Acute administration of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective 5-HT-receptor agonist,causes a biphasic blood pressure response and a bradycardia in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat

Summary 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) is a new serotonin (5-HT) receptor agonist that binds selectively to the 5-HT_1A binding site. In the present paper we investigated the cardiovascular effects of 8-OH-DPAT in the normotensive Sprague-Dawley rat and in the spontaneously hypertensive rat. The acute i.v. administration of 8-OH-DPAT (5–150g/kg) was in both rat strains associated with a biphasic blood pressure response and a bradycardia. The initial pressor response was due to a direct vascular effect of 8-OH-DPAT involving activation of-adrenoceptors since it was present in pithed rats and in reserpine pretreated rats and since it was attenuated by prazosin. The longer lasting hypotension was not due to a direct vascular relaxation or a presynaptic inhibition of transmitter release since the hypotension was not evident in pithed rats and since 8-OHDPAT did not influence the pressor responses to electrical stimulation in pithed rats. Rather, the combination of hypotension and bradycardia would suggest a central site of action although the intracerebroventricular (lat. ventricles) route of administration was not more efficient (to induce hypotension) than i.v. administration. At least the bradycardia was mediated by changes in vagal as well as sympathetic discharge since it was prevented by pretreatment with atropine and propranolol in combination but not by pretreatment with either agent alone. The cardiovascular effects of 8-OH-DPAT were not prevented by pretreatment with methergoline, methiothepin, pirenperone or cianserine or by 5-HT depletion by means of p-chlorophenylalanine, which suggests that the putative 5-HT receptor that is responsible for the hypotension and bradycardia to 8-OH-DPAT is not of a presynaptic type and does not have the pharmacological characteristics of a general 5-HT₁ receptor.     

8-hydroxy-2-(di-n-propylamino)tetralin intervenes with neural cell apoptosis following diffuse axonal injury

Previous studies have reported a neuroprotective effect of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) against traumatic brain injury. In accordance with the Marmarou method, rat models of diffuse axonal injury were established. 8-OH-DPAT was intraperitoneally injected into model rats 8-OH-DPAT treated rats maintained at constant temperature served as normal temperature controls TUNEL results revealed that neural cell swelling, brain tissue necrosis and cell apoptosis occurred around the injured tissue. Moreover, the number of Bax-, Bcl-2- and caspase-3-positive cells increased at 6 hours after diffuse axonal injury, and peaked at 24 hours. However, brain injury was attenuated, the number of apoptotic cells reduced, Bax and caspase-3 expression decreased, and Bcl-2 expression increased at 6, 12, 24, 72 and 168 hours after diffuse axonal injury in normal temperature control and in 8-OH-DPAT-intervention rats. The difference was most significant at 24 hours. All indices in 8-OH-DPAT-intervention rats were better than those in the constant temperature group. These results suggest that 8-OH-DPAT inhibits Bax and caspase-3 expression, increases Bcl-2 expression, and reduces neural cell apoptosis, resulting in neuroprotection against diffuse axonal injury. This effect is associated with a decrease in brain temperature.     

Effect of 8-hydroxy-2-(di-n-propylamino) tetralin on rat prolactin secretion

Summary 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino] tetralin) is a novel aminotetralin derivative which has been proposed to be a serotonin (5-HT) agonist devoid of dopamine agonist effects. We now report that the administration of 8-OH-DPAT, like known 5-HT agonists, produced a rapid elevation of serum prolactin concentrations in male rats. The prolactin response to 8-OH-DPAT, like that induced by other 5-HT agonists, was greatly potentiated in animals pretreated with the tryptophan hydroxylase inhibitor, para-chlorophenylalanine. However, the 8-OH-DPAT-induced elevation of serum prolactin cocentrations in untreated rats was not dose-dependent and was modest in magnitude compared to that produced by known 5-HT agonists. In contrast to the stimulatory effects of 8-OH-DPAT on prolactin secretionin vivo 8-OH-DPAT suppressed the secretion of prolactin from anterior pituitary tissuein vitro, and this effect was blocked by haloperidol. The results of the present study are supportive of the view that 8-OH-DPAT has dopamine agonist, as well as 5-HT agonist, properties.     

