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PubMed1986

Differential effects of 5-hydroxytryptamine1a selective drugs on the 5-HT behavioral syndrome.

The effects of 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), buspirone and isapirone were examined at 5-hydroxytryptamine1A (5-HT1A) binding sites and on the 5-HT behavioral syndrome in the rat. 8-OH-DPAT, 5-MeODMT, buspirone and isapirone are all potent inhibitors of 3H-8-OH-DPAT binding to rat brain membranes (Ki values = 1.9-13 nM). However, these drugs have differential effects on the 5-HT behavioral syndrome. 8-OH-DPAT, 5-MeODMT and buspirone induce hindlimb abduction, flattened body posture and Straub tail. Isapirone induces only a slight flattening of body posture. By contrast, 8-OH-DPAT and 5-MeODMT, but not buspirone and isapirone, and isapirone, also induce forepaw treading, head-weaving and tremor. However, both buspirone and isapirone antagonize the induction of these three behaviors by 8-OH-DPAT or 5-MeODMT. These data show that 8-OH-DPAT and 5-MeODMT are "full agonists" in relation to six components of the 5-HT behavioral syndrome. Buspirone and isapirone, on the other hand, act as "antagonists" in relation to forepaw treading, head-weaving and tremor. Therefore, these data suggest that specific components of the 5-HT behavioral syndrome are mediated by 5-HT1A receptors.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1987

The effects of 8-hydroxy-2-(di-n-propylamino)tetralin and other serotonergic agonists on performance in a radial maze: a possible role for 5-HT1A receptors in memory.

A group of ten rats was trained to obtain food pellets in an 8-arm radial maze. The effects of pretreatment with (+)-Lysergic acid diethylamide (+)-tartrate (LSD), m-trifluoromethylphenylpiperazine (TFMPP), 5-methoxy-N,N-dimethyltryptamine oxalate (5-MeO-DMT), racemic 8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT), and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole succinate (RU 24969) were then evaluated. All drugs were administered IP 15 min before testing. With the exception of an increased rate of responding at a dose of 0.1 mg/kg of 8-OH-DPAT, all drugs produced a dose-related decline in response rate. In addition, LSD, RU 24969, and 8-OH-DPAT caused a statistically significant decrease in efficiency of responding. Of the three, 8-OH-DPAT was clearly the most active. Doses of 0.3, 1.0, and 3.0 mg/kg resulted in efficiencies of 61%, 53%, and 44%, respectively. The present results taken in light of 8-OH-DPAT's preferential binding to 5-HT1A receptors, the high density of these receptors in hippocampus, and the observation that the number of 5-HT1A receptors is decreased in Alzheimer's disease, suggest a possible role for this serotonergic receptor subtype in memory.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1987

Inhibition of mouse killing behavior by serotonin-mimetic drugs: effects of partial alterations of serotonin neurotransmission.

Rats which do not kill mice and which acquire mouse killing behavior after partial lesion of the serotonin neurotransmission, either by p-chlorophenylalanine treatment or by electrolytical lesions of dorsal and median raphe nucleus, were treated by IP injection of serotonin-mimetics. The following drugs were used: 5-methoxy-N-N-dimethyl-tryptamine and 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide, serotonin-agonists, fluoxetine and citalopram, inhibitors of serotonin uptake. All these serotonin-mimetics inhibit mouse killing behavior without apparent secondary effects. When these compounds were tested on killer rats, a stronger antimuricidal effect was observed in rats having altered serotonin neurotransmission. These results support a role for the serotoninergic supersensitivity in a model of aggressive behavior.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1988

Both prenatal and postnatal factors contribute to the effects of maternal stress on offspring behavior and central 5-hydroxytryptamine receptors in the rat.

