derivative which is a 5-HT1A receptor agonist and a 5-HT2 receptor antagonist. Treatment with FG 5893 (0.1-6.0 mg kg-1) stimulated male rat sexual behavior, as evidenced by a decrease in the number of mounts and intromissions to elicit ejaculation, and a shortening of the ejaculation latency. The stimulatory effects varied in a dose-dependent manner, reaching a maximum at 3.0 mg kg-1. Pretreatment with (+/-)-pindolol (0.5 mg kg-1 -30 min), a selective 5-HT1A receptor antagonist, completely antagonized the stimulatory effects of FG 5893 (1 mg kg-1 -20 min) on male sexual behavior. In addition, the behavioral action of FG 5893 was investigated on various components of the 'serotonin behavior syndrome' including flat body posture, forepaw treading, and lower lip retraction. The effects obtained were compared with those induced by treatment with 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT), the prototype of a 5-HT1A receptor agonist. Compared to 8-OH-DPAT, a 100 times higher dose of FG 5893 (10 mg kg-1) was needed to elicit flat body posture while forepaw treading was never seen. Lower lip retraction was elicited by the lowest doses of FG 5893 (0.1 mg kg-1) and 8-OH-DPAT (0.03 mg kg-1). Treatment with (+/-)-pindolol reduced flat body posture elicited by 8-OH-DPAT and completely eradicated the flat body posture induced by FG 5893.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of long-term treatment with the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT2/1C receptor agonist DOI in the neonatal rat.

The rat pup ultrasonic call was used to study the effects of acute and long-term treatment with the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the 5-HT2/1C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) during the neonatal period. Acute administration of 8-OH-DPAT and DOI reduced the number of ultrasonic calls. The reduction induced by 8-OH-DPAT and DOI was antagonized by the 5-HT1A antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301) and the 5-HT2 antagonist ketanserin, respectively. The long-term treatments were started on postnatal day 1. On postnatal day 7, the response of the long-term DOI-treated group was clearly attenuated in comparison to that of the acute DOI-treated group. In contrast, no tolerance to the effect of 8-OH-DPAT was achieved after an analogous treatment. The data indicate that there is a diversity in the ontogeny of the ability to develop tolerance to 5-HT1A agonists in comparison to 5-HT2/1C agonists.

5-HT1C/5-HT2 receptor blockade prevents 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane-, but not stress-induced increases in brain tryptophan.

We have previously shown that acute administration of the 5-HT1C/5-HT2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)2-aminopropane (DOI), elevates brain tryptophan levels. The present work aimed to investigate the mechanisms responsible for this elevation. Acute s.c. administration of a 2-mg/kg dose of DOI increased brain tryptophan levels but did not affect either plasma free tryptophan, plasma total tryptophan, brain 5-HT, or brain 5-hydroxyindoleacetic acid. Pretreatment with the 5-HT1C/5-HT2 receptor antagonist, LY 53857, prevented the DOI-induced increase in brain tryptophan levels, whilst the increase was reduced by the 5-HT2 receptor/alpha 1-adrenoceptor antagonist, ketanserin, and to a lesser extent, by the ganglionic blocker, chlorisondamine. On the other hand, pretreatment with either the peripherally acting 5-HT1C/5-HT2 receptor blocker, BW 501C67, the 5-HT uptake enhancer, tianeptine, the 5-HT uptake blocker, paroxetine, or the beta 2-adrenoceptor antagonist, ICI 118.551, proved ineffective. Lastly, pretreatment with LY 53857 did not affect the immobilization-induced elevation in brain tryptophan levels. It is concluded that the elevation in brain tryptophan levels induced by DOI but not that induced by stress is due to central 5-HT1C and 5-HT2 receptor stimulation.

5-HT1A receptor agonists induce anterograde amnesia in mice through a postsynaptic mechanism.