Characteristics of feeding induced by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)

The effects of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) on food intake in freely-feeding and food deprived rats were examined. In freely-feeding rats, low doses of 8-OH-DPAT (15-60 micrograms/kg) significantly increased food intake without affecting drinking, grooming, rearing or locomotion. Higher drug doses (125-4000 micrograms/kg) also produced feeding and caused locomotor stimulation and serotonin-related stereotyped behaviour (i.e., forepaw padding, headweaving, wet dog shakes, flat body posture). When feeding and stereotypy were observed concurrently, response competition was evident and feeding behaviour was fragmented into numerous short eating bouts. As drug-induced stereotypy declined with time, this fragmented pattern of eating was succeeded by long bouts of eating which were similar to those observed at doses of 15-60 micrograms/kg 8-OH-DPAT. In 24 hr food deprived rats, low doses of 8-OH-DPAT had no effect on food intake. However, high doses of 8-OH-DPAT (250-4000 micrograms/kg) decreased feeding in food deprived animals, an effect which was probably secondary to the induction of stereotypy. It is proposed that the behavioural effects of 8-OH-DPAT may be explained by a dual effect on brain serotonergic mechanisms, which is dose dependent. Thus, low doses of the drug may preferentially activate inhibitory presynaptic serotonin receptors (autoreceptors), decrease serotonin metabolism and thereby increase feeding. In contrast, high doses of 8-OH-DPAT appear to stimulate postsynaptic serotonin receptors and thus produce stereotypy. Alternatively, it is possible that 8-OH-DPAT may elicit feeding by postsynaptic serotonin receptor blockade.     

Rat brain serotonin: Biochemical and functional evidence for a sex difference

Summary Male and female rats were compared with respect to brain serotonin (5-HT) levels, synthetic capacity, receptor sensitivity, and CNS functions. Levels of whole brain 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) were higher in females. The accumulation of 5-HT after treatment with the monoamine oxidase inhibitor pargyline alone and in combination with the 5-HT precursor L-tryptophan was greater in females than in males. 5-HT increased and 5-HIAA decreased to the same extent in both sexes after administration of the 5-HT agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The temperature fall after all drug treatments was greater in females, but the 5-HT behavioural syndrome was more pronounced in females merely after pargyline plus tryptophan; the behavioural response after 8-OH-DPAT did not differ between the sexes. These results are indicative of sex differences in the brain 5-HT neuronal systems. They are discussed in relation to differences between males and females in sexual behaviour, aggression and affective disorders.     

Gonadotropin and prolactin secretion in prepubertal female rats treated with 8-hydroxy-2-(di-n-propylamino) tetralin

Summary The effect of serotoninergic activation on gonadotropin and prolactin release were analysed in 16-day-old intact female rats. In the first experiment, females were decapitated 30 min after i.p. administration of 100nig/kg of 5-hydroxytryptophan (5-HTP) or vehicle; in the second experiment the rats were decapitated 15 and 30min after i.p. injection of vehicle or some doses (0.1, 1 and 10mg/kg) of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a selective agonist of the serotonin (5-HT)_1A receptors. We found that: 1) serum follicle-stimulating hormone (FSH), luteinizing-hormone (LH) and prolactin concentrations increased after 5-HTP administration; 2) serum LH and prolactin concentrations and pituitary prolactin content increased after administration of 8-OH-DPAT. Our results indicate that in prepubertal rats, activation of serotoninergic system stimulated gonadotropin and prolactin release, and that 5-HT_1A receptors are involved in this effect. In addition, the simultaneous increase in serum and pituitary prolactin content suggests that 8-OH-DPAT enhances prolactin synthesis.     

Anxiolytic effect of the 5-HT1A compounds 8-hydroxy-2-(di-n-propylamino) tetralin and ipsapirone in the social interaction paradigm: Evidence of a presynaptic action

This study analyses at which site, pre- or postsynaptic, the 5-HT_1A ligands—8-hydroxy-2(dl-n-propyilamino)tetralin (8-OH-DPAT) and ipsapirone—induce their amdoytic action. The experimental anxiety was assessed in the social interaction test. An anxioyfic action was observed after the systemic administration of 8-OH-DPAT (025 and 0.5 mg/kg and ipsapirone (5 but not 10 mg/kg). In 5,7-dihydroxytrpytamine (5,7-DHT, 150 μg/10 μl) lesioned rats the arodoytie effect of 8-OH-DPAT and ipsapirone was not observed, suggesting a presynaptic action of these drugs.dnVs. When directly injected into the dorsal raphe nucleus 8-OH-DPAT (0.1 μgμl) and ipsapirone (0.2 μg/μl), both compounds produce an)dolytic effects. At same doses, these drugs lacked an effect after their intrahippocampal infusion. All data strongly suggest that both drugs act presynaptically to reduce the anxiety levels in the social interaction paradigm.     