Litters from stressed and control females were cross-fostered at birth to determine whether the effects of maternal stress on the offspring originated prenatally or during the neonatal period. Offspring of stressed females reared by control mothers from birth showed a reduced behavioral response to injections of the 5-hydroxytryptamine (5-HT) agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), increased 5-HT2 receptor binding in cerebral cortex and increased open field activity when tested at 60 days of age. In contrast, control litters reared by previously stressed females showed an increased behavioral response to 5-MeODMT, increased 5-HT2 receptor binding and only minor changes in open-field activity. These results provide further evidence that adult rat behavior can be significantly altered by exposure to the effects of maternal stress in utero. However, the effect of maternal stress on central 5-HT receptors is also strongly influenced by the postnatal rearing conditions.

Animals↗

PubMed1988

Effects of maternal stress during different gestational periods on the serotonergic system in adult rat offspring.

Pregnant Sprague-Dawley rats were exposed to mild stress treatments during different gestational periods and the offspring were investigated at 60 days of age. In the first study, stress from embryonic day (ED) 11 to ED 20 produced effects similar to those reported following stress throughout pregnancy; increased numbers of 5-HT2 binding sites in cerebral cortex and a reduced intensity of the behavioral syndrome produced by injections of the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). In the second study, stress from ED 3 to ED 14 had no significant effect on the intensity of the 5-MeODMT-elicited 5-HT syndrome while stress from ED 15 to ED 20 had a similar effect as stress throughout pregnancy. These data provide evidence that the critical period for prenatal stress-induced changes in brain 5-HT neurons is between ED 15 and birth. This suggests that the mechanism involves an interaction with developmental events occurring within this time span such as the growth of nerve axons and the formation of synaptic contacts. Our findings also provide further evidence that stress during the final trimester of pregnancy may have serious adverse effects on fetal brain development.

Animals↗

PubMed1989

Selective cross-tolerance to 5-HT1A and 5-HT2 receptor-mediated temperature and corticosterone responses.

The repeated administration of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 3 mg/kg, twice daily for 14 days) significantly diminished hypothermia and corticosterone secretion induced by an acute challenge with the 5-HT1A agonist 8-OH-DPAT (0.1 mg/kg) when compared to the responses in animals treated chronically with the solvent vehicle. In contrast, the chronic administration of 5-MeODMT did not alter the magnitude of hyperthermia or corticosterone secretion induced by the acute administration of MK-212 (1.0 mg/kg). The repeated administration of the 5-HT2 agonist DOI (1.0 mg/kg, daily for 7 days) significantly reduced the increase in corticosterone, but not body temperature, produced by MK-212. Chronic treatment with DOI did not alter the hypothermia or increase in corticosterone secretion elicited by 8-OH-DPAT. These data are consistent with other evidence that these physiological effects of 8-OH-DPAT and MK-212 are mediated by 5-HT1A and 5-HT2 receptors, respectively. Thus, data presented in these studies are suggestive that the chronic administration of 5-MeODMT diminishes the responsiveness of 5-HT1A receptor-mediated changes in body temperature and corticosterone secretion without altering the responses mediated by 5-HT2 receptors. In contrast, the chronic administration of DOI selectively diminishes the magnitude of 5-HT2 receptor-mediated changes in corticosterone secretion without affecting the responsiveness of those receptors involved in thermoregulatory responses. These selective changes in receptor responsiveness following the chronic administration of these 5-HT agonists further establishes the independence of 5-HT1A and 5-HT2 receptor-mediated pharmacological effects.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

Serotonergic modulation of the acoustic startle response in rats during preweaning development.

