Decrease in gastric sensitivity to distension by 5-HT1A receptor agonists in rats

Using an in vivo model for evaluation of gastric sensitivity in awake rats, we aimed to determine whether 5-hydroxytryptamine 1A (5-HT1A) agonists modify pain threshold and gastric compliance specifically through 5-HT1A receptors. Isobaric gastric distensions were performed with a barostat using steps of 5 mm Hg in male rats equipped with a gastric balloon and electrodes implanted in the neck muscles. Gastric distension at 15 or 20 mm Hg induced a typical posture associated with contractions of the neck muscles. Rats received drugs 30 min before gastric distension. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), administered intraperitoneally (0.5 mg/kg) increased gastric pain threshold and gastric tone. These effects were reproduced when administered centrally (0.05 mg/kg) and blocked by intracerebroventricular administration of the 5-HT1A antagonist WAY 100635. Flesinoxan (4 mg/kg, intraperitoneally), another 5-HT1A agonist reproduced the effects of 8-OH-DPAT on pain threshold and gastric tone and the alpha2-receptor antagonist yohimbine did not modify the action of 8-OH-DPAT. Our results indicate that activation of 5-HT1A receptors at the level of the central nervous system increases gastric tone and decreases gastric sensitivity to distension.     

The effects of 5-HT1A receptor agonists, 5-HT1A receptor antagonists and their interaction on the fear-potentiated startle response

Time-resolved small-angle X-ray scattering (TR-SAXS) was used to monitor the structural changes that occur upon the binding of the natural substrates to a mutant version of the allosteric enzyme aspartate transcarbamoylase from Escherichia coli, in which the creation of a critical link stabilizing the R state of the enzyme is hindered. Previously, SAXS experiments at equilibrium showed that the structures of the unligated mutant enzyme and the mutant enzyme saturated with a bisubstrate analog are indistinguishable from the T and R state structures, respectively, of the wild-type enzyme (Tauc et al., Protein Sci. 3:1998-2004, 1994). However, as opposed to the wild-type enzyme, the combination of one substrate, carbamoyl phosphate, and succinate, an analog of aspartate, did not convert the mutant enzyme into the R state. By using TR-SAXS we have been able to study the transient steady-state during catalysis using the natural substrates rather than the nonreactive substrate analogs. The steady-state in the presence of saturating amount of substrates is a mixture of 60% T and 40% R structures, which is further converted entirely to R in the additional presence of ATP. These results provide a structural explanation for the reduced cooperativity observed with the mutant enzyme as well as for the stimulation by ATP at saturating concentrations of substrates. They also illustrate the crucial role played by domain motions and quaternary-structure changes for both the homotropic and heterotropic aspects of allostery.     

Alcohol-heightened aggression in mice: attenuation by 5-HT1A receptor agonists

One of the critical mechanisms by which alcohol heightens aggression involves forebrain serotonin (5-HT) systems, possibly via actions on 5-HT1A receptors. The present experiments tested the hypothesis that activating 5-HT1A receptors by selective agonists will block the aggression-heightening effects of ethanol. Initially, the selective antagonist WAY 100635 was used to assess whether or not the changes in aggressive behavior after treatment with 8-OH-DPAT and flesinoxan result from action at the 5-HT1A receptors. Resident male CFW mice engaged in aggressive behavior (i.e. attack bites, sideways threats, tail rattle) during 5-min confrontations with a group-housed intruder male. Quantitative analysis of the behavioral repertoire revealed systematic reductions in all salient elements of aggressive behavior after treatment with 8-OH-DPAT (0.1-0.3 mg/kg, i.p.) or flesinoxan (0.1-1.0 mg/kg, i.p.). The 5-HT1A agonists also reduced motor activities such as walking, rearing and grooming, although to a lesser degree. Pretreatment with the antagonist WAY 100635 (0.1 mg/kg, i.p.) shifted the agonist dose-effect curves for behavioral effects to the right. In a further experiment, oral ethanol (1.0 g/kg, p.o.) increased the frequency of attacks in excess of 2 SD from their mean vehicle level of attacks in 19 out of 76 resident mice. Low doses of 8-OH-DPAT (0.03-0.3 mg/kg) and flesinoxan (0.1, 0.3, 0.6 mg/kg), given before the ethanol treatment, attenuated the alcohol-heightened aggression in a dose-dependent fashion. By contrast, these low 5-HT1A agonist doses affected motor activity in ethanol-treated resident mice to a lesser degree, suggesting behavioral specificity of these anti-aggressive effects. The current results support the hypothesized significant role of 5-HT1A receptors in the aggression-heightening effects of alcohol. If these effects are in fact due to action at somatodendritic 5-HT1A autoreceptors, then the anti-aggressive effects would be associated with decreased 5-HT neurotransmission.     