The effect of the 5-HT1A receptor partial agonist tandospirone on memory was investigated in mice using a single trial, step-through passive avoidance task. Tandospirone disrupted performance in a dose-dependent manner when administered before the training trial but not when injected immediately post-training. The pre-training effect was not the result of reduced responsiveness to foot shock because tandospirone did not alter current threshold intensity to elicit flinch, run and vocalization responses. The performance deficit was alleviated by treatment with d-amphetamine prior to the retention test. The memory impairment by tandospirone was mimicked by the 5-HT1A receptor agonist 8-OH-DPAT (8-hydroxy-dipropylaminotetralin HBr) and blocked by the 5-HT1A receptor antagonist BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspirol-[4]- decane-7,9-dione). BMY7378 alone was ineffective. Treatment with the 5-HT synthesis inhibitor PCPA (parachlorophenylalanine) resulted in apparent enhancement rather than disruption of the avoidance behavior. However, the anterograde amnestic effects of tandospirone and 8-OH-DPAT were not affected by PCPA, and lack of interactions between PCPA and the 5-HT1A agonists revealed in the statistical analyses indicated that the effects of PCPA were not mediated by 5-HT1A receptors. It is concluded that 5-HT1A receptor agonists and partial agonists produce a reversible anterograde amnesia that is mediated by postsynaptic 5-HT1A receptors.

Adrenoceptors and dopamine receptors are not involved in the discriminative stimulus effect of the 5-HT1A receptor agonist flesinoxan.

Using a two-lever operant drug discrimination procedure, rats were trained to discriminate the 5-HT1A receptor agonist, flesinoxan (0.5 mg/kg i.p.), from saline. Hereafter, several non-serotonergic drugs were tested in generalization and antagonism tests. The flesinoxan stimulus did not generalize to the stimuli of either the alpha 1-adrenoceptor antagonist, prazosin, the alpha 2-adrenoceptor agonist, clonidine, the dopamine receptor agonist, apomorphine, the dopamine receptor antagonists, haloperidol and pimozide, the benzodiazepine receptor agonist, chlordiazepoxide, nor to the peripherally acting vasodilator, hydralazine. In antagonism studies, prazosin, haloperidol, pimozide and the alpha 2-adrenoceptor antagonist, idazoxan, failed to block the flesinoxan stimulus. In substitution tests, however, flesinoxan partially generalized to idazoxan and completely to the alpha 2-adrenoceptor antagonist, yohimbine. The affinities of yohimbine and idazoxan for the 5-HT1A receptor may explain the latter result. The present findings suggest that the central mechanism through which flesinoxan exerts its discriminative stimulus effects does not involve alpha 1- and alpha 2-adrenoceptors, dopamine and benzodiazepine receptors. Finally, the results with the blood pressure lowering agents, hydralazine, clonidine and prazosin do not support the suggestion that the centrally mediated blood pressure lowering effects of flesinoxan contribute to its internal stimulus effect.

5-HT and carbohydrate suppression: effects of 5-HT antagonists on the action of d-fenfluramine and DOI.

The effects of several 5-hydroxytryptamine (5-HT) receptor antagonists on the anorectic effect of d-fenfluramine and the 5-HT2/5-HT1C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were examined in a dietary paradigm that appears to be sensitive to 5-HT-induced carbohydrate suppression. In this paradigm, deprived rats are provided with a nutritionally complete hydrated chow mash diet together with an optional carbohydrate supplement of powdered Polycose. Both d-fenfluramine and DOI produced a clear suppression of total energy intake and carbohydrate (Polycose) intake. However, the mechanisms underlying these effects are different. The effect of d-fenfluramine in this paradigm was attenuated by the 5-HT1/5-HT2 receptor antagonist metergoline and partially attenuated by the 5-HT1A/5-HT1B receptor antagonist (+/-)cyanopindolol. In contrast, d-fenfluramine's effect was not antagonised by the 5-HT2 receptor antagonist ketanserin, the 5-HT3 receptor antagonist (3 alpha-tropanyl)-1H-indole-3-carboxylic acid ester (ICS-205,930), the 5-HT2/5-HT1C receptor antagonist ritanserin, or the peripheral 5-HT receptor antagonist xylamidine. However, the effect of DOI in this paradigm was significantly attenuated by ketanserin but was not antagonised by either ritanserin or (+/-)cyanopindolol. Therefore, the suppressive effect of these two 5-HT drugs on total and Polycose intake appears to be mediated, respectively, by 5-HT1B/5-HT1C receptors (d-fenfluramine) and 5-HT2 receptors (DOI).