The involvement of serotonin (5-HT) in modulating the acoustic startle response (ASR) is well established in adult rats, but 5-HT involvement during the preweaning period, when 5-HT neurons undergo extensive development, has not previously been described. Three 5-HT receptor subtypes are reported to modulate the ASR in adult rats: 5-HT1A and 5-HT2 receptor agonists facilitate the ASR, whereas 5-HT1B agonists decrease the response. In the present study, the effects of 5-HT agonists and generalized 5-HT depletion on the ASR were studied in preweanling animals, using independent groups of Long-Evans rats tested on postnatal day (PND) 13, 17 and 21. 8-Hydroxy-2-(di-n-propylamino) tetralin (8OHDPAT, 62-1000 micrograms/kg), a 5-HT1A receptor agonist, and 5-methoxy-N,N-dimethyl tryptamine (MeODMT, 2-4 mg/kg), a nonselective 5-HT agonist, had no effect on PND 13 and then increased the ASR on PND 17 and 21. The 5-HT2 receptor antagonists cyproheptadine (5 mg/kg) and ketanserin (5 mg/kg) blocked the effect of MeODMT at both ages, providing some evidence that MeODMT increased the ASR through 5-HT2 receptors. 1-(m-Chlorophenyl) piperazine (mCPP, 1-5 mg/kg), a 5-HT1B agonist, had no effect on ASR amplitude on PND 13 or 17 and then produced a dose-related decrease in the response on PND 21. Generalized depletion of 5-HT by 80-90% in whole-brain and spinal cord, using p-chlorophenylalanine (PCPA, 300 mg/kg 24 hr prior to testing), did not alter ASR amplitude at any age.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1989

Stress adaptation and hypersensitivity in 5-HT neuronal systems after repeated foot shock.

The relationship between adaptation to stress and change in sensitivity of the 5-hydroxytryptamine (5-HT) neuronal system was studied in rats exposed to repeated foot shock stress for up to 10 days. Although hypolocomotion, freezing behavior and loss of weight were observed after in the initial stress, relief from these behavioral changes developed by the 3rd and persisted for another 7 days, indicating the development of stress adaptation. Following an IP injection of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), rats exposed to the stress for 10 days, but not for 5 days, displayed enhanced forepaw treading, tremor and Straub tail compared to control rats. These results suggest that the hypersensitivity of the 5-HT system after repeated stress may be in part related to the neuronal mechanism of stress adaptation. However, since hypersensitivity was not observed after exposure for 5 days, when adaptation was maximal, it is proposed that the 5-HT system may participate in the maintenance of adaptation rather than its development. On the other hand, no change in 5-HT1, 5-HT1a and 5-HT2 receptor binding assays was found after chronic stress, suggesting that the hypersensitivity of 5-HT system may not be accompanied with changes in the numbers of 5-HT receptor binding sites. The results of beta-adrenergic receptor binding determined simultaneously were also discussed with reference to previous reports of stress-induced reduction in beta-adrenergic receptor density.

Adaptation, Physiological↗

PubMed1990

Do functional relationships exist between 5-HT1A and 5-HT2 receptors?

To investigate the possible functional relationship between 5-HT1 and 5-HT2 receptors, we studied the effects of a nonselective 5-HT agonist (5-MeO DMT), a 5-HT1A-selective (8-OH-DPAT) and a 5-HT1B/5-HT1C-selective (TFMPP) agonist on the head-twitch behavior induced by the putative 5-HT2-selective receptor agonist (+/-)-DOI. In the mouse (+/-)-DOI produced the head-twitch response in a dose-dependent manner and (-)-DOI was twice as potent as the (+) isomer. Selective 5-HT2 antagonists, ketanserin and spiperone, dose-dependently inhibited the (+/-)-DOI-induced head-twitch response. The nonselective and the 5-HT1A-selective agonists also dose-dependently reduced the behavior, whereas 5-HT1B/5-HT1C-selective agonist (TFMPP) failed to affect the (+/-)-DOI-induced response. Taken together with previously published literature data, we propose a 5-HT1A inhibitory action on the 5-HT2 receptor-mediated response when induced by its selective agonist (+/-)-DOI.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1990

Effect of chronic variable stress on monoamine receptors: influence of imipramine administration.