Chronic treatments with 5-HT1A agonists attenuate posthypoxic myoclonus in rats

Following 10 min cardiac arrest and resuscitation, male Sprague-Dawley rats developed posthypoxic myoclonus. This phenomenon peaked at 14 days and disappeared by 60 days after cardiac arrest. From previous results, the 5-hydroxytryptamine (5-HT) system was implicated in the pathogenesis of the disease. In the present study, we investigated the involvement of 5-HT1A receptors in posthypoxic myoclonus in rats. Single injections of 5-HT1A agonists, buspirone (5 and 10 mg/kg body wt.) or 8-OH-DPAT (1, 2, and 4 mg/kg), had no effect on either the intensity or time course of the disease. In contrast, multiple injections (twice a day for 7 or more days) of buspirone (10 mg/kg) or 8-OH-DPAT (4 mg/kg) significantly attenuated the myoclonus scores of animals (p < 0.05). The results indicate that chronic stimulation of 5-HT1A receptors in the brain may accelerate endogenous compensatory mechanisms and shorten the time course of the disease.     

Differential inhibition of stress-induced adrenocortical responses by 5-HT1A agonists and by 5-HT2 and 5-HT3 antagonists

The present studies were designed to determine the effects of 5-HT1A receptor agonists and 5-HT2A/2C and 5-HT3 antagonists on adrenocortical responses to a variety of stress paradigms in conscious male rats. The following stressors were examined: acoustic stress (105 dB for 2 min); foot shock (0.2 mA, five shocks over 5 min); conditioned fear (animals placed in the foot shock chamber for 5 min, 24 h after foot shock); restraint (Plexiglas restrainer for 5 min); injection of recombinant human interleukin-1 alpha (IL-1, 20 micrograms/kg, IP); injection of cocaine hydrochloride (20 mg/kg, IP). Drug treatments consisted of intracerebroventricular (ICV) or intraperitoneal (IP) injections of the 5-HT1A agonists, 8-OH-DPAT and ipsapirone (0.1 pmol, ICV), the 5-HT2A/2C antagonist, ketanserin (2 mumol/kg, IP), and the 5-HT3 antagonist, MDL-72222 (20 nmol, ICV). The plasma corticosterone (CS) responses to foot shock and restraint stress were not affected by any of the serotonergic drugs tested. The 5-HT1A agonist, 8-OH-DPAT, was able to attenuate the adrenocortical responses to acoustic stimulation, conditioned fear, IL-1 alpha, and cocaine administration, with ipsapirone also being effective in reducing the responses to acoustic stimulation and cocaine injection. The 5-HT2 antagonist, ketanserin was able to reduce the adrenocortical response in the conditioned fear paradigm and the response to IL-1 alpha injection. The 5-HT3 antagonist, MDL-72222 was only effective in reducing the response to acoustic stimulation. Thus, adrenocortical responses to each of the applied stressors were differentially affected by the 5-HT receptor ligands tested. The results of this study indicate that 5-HT1A agonists may be efficient stress response-reducing agents. However, their efficacy depends on the lack of a somatosensory component to the applied stressor and their agonist properties suggest that their action may not involve direct effects on serotonergic pathways mediating the observed responses. In contrast, the specificity of the 5-HT2 and 5-HT3 antagonists in blocking adrenocortical responses to certain stressors suggests that these drugs exert their effects by blocking serotonergic neurotransmission in pathways mediating the adrenocortical responses to specific stimuli.     