ICV injection of the serotonin 5-HT1B agonist CP-93,129 increases the secretion of ACTH, prolactin, and renin and increases blood pressure by nonserotonergic mechanisms.

This study tested whether a new serotonin (5-HT1B) agonist, 3-(1,2,5,6-tetrahydro-4-pyridyl)-5-propoxy-pyrrolo[3,2-b]pyridine (CP-93,129), could be used to study the potential role of 5-HT1B receptors in the secretion of adrenocorticotropic hormone (ACTH), prolactin, and renin. CP-93,129 has a high affinity for 5-HT1B receptors but low affinity for other 5-HT receptor subtypes. In addition, CP-93,129 does not readily cross the blood-brain barrier. The secretion of ACTH, prolactin, and renin is known to be increased after activation of 5-HT receptors. ICV injections of CP-93,129 (100 micrograms/kg) increased the plasma concentrations of ACTH, prolactin, and renin. CP-93,129 also increased blood pressure and reduced heart rate. To determine whether these effects of CP-93,129 are centrally mediated, we compared them with IP injection of the same dose of CP-93,129. IP-injected CP-93,129 did not alter blood pressure or heart rate and did not elevate plasma prolactin and renin concentrations. To determine whether 5-HT1B receptors mediate the central effects of CP-93,129, rats were pretreated with the 5-HT antagonists l-propranolol or metergoline prior to ICV injections of doses of CP-93,129 (0-100 micrograms/kg). The 5-HT1A/1B/2A/2C antagonist metergoline (0.5 mg/kg, IP) failed to inhibit the CP-93,129-induced elevation of ACTH, prolactin, or renin concentrations. In contrast, the 5-HT1A/1B/beta antagonist l-propranolol (20 micrograms/kg, ICV) inhibited the renin but not the ACTH or prolactin responses to ICV CP-93,129.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigations on the synthesis and properties of some N-heteroarylpiperazinylalkyl derivatives of imides of 3,4-pyridinedicarboxylic acids.

The synthesis of N-heteroarylpiperazinylalkyl derivatives of imides of 3,4-pyridinedicarboxylic acids is described. In pharmacological screening some of the obtained compounds proved to be pharmacologically active.

Synthesis and pharmacological properties of N-(4-substituted-1-piperazinylalkyl)-1-butyl-2,5-dimethylpyrrole-3,4- dicarboxyimide derivatives.

The preparation of a number of N-(4-substituted-1-piperazinylalkyl)-1-butyl-2,5-dimethylpyrrol e-3,4- dicarboxyimides (3) is described. The structures of the novel compounds were confirmed by elemental and spectral analyses. The results of a preliminary pharmacological study of CNS effects caused by compounds 3 are reported.

5-Hydroxytryptamine 1a receptor agonists block prepulse inhibition of acoustic startle reflex.

Presentation of a nonstartling stimulus (prepulse) 100 msec before a startle-eliciting auditory stimulus (pulse) reduces startle reflex amplitude in mammals. Prepulse inhibition of acoustic startle reflex is smaller in schizophrenics than in nonschizophrenics, a phenomenon that has been hypothesized to reflect sensorimotor gating deficits underlying schizophrenic psychosis. Five 5-hydroxytryptamine1a (5-HT1a, serotonin) receptor agonists: 8-hydroxy-2-(di-n-propylamino) tetraline (8-OHDPAT), 5-methoxydimethyltryptamine, buspirone, gepirone and ipsapirone, were tested for effects on prepulse inhibition and startle reflex amplitude in rats. All five agents reduced prepulse inhibition at doses that had no effect on startle reflex amplitude or motor activity. Reduction of prepulse inhibition by 8-OHDPAT was antagonized by (-)propranolol, a 5-HT1a receptor antagonist, and partially by haloperidol, a dopamine D2 receptor antagonist, but not by ketanserin or methysergide, 5-HT2 receptor antagonists. 8-OHDPAT did not reduce prepulse inhibition in subjects pretreated with reserpine or tetrabenazine to deplete neuronal amines, but interpretation of this result is complicated because reserpine and tetrabenazine given alone reduced prepulse inhibition. The results indicate that 5-HT1a receptor agonists block prepulse inhibition of acoustic startle reflex, possibly via dopaminergic mechanisms.