GW117: A novel serotonin (5-HT2C) receptor antagonist and melatonin (MT1/MT2) receptor agonist with potential antidepressant-like activity in rodents

AimsTo evaluate the antidepressant‐like effect of compound GW117 in rodents using in vitro binding and uptake assays as well in vivo behavioral tests.MethodsWe investigated the target profile of GW117 using [³⁵S]‐GTPγS and [³H]PIP binding. Using the forced swimming test and chronic unpredictable stress in rats, tail suspension test in mice and rats, and learned helplessness model in mice, we further revealed the antidepressant‐like and anxiolytic‐like effects of GW117.ResultsThe current study suggests that GW117 displays serotonin 2C (5‐HT_2C) receptor antagonist and melatonin type 1 and 2 (MT₁/MT₂) receptor agonist properties, as well as evident antidepressant and anxiolytic effects.ConclusionThese data suggest that GW117 is probably a potent antidepressant.     

Activation of 5-hydroxytryptamine1A receptors increases the affinity of galanin receptors in di- and telencephalic areas of the rat.

Since galanin in vitro selectively increases theK_D value of 5-HT_1A receptors without altering the binding of 5-HT_1B or 5-HT₂ receptors, we have studied whether 5-HT_1A receptor activation in turn may affect galanin binding in the ventral di- and telencephalon and the substantia nigra of the rat. As analyzed by autoradiography, the binding of¹²⁵I-galanin was increased by about 55% in the presence of 3–30 nM of 8-OH-2-(di-npropylamino)-tetralin (DPAT) in the paraventricular thalamic nucleus, the nucleus reuniens and rhomboideus, the zona incerta, the medial and the lateral hypothalamus, and the medial and the lateral amygdaloid area, but not in the pars compacta of the substantia nigra, which lacks 5-HT_1A binding sites. DPAT (10 nM) reduced the IC₅₀ values of galanin at¹²⁵I-galanin binding sites by approximately 55% within all the analyzed di- and telencephalic regions. The overall increase inB_O values was50 ± 11%. Using the filter wipe technique in cryostat sections at Bregma -2.8 mm covering all the brain regions at this level, DPAT (10 nM) decreased the IC₅₀ values of galanin from21.6 ± 1.1nM (control) to15.5 ± 0.9nM, and increased theB_O values by19.4 ± 4.1%. In membrane preparations from the ventral di- and telencephalon, DPAT decreased the IC₅₀ values of galanin binding sites by20 ± 3% at 100 nM of DPAT. This effect could be completely blocked by the specific 5-HT_1A receptor antagonist 1-(2-methoxyphenyl)-4-[4-(2-pthalimido)butyl]piperazine. GTP (0.1 nM) produced a17 ± 5% increase in the IC₅₀ value of galanin and a23 ± 4% decrease in theB_O value of¹²⁵I_galanin binding sites. However, DPAT (100 nM) was still able to decrease the IC₅₀ values of galanin in the presence of GTP (-8 ± 3%;control-10 ± 3%). TheB_max value of¹²⁵I-galanin binding was not affected by DPAT. The increased affinity of galanin binding sites by DPAT seems to reflect a G-protein-independent intramembrane receptor-receptor interaction between 5-HT_1A and galanin receptors. This interaction may represent an intramembrane inhibitory feed-back mechanism of 5-HT_1A receptor sensitivity, and may be important both under normal conditions and in 5-HT-mediated mental disorders.     

Effects of zimeldine, a selective 5-HT reuptake inhibitor, combined with ritanserin, a selective 5-HT2 antagonist, on waking and sleep stages in rats

Sleep and waking in rats were studied 8 h following administration of a selective 5-hydroxytryptamine (5-HT) reuptake inhibitor (zimeldine), a selective 5-HT₂ antagonist (ritanserin) and a combination of ritanserin and zimeldine. Consistent with earlier findings, zimeldine gave a biphasic effect on sleep and waking. Waking was increased the first 3 h, followed by an increase in deep slow wave sleep (SWS-2), maximal in hours 4 and 5. Ritanserin gave an increase in SWS-2 that was spread out over the recording period. Ritanserin + zimeldine also gave a biphasic effect as zimeldine did, and the initial increase in waking and the following increase in SWS-2 tended to be stronger. Thus, ritanserin did not block the initial waking effect seen after zimeldine administration, indicating that this waking effect was not due to 5-HT₂ stimulation. The increase in SWS-2 seemed to reflect an addition of the increases following the zimeldine and ritanserin alone conditions. This suggests that the increase in SWS-2 seen after 5-HT reuptake inhibition and 5-HT₂ blockade are independent phenomena. Zimeldine alone, ritanserin alone and the combination all gave a clear reduction of rapid eye movement sleep.     