Direct injection of 5-HT2A receptor agonists into the medial prefrontal cortex produces a head-twitch response in rats

The serotonin (5-HT)(2A/2c) agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), the 5-HT2C agonist 6-chloro-2-[1-piperazinyl]-pyrazine and the 5-HT2A partial agonist m-chloro-phenylpiperazine (mCPP) were injected bilaterally into the medial prefrontal cortex of male rats. DOI and mCPP, but not 6-chloro-2-[1-piperazinly]-pyrazine, elicited a dose-dependent head-twitch response (HTR). DOI-induced HTR had an ED50 of 12.8 nmoles/0.5 microl/side and was inhibited by the 5-HT2A antagonists ketanserin and MDL 100,907 but was not blocked by pretreatment with the selective 5-HT(2C/2B) antagonist SDZ SER 082. The HTR to mCPP demonstrated a bell-shaped dose-response curve with an ED50 of 1.5 nmoles/0.5 microl/side and a peak effect after 3 nmoles/side. The response to mCPP was greatly diminished by both ketanserin and MDL 100,907 and was partially reversed by SDZ SER 082. These findings suggest that the HTR produced by the direct injection of serotonergic agonists into the medial prefrontal cortex is, in part, mediated by the activation of 5-HT2A receptors. Pretreatment of rats with the 5-HT1A agonist (+/-)-8-hydroxy-dipropylaminotetralin hydrobromide inhibited the HTR to DOI. This is consistent with other evidence that suggests a functional antagonism between 5-HT1A and 5-HT2A receptor activation. The HTR to DOI was potentiated by the novel 5-HT1A selective antagonist WAY 100,635, which suggests that 5-HT1A receptors tonically regulate this behavioral response to stimulation of cortical 5-HT2A receptors.     

Hippocampal 5-HT1A receptor binding site densities, 5-HT1A receptor messenger ribonucleic acid abundance and serotonin levels parallel the activity of the hypothalamo-pituitary-adrenal axis in rats

We have previously demonstrated that susceptibility of the Lewis rat to inflammatory disease, compared to the relatively resistant Fischer F344 rat, is related to a hyporesponsive hypothalamopituitary adrenal axis to inflammatory and other stress mediators. Since 5-HT and the 5HT1A receptor are important stimulators of this axis, we have investigated the levels of 5-HT1A receptor binding sites and encoding mRNA, 5-HT and 5-hydroxyindole acetic acid in various brain regions of Lewis, Harlan Sprague Dawley and Fischer F344 rats. Lewis rats expressed significantly less hippocampal and frontal cortical 5-HT1A receptor binding sites and mRNA than Harlan Sprague-Dawley and Fischer F344 rats. Adrenalectomy increased the number of 5HT1A receptor binding sites and mRNA expression in the hippocampus of all three strains. The levels of hippocampal 5-HT in Fischer F344 rats were significantly greater than levels detected in the same regions for the other two strains. Hypothalamic 5-HT and 5-hydroxyindole acetic acid levels in Harlan Sprague-Dawley rats were higher than the same area from the other two strains. Adrenalectomy increased the levels of 5-hydroxyindole acetic acid in the hypothalamus of all three strains. We conclude that hippocampal 5-HT1A receptor densities and 5-HT levels in the rat parallel the the activity and responsiveness of the hypthalamopituitary-adrenal axis. We have published these data in an earlier report.     