Adult male rats were exposed to a series of unpredictable stressors, a paradigm considered to be a model of experimental depression, with or without concurrent administration of imipramine. One day after the last stress event of the chronic regime, binding of cortical beta-adrenoreceptors and the behavioral serotonin (5-HT) syndrome induced by 5-methoxy-N,N,dimethyltryptamine (5-MeODMT) were determined in all the experimental groups. Stressed rats showed an "up-regulation" of cortical beta-adrenergic sites, while similar values to control rats were observed when stressed animals were administered imipramine. Regarding the behavioral 5-HT syndrome, comparable behavioral scores were observed between controls and chronically stressed rats. The combination of chronic exposure to different stressors with imipramine treatment resulted in a significant increase of forepaw treading and Straub tail scores. The probable facilitation of behavioral deficits induced by this scheme of chronic stress and the recovery following concurrent administration of imipramine are discussed.

Animals↗

PubMed1990

Behavioral reactivity following 5-MeODMT administration in 5,7-DHT-pretreated killer rats.

Grouped, nonkiller and killer animals were centrally injected either with vehicle or with 5,7-dihydroxytryptamine. After a period of 7-10 days, forepaw treading and hindlimb abduction were induced by 5-MeODMT administration in all sham and lesioned rats. As expected, behavioral supersensitivity was observed in grouped and nonkiller lesioned rats. A reduced increase in 5-MeODMT-induced behaviors was obtained in killer lesioned animals. 5-HT uptake studies showed a comparable reduction of 5-HT uptake within all the lesioned rats. This evidence suggests an altered capacity to promote adaptive changes on 5-HT sites in killer rats following the destruction of central serotonergic fibers.

5,7-Dihydroxytryptamine↗

PubMed1990

Stimulus properties of tiflucarbine: a novel antidepressant agent.

Tiflucarbine is a structurally novel antidepressant that binds at central serotonin (5-HT) binding sites. There is also evidence that this agent is both a 5-HT1 and a 5-HT2 agonist. To further characterize the serotonergic actions of this agent, tiflucarbine was evaluated in groups of rats trained to discriminate the 5-HT1A agonist 8-OH DPAT, the 5-HT2 agonist DOM, and the nonselective 5-HT agonist 5-OMe DMT from saline. Tiflucarbine resulted in partial generalization in the DOM-trained and in the 8-OH DPAT-trained animals. Although two-thirds of the animals were disrupted, 10 mg/kg of tiflucarbine resulted in stimulus generlization in the 5-OMe DMT-trained animals. It is concluded that tiflucarbine is most likely a nonselective 5-HT agonist.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1991

Region-selective reduction of brain serotonin turnover rate and serotonin agonist-induced behavior in mice treated with clonazepam.

Evidence supports a complex interaction between benzodiazepines and the central serotonergic system. This study attempts to correlate biochemical changes in the serotonin (5HT) system induced by clonazepam (CLON) with the behavioural response to a 5HT agonist. The acute administration of CLON to mice produced a time-dependent decrease in 5HT turnover rate in the raphe area (dorsal and medial raphe nuclei) and modified the serotonergic syndrome induced by 5-methoxy-N,N,-dimethyltryptamine (DMT). One hour after CLON administration, a dose-dependent increase in 5HT concentration was found in the raphe area, while 5-hydroxyindoleacetic acid (5HIAA) levels remained stable, leading to an increase in 5HT/5HIAA ratio, indicative of reduced 5HT turnover rate. No significant changes were detected in the frontal cortex of CLON-treated mice. After 4 days of CLON treatment, the 5HT turnover rate was still decreased in the raphe area and unchanged in the frontal cortex. Acute CLON administration produced dose-dependent alterations in locomotor activity, not observed after subchronic administration. Lateral head weaving, a motor manifestation of the serotonergic syndrome produced by DMT, was less intense in CLON-treated animals. The modifications in the 5HT system induced by CLON are region selective, suggesting differences in the receptors implicated in the interaction. Altered synaptic availability of 5HT as a result of CLON administration may be responsible for the differential response to DMT in control and CLON-treated mice.