Plasticity of 5-hydroxytryptamine1B receptors during postnatal development in the rat visual cortex

The distribution of 5-hydroxytryptamine_1A and 5-hydroxytryptamine_1B receptors in the visual cortex was studied by quantitative autoradiography during postnatal development. Overall, receptor densities increased throughout development, but exhibited regional rearrangements, particularly in the case of 5-hydroxytryptamine_1B receptors. Neonatal treatment with 5,7-dihydroxytryptamine, which causes selective degeneration of serotoninergic neurons, had no effect on the density of 5-hydroxytryptamine_1A receptors in the visual cortex. However, a transient increase in 5-hydroxytryptamine_1B at postnatal days 10–12 was observed after this treatment, suggesting a regulation of postsynaptic receptors. Neonatal enucleation resulted in a marked increase in 5-hydroxytryptamine_1B binding sites in all layers of the visual cortex by P16, whereas it had no effect upon 5-hydroxytryptamine_1A binding sites.These results show that both receptor subtypes do not exhibit striking transient features in the visual cortex during postnatal development, but rather undergo discrete reorganizations. 5-Hydroxytryptamine_1B receptors show changes in density after either neonatal degeneration of serotoninergic neurons or enucleation, indicating that the serotoninergic system involving this receptor subtype can exhibit some postnatal plasticity in the visual cortex.     

R(+)-8-OH-DPAT, a selective 5-HT1A receptor agonist, attenuated amphetamine-induced dopamine synthesis in rat striatum, but not nucleus accumbens or medial prefrontal cortex

R(+)-8-OH-DPAT (0.05, but not 0.025, 0.1, 1 mg/kg), a 5-HT_1A receptor agonist, decreased l-3,4-dihydroxyphenylalanine (DOPA) accumulation in rat striatum following NSD-1015, an l-aromatic amino acid decarboxylase inhibitor. Amphetamine (1 mg/kg) increased striatal DOPA accumulation, an effect attenuated by R(+)-8-OH-DPAT (0.05 mg/kg). However, both amphetamine (1 mg/kg) and R(+)-8-OH-DPAT (0.05 mg/kg) decreased cortical DOPA accumulation; there were no additional decreases from their combination. Neither amphetamine (1 mg/kg), R(+)-8-OH-DPAT (0.05 mg/kg), or the combination, significantly affected DOPA accumulation in the nucleus accumbens. The significance of and possible mechanisms for these findings are discussed.     

The 5-HT1A agonist 8-OH-DPAT increases the number of spike-wave discharges in a genetic rat model of absence epilepsy

The effects of the 5-HT_1A receptor agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) on the epileptiform activity has been investigated in adult WAG/RIJ rats. Either intraperitoneal (0.1–0.5 mg/kg) or intracerebroventricular (2–20 μg/rat) administration of 8-OH-DPAT caused marked, dose-dependent increases in the number and mean cumulative duration of spike-wave discharges. These effects were attenuated by NAN-190, a 5-HT_1A receptor antagonist. These data indicate that serotonergic system regulates the epileptiform activity in this genetic model of human absence epilepsy.     

Anxiolytic actions of the substance P (NK1) receptor antagonist L-760735 and the 5-HT1A agonist 8-OH-DPAT in the social interaction test in gerbils

The gerbil social interaction test has previously detected anxiolytic effects of nicotine and diazepam. In the present study, the high affinity substance P (NK(1)) receptor antagonist L-760735 (3 mg/kg) significantly increased the time spent in social interaction, whereas its low affinity analogue L-781773 (3 mg/kg) was without effect. Diazepam (0.1 mg/kg) and the 5-HT(1A) receptor agonist 8-OH-DPAT (0.003 and 0.01 mg/kg) also increased social interaction, whereas an acute dose of the selective serotonin re-uptake inhibitor fluoxetine (10 mg/kg) decreased the time spent in social interaction. Diazepam (0.1 mg/kg) significantly increased locomotor activity, but this effect was independent of the increase in social interaction. The other drugs tested were without effect on locomotor activity. The present findings suggest that the gerbil social interaction may well provide a useful assay for detecting both anxiolytic and anxiogenic compounds, and suggests that the high affinity NK(1) receptor antagonist L-760735 may prove to be useful as an anxiolytic therapy.     