Role of 5-hydroxytryptamine receptor subtypes in the 1-[3-(trifluoromethyl)phenyl] piperazine-induced increase in threshold for maximal electroconvulsions in mice.

The effect of 1-[3-(trifluoromethyl)phenyl] piperazine (TFMPP), a 5-hydroxytryptamine (5-HT) receptor agonist, on the threshold for maximal electroconvulsions was studied in mice. TFMPP in intraperitoneal (i.p.) doses of 10, 20 and 40 mg/kg increased the convulsive threshold (the amperage necessary to produce the hindleg tonic extensor component of seizures in 50% of animals) by 28, 60, and 85%, respectively. The effect of TFMPP (20 mg/kg) was dose-dependently blocked by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine (NAN-190), prazosin, spiperone, mesulergine, ketanserin, and ritanserin. On the other hand, pindolol and cyanopindolol had no effect on the convulsive threshold increased by TFMPP. The results indicate that the TFMPP-induced decrease in the susceptibility to seizures is connected to stimulation of 5-HT2 or of both 5-HT1C and 5-HT2 receptors. Moreover, alpha 1-adrenoceptors also appear to be engaged in this effect.

5-HT1A receptors and the tail-flick response. VI. Intrinsic alpha 1A-adrenoceptor antagonist properties can mask the actions of 5-HT1A receptor agonists in the spontaneous tail-flick paradigm.

In view of the involvement of central alpha 1-adrenoceptors in the expression of 5-HT1A receptor-mediated spontaneous tail-flicks (STFs) in the rat, this study examined whether the putative alpha 1-adrenoceptor antagonist (alpha 1-antagonist) properties of certain 5-HT1A receptor agonists, (+)-flesinoxan and LY 165,163, might modify their behavior in the STF paradigm. Whereas the 5-HT1A receptor agonists 8-OH-DPAT and WY 48,723 dose-dependently elicited STFs, (+)-flesinoxan was only weakly active and LY 165,163 was ineffective. Further, (+)-flesinoxan and LY 165,163 antagonized the induction of STFs by 8-OH-DPAT and WY 48,723. Nevertheless, (+)-flesinoxan and LY 165,163 mimicked 8-OH-DPAT and WY 48,723 in eliciting a pronounced rise in plasma corticosterone and a marked hypothermia: these actions were blocked by the 5-HT1A receptor antagonist, (-)-alprenolol, but they were not affected by the alpha 1-antagonist prazosin. Reflecting its antagonist actions at alpha 1-adrenoceptors, prazosin evoked a pronounced ptosis, an action mimicked by the preferential alpha 1A-antagonists WB 4101, methylurapidil and benoxathian, whereas chlorethylclonidine, which irreversibly inactivates alpha 1B- but not alpha 1A-adrenoceptors, was inactive. Although 8-OH-DPAT and WY 48,723 failed to modify palpebral aperture, (+)-flesinoxan and LY 165,163 provoked a ptosis, suggesting that they possess alpha 1A-antagonist properties. The alpha 1-agonists cirazoline and ST 587 did not elicit STFs alone and failed to modify the induction of STFs by 8-OH-DPAT and WY 48,723. By contrast, they greatly facilitated the ability of both (+)-flesinoxan and LY 165,163 to induce STFs. STFs elicited by (+)-flesinoxan and LY 165,163 in the presence of cirazoline or ST 587 were blocked not only by prazosin but also by (-)-alprenolol, BMY 7378 and S 15535, all of which are antagonists of postsynaptic 5-HT1A receptors. The facilitatory actions of cirazoline and ST 587 were selective in that they did not permit the induction of STFs by agonists at other 5-HT receptor subtypes (5-HT1B, 5-HT1C, 5-HT2 or 5-HT3). In conclusion, in the STF paradigm, the high-efficacy agonist actions of (+)-flesinoxan and LY 165,163 at 5-HT1A receptors are "masked" by their "intrinsic" alpha 1A-antagonist properties, the neutralization of which by alpha 1-agonists reveals the activation of 5-HT1A receptors.