Animals↗

PubMed1991

Spontaneous alternation behavior: an animal model for obsessive-compulsive disorder?

This study entailed the adoption of a well-established behavioral paradigm, spontaneous alternation, as a possible animal model for some of the symptoms observed in obsessive-compulsive disorder (OCD) in humans. Food-deprived rats were run in a T-maze in which both a black and a white goal box were equally baited with a small amount of chocolate milk. Each rat was given 7 trials every other day during which it was placed in the start box and allowed to make a choice. The mean number of choices until an alternation occurred was recorded. After a stable baseline of spontaneous alternation was achieved the effects of manipulating the serotonergic system were tested. Both the nonselective 5-HT agonist 5-MeODMT (1.25 mg/kg) and the more selective 5-HT1A agonist 8-OH-DPAT (2 mg/kg) disrupted spontaneous alternation. A course of chronic treatment (2 x 5 mg/kg for 21 days) with the selective 5-HT uptake blocking agent fluoxetine had a protective effect on the 5-MeODMT-induced disruption of spontaneous alternation behavior. Serotonergic manipulations of spontaneous alternation may be a simple animal model for the perseverative symptoms or indecisiveness seen in people diagnosed with OCD.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1991

Opposite effects of 5-methoxy-N,N-di-methyl-tryptamine and 5-hydroxytryptophan on male rat sexual behavior.

The administration of 5-methoxy-N,N-di-methyl-tryptamine (5-MeODMT), O-2.0 mg.kg-1 SC -15 min, produced a dose-dependent facilitation of the male rat sexual behavior, as evidenced by a decrease in the number of intromissions to ejaculation and in the ejaculation latency. The effects produced by 5-MeODMT (1 mg.kg-1) were antagonized by pindolol (4 mg.kg-1 SC -30 min), but not pirenperone (0.25 mg.kg-1 SC -30 min) or metergoline (1 mg.kg-1 SC -30 min), administration. As expected, 5-HTP (25 mg.kg-1 SC -60 min) produced an increased number of mounts and intromissions to ejaculation and an increase in the ejaculation latency in benserazide (25 mg.kg-1 SC -90 min) pretreated animals. Pindolol (4 mg.kg-1) by itself produced the same effects as seen after 5-HTP administration, and the combination of these compounds produced additive effects. Betaxolol (8 mg.kg-1 SC -30 min) had no effects of its own and did not interact with 5-HTP. The results suggest that stimulation of brain 5-HT1 or 5-HT2 receptors produces facilitation and inhibition, respectively, of the male rat sexual behavior.

5-Hydroxytryptophan↗

PubMed1992

Repeated administration of low doses of cocaine enhances the sensitivity of 5-HT2 receptor function.

The acute and chronic effects of cocaine were evaluated on the 5-hydroxytryptamine (5-HT)-receptor 5-HT2 mediated behavioral function, the head-twitch response (HTR), in mice. In a recent study, we reported that the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI)-induced HTR was dose dependently reduced by cocaine via indirect stimulation of serotonergic 5-HT1A and adrenergic alpha 2 receptors. In the present investigation, the HTR was evoked by the nonselective 5-HT agonist 5-methoxy-N,N-dimethyltryptamine hydrogen oxolate (5-MeO-DMT). Cocaine by itself failed to produce HTR but dose dependently inhibited the 5-MeO-DMT-induced behavior. Cocaine's effects were not due to 5-HT3 antagonism since acute administration of the more potent 5-HT3 antagonist (ICS-205,930) failed to produce or modify the 5-MeO-DMT-induced behavior. During withdrawal from chronic cocaine treatment (5-20 mg/kg), 5-MeO-DMT-induced HTR was enhanced. Depending upon the cocaine dose used, the induced supersensitivity persisted up to 172 h following cessation of cocaine treatment. The mechanisms of cocaine-induced supersensitivity were further investigated using the more selective 5-HT2 agonist DOI. Withdrawal from a low-dose (0.03-1.25 mg/kg) chronic cocaine treatment caused the DOI-induced HTR to increase, whereas withdrawal from a 5- and 10-mg/kg cocaine regimen had no significant effect. The maximal effect persisted up to 36 h following termination of cocaine treatment. Relative to vehicle-exposed controls, withdrawal from cocaine treatment enhanced the inhibitory potency of the 5-HT1A agonist (+-)-8-hydroxy-2-(di-n-propylamino)tetralin HBr (8-OH-DPAT) on DOI-induced HTR.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗

PubMed1992

5-HT1A and 5-HT2 receptors mediate discrete behaviors in the Mongolian gerbil.

Although the ability of agonists at specific serotonin (5-HT) receptor subtypes to induce distinct behaviors has been well documented in the rat, similar studies have not been reported in the Mongolian gerbil. We have found that the 5-HT1A/5-HT2 agonist 5-methoxy,N-N dimethyltryptamine (5-MeODMT) (0.5-8 mg/kg, SC), the specific 5-HT1A agonist 8-hydroxy(di-n-propylamino)tetralin (8-OH-DPAT) (0.125-16 mg/kg, SC), and the 5-HT precursor L-5-hydroxytryptophan (L-5-HTP) (100-250 mg/kg, SC) all elicit a 5-HT syndrome in the gerbil. This syndrome, analogous to the 5-HT syndrome in the rat, consists of reciprocal forepaw treading (RFT), hindleg abduction (HA), body tremors (BT), and Straub tail (ST). The putative 5-HT1A antagonist NAN-190 (0.25-8 mg/kg, SC) when dosed 15 min prior to either 5-MeODMT (4 mg/kg, SC) or 8-OH-DPAT (16 mg/kg, SC) blocked both RFT and HA in a dose-dependent manner, suggesting these 5-HT syndrome behaviors are mediated via 5-HT1A receptor activation. We also identified a unique, dose-responsive behavior in the gerbil, induced selectively by 5-HT1A agonists such as quipazine (2-16 mg/kg, SC) and (+-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.125-8 mg/kg, SC). This reciprocal hindleg body scratch (RHBS) behavior is dose dependently inhibited by pretreatment with the selective 5-HT2 antagonist ritanserin (0.0125-0.2 mg/kg, SC). RHBS behavior is also potently inhibited by pretreatment with the selective 5-HT1A agonist 8-OH-DPAT (0.005-0.04 mg/kg, SC), demonstrating a 5-HT1A/5-HT2 receptor subtype interaction.(ABSTRACT TRUNCATED AT 250 WORDS)

5-Hydroxytryptophan↗

PubMed1994

Lack of adaptive changes in 5-HT sites in perinatally undernourished rats after chronic stress: opioid influence.

The reactivity of 5-HT receptors following repeated immobilization sessions or after immobilization plus morphine was measured through 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) or 8-hydroxy-2-(dipropyl-amino)tetralin (8-OH-DPAT)-induced serotonergic syndrome in adult rats undernourished at perinatal age. Repeated stress enhanced the scores of forepaw treading and hindlimb abduction elicited by 5-MeODMT in control animals. In a similar way, forepaw treading induced by 8-OH-DPAT was enhanced in chronically stressed control rats. These results indicate the development of supersensitivity in 5-HT1 receptors. Conversely, this effect was not observed in undernourished animals. Morphine injections before each stress session instaured the increased reactivity to 5-HT1 sites in malnourished animals. An injection of naloxone prior to morphine before each stress session fully antagonized the increased behavioral reactivity to 5-MeODMT observed in deprived animals. A possible deficiency in the functional role of the opiate system involved in the process of adaptation to chronic stress in early undernourished rats is suggested.

8-Hydroxy-2-(di-n-propylamino)tetralin↗