CPP, a new potent and selective NMDA antagonist. Depression of central neuron responses, affinity for [H]d-AP5 binding sites on brain membranes and anticonvulsant activity

Properties of a new potent antagonist acting selectively at N-methyl-D-aspartate (NMDA) type excitatory amino acid receptors are described. This compound, 3-((+/-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) is more potent than all previously reported NMDA antagonists in depressing mammalian spinal neuronal responses (cat and immature rat), in its affinity for [3H]D-AP5 (a radiolabelled NMDA antagonist) binding sites on rat brain membranes, and as an anticonvulsant in mice.     

Effects of 8-OH-DPAT, a 5-HT1A receptor agonist, and DOI, a 5-HT2A/2C agonist, on monosynaptic transmission in spinalized rats

We investigated the effect of the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and the 5-HT_2A/2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on monosynaptic transmission in spinalized rats. 8-OH-DPAT significantly inhibited the excitation of α-motoneurons evoked by monosynaptic transmission without a direct effect on α-motoneuron excitation. DOI potentiated the excitation of α-motoneurons by both direct stimulation and monosynaptic transmission. These results indicate that activation of 5-HT_1A receptors inhibits monosynaptic transmission, whereas activation of 5-HT_2A/2C receptors enhances it.     

The acute and chronic administration of (+/-)-8-hydroxy-2-(Di-n-propylamino)tetralin significantly alters the activity of spontaneously active midbrain dopamine neurons in rats: an in vivo electrophysiological study

This study examined the effect of the acute and chronic systemic administration of (+/-)-8-Hydroxy-2-(Di-n-propylamino)Tetralin(8-OH-DPAT) on the number and firing pattern of spontaneously active dopamine (DA) neurons in the ventral tegmental area (VTA or A10) and substantia nigra pars compacta (SNC or A9) in anesthetized male rats. These parameters were measured using extracellular in vivo electrophysiology. A single s.c. injection of 0.01, 0.1, or 1 mg/kg of 8-OH-DPAT did not significantly alter the number of spontaneously active SNC DA neurons compared to vehicle-treated animals (controls). The acute administration of 0.01 or 0.1 mg/kg of 8-OH-DPAT did not significantly alter, whereas the 1 mg/kg dose significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The acute administration of 8-OH-DPAT significantly increased the percentage of VTA DA neurons firing in a bursting pattern. In contrast, there was a significant decrease in the percentage of SNC DA neurons firing in a bursting pattern following the acute administration of 8-OH-DPAT. The number of spontaneously active SNC DA neurons was not significantly altered by the chronic s.c. administration of 8-OH-DPAT (0.01, 0.1, or 1 mg/kg s.c.) as compared to controls. However, the chronic s.c. administration of all doses of 8-OH-DPAT significantly decreased the number of spontaneously active VTA DA neurons compared to controls. The i.v. administration of (+)-apomorphine (50 microg/kg) did not reverse the 8-OH-DPAT-induced decrease in the number of spontaneously active VTA DA neurons, suggesting that this effect is unlikely due to depolarization blockade. The percentage of VTA DA neurons exhibiting burst firing was significantly increased by 0.01 and 0.1 mg/kg, but significantly decreased by 1 mg/kg of 8-OH-DPAT. Overall, the systemic administration of 8-OH-DPAT preferentially affects the activity of spontaneously active A10 DA neurons in rats.     

Influence of aminophylline and 8-(p-sulfophenyl)theophylline on the anticonvulsive action of diphenylhydantoin,phenobarbital, and valproate against maximal electroshock-induced convulsions in mice

Summary Aminophylline (theophylline₂·ethylenediamine) in the dose of 12.5 mg/kg (i.p.) was ineffective upon all antiepileptic drugs studied and at the higher dose of 25 mg/kg, impaired the anticonvulsant action of phenobarbital and valproate against maximal electroshock in mice. The protection offered by diphenylhydantoin was diminished by aminophylline at 50 mg/kg (0.238 mmol of anhydrous theophylline/kg). In contrast, 8-(p-sulfophenyl)theophylline (a theophylline derivative unable to cross the blood-brain barrier) in the dose of 80 mg/kg (0.238 mmol/kg) did not influence the protective activity of diphenylhydantoin, phenobarbital, and valproate.It might be concluded that the aminophylline-induced impairment of the anticonvulsant action of common antiepileptic drugs results from the central effects of this methylxanthine.