Antagonism of muscarinic receptors in the rabbit iris-ciliary body by 8-OH-DPAT and other 5-HT1A receptor agonists

Physiological studies have shown that serotonin and 5-HT1A agonists can influence muscarinic function in the rabbit iris-ciliary body (ICB). The purpose of this study was to examine whether a direct interaction exists between muscarinic and 5-HT1A receptors in the ICB. At high concentrations, the 5-HT1A agonist 8-OH-DPAT attenuated the carbachol-induced stimulation of inositol phosphates (InsPs) production, but this was not blocked by the presence of 5-HT1A antagonists. In contrast, serotonin failed to influence carbachol-induced InsPs formation. Moreover, 8-OH-DPAT but not serotonin displayed affinity for [3H]QNB binding sites in the ICB. The combined data suggest that activation of 5-HT1A receptors in the ICB does not cause a modulation of muscarinic receptor-stimulated phosphoinositide turnover. The data instead suggest that, at high concentrations, 8-OH-DPAT acts as an antagonist at muscarinic receptors and in this way influences muscarinic receptor function. The mechanism of 5-HT-induced modulation of muscarinic function in the ICB therefore remains to be elucidated.     

Isoquinoline derivatives isolated from the fruit of Annona muricata as 5-HTergic 5-HT1A receptor agonists in rats: unexploited antidepressive (lead) products

The fruit and the leaves of Annona muricata (Annonaceae) are used in traditional medicine for their tranquillizing and sedative properties. Extracts of the plant have been shown to inhibit binding of [3H]rauwolscine to 5-HTergic 5-HT1A receptors in calf hippocampus, and three alkaloids, annonaine (1), nornuciferine (2) and asimilobine (3), isolated from the fruit have been shown to have IC50 values of 3 microM, 9 microM and 5 microM, respectively, although in ligand-binding studies it was not possible to determine whether interaction of these ligands with the receptor was agonistic or antagonistic. This paper presents the results of functional assays of the alkaloids. The inhibition of cAMP accumulation was tested in NIH-3T3 cells stably transfected with the 5-HT1A receptor from man. None of the alkaloids showed antagonistic properties towards the 5-HT1A receptors because in the antagonistic tests no influence on the forskolin-stimulated increase of cAMP level was detected. Full agonistic properties were measured for all three compounds; the inhibition constants (Ki) for 1, 2 and 3 were < 10 microM. Inhibition of the binding of the radioligand to the 5-HT1A receptor was observed in every ligand-binding assay performed with the alkaloids; the Ki values for 1, 2 and 3 were in the microM range. These results imply that the fruit of Annona muricata possesses anti-depressive effects, possibly induced by compounds 1, 2 and 3, and that in the past potent leads for the development of anti-depressive therapeutics have not been used.     

Head and whole-body jerking in guinea pigs are differentially modulated by 5-HT1A, 5-HT1B/1D and 5-HT2A receptor antagonists

The effects of a serotonin (5-HT) releasing drug, p-chloroamphetamine, on plasma glucose levels were investigated in rats. p-Chloroamphetamine elicited a significant hyperglycemia. The hyperglycemic effects of p-chloroamphetamine were completely prevented by the 5-HT synthesis inhibitor, p-chlorophenylalanine. Prior adrenodemedullation abolished the hyperglycemia elicited by p-chloroamphetamine. p-Chloroamphetamine-induced hyperglycemia was prevented by methysergide, which blocks the 5-HT1 and 5-HT2 receptor, the 5-HT1A/1B/2C receptor antagonist, (-)-propranolol, the selective 5-HT1A receptor antagonist, 4-(2'-methoxyphenyl-1-[2'-n-2"pyridinyl)-p-iodobenzamido]-ethyl-pi perazine (p-MPPI), the 5-HT2A/2B/2C receptor antagonists, ritanserin and 4-isopropyl-7-methyl-9-(2-hydroxy-1-methyl-propoxycarbonyl)-4,6A,7 ,8,9,10,10A-octahydro-indolo[4,3-FG]quinolone maleate(LY 53857). However, the 5-HT3 and 5-HT4 receptor antagonist, tropisetron, the 5-HT4 receptor antagonist, 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino) ethyl ester (SDZ 205-557), and the 5-HT2A receptor antagonist, ketanserin, did not affect the p-chloroamphetamine-induced hyperglycemia. These results suggest that p-chloroamphetamine-induced hyperglycemia is elicited by an enhanced 5-HT release and facilitated adrenaline release. Moreover, our results indicate that p-chloroamphetamine-induced hyperglycemia is mediated by 5-HT1A and 5-HT2B/2C receptors.     

Effect of a selective 5-HT reuptake inhibitor in combination with 5-HT1A and 5-HT1B receptor antagonists on extracellular 5-HT in rat frontal cortex in vivo

1. Selective 5-hydroxytryptamine (5-HT; serotonin) reuptake inhibitors (SSRIs) cause a greater increase in extracellular 5-HT in the forebrain when the somatodendritic 5-HT1A autoreceptor is blocked. Here, we investigated whether blockade of the terminal 5-HT1B autoreceptor influences a selective 5-HT reuptake inhibitor in the same way, and whether there is an additional effect of blocking both the 5-HT1A and 5-HT1B autoreceptors. 2. Extracellular 5-HT was measured in frontal cortex of the anaesthetized rat by use of brain microdialysis. In vivo extracellular recordings of 5-HT neuronal activity in the dorsal raphe nucleus (DRN) were also carried out. 3. The selective 5-HT reuptake inhibitor, paroxetine (0.8 mg kg-1, i.v.), increased extracellular 5-HT about 2 fold in rats pretreated with the 5-HT1A receptor antagonist, WAY100635. When administered alone neither paroxetine (0.8 mg kg-1, i.v.) nor WAY100635 (0.1 mg kg-1, i.v.) altered extracellular 5-HT levels. 4. Paroxetine (0.8 mg kg-1, i.v.) did not increase 5-HT in rats pretreated with the 5-HT1B/D receptor antagonist, GR127935 (1 mg kg-1, i.v.). GR127935 (1 and 5 mg kg-1, i.v.) had no effect on extracellular 5-HT when administered alone. 5. Interestingly, paroxetine (0.8 mg kg-1, i.v.) caused the greatest increase in 5-HT (up to 5 fold) when GR127935 (1 or 5 mg kg-1, i.v.) was administered in combination with WAY100635 (0.1 mg kg-1, i.v.). Administration of GR127935 (5 mg kg-1, i.v.) plus WAY100635 (0.1 mg kg-1, i.v.) without paroxetine, had no effect on extracellular 5-HT in the frontal cortex. 6. Despite the lack of effect of GR127935 on 5-HT under basal conditions, when 5-HT output was elevated about 3 fold (by adding 1 microM paroxetine to the perfusion medium), the drug caused a dose-related (1 and 5 mg kg-1, i.v.) increase in 5-HT. 7. By itself, GR127935 slightly but significantly decreased 5-HT cell firing in the DRN at higher doses (2.0-5.0 mg kg-1, i.v.), but did not prevent the inhibition of 5-HT cell firing induced by paroxetine. 8. In summary, our results suggest that selective 5-HT reuptake inhibitors may cause a large increase in 5-HT in the frontal cortex when 5-HT autoreceptors on both the somatodendrites (5-HT1A) and nerve terminals (5-HT1B) are blocked. This increase is greater than when either set of autoreceptors are blocked separately. The failure of a 5-HT1B receptor antagonist alone to enhance the effect of the selective 5-HT reuptake inhibitor in our experiments may be related to a lack of tone on the terminal 5-HT1B autoreceptor due to a continued inhibition of 5-HT cell firing. These results are discussed in relation to the use of 5-HT autoreceptor antagonists to augment the antidepressant effect of selective 5-HT reuptake inhibitors.     

5-HT1A receptor activation: short-term effects on the mRNA expression of the 5-HT1A receptor and galanin in the raphe nuclei

Systemic administration of the 5-HT1A receptor agonist 8-OH-2-(di-n-propylamino)-tetralin (8-OH-DPAT; 0.3 mg/kg, s.c.) was used to explore the effects of activation of 5-HT1A receptors on expression of mRNA coding for 5-HT1A receptor, tryptophan hydroxylase (TPH) and galanin in the ascending raphe nuclei. 8-OH-DPAT increased the hybridization signal of the 5-HT1A receptor by 105% in the dorsal raphe nucleus (B7) 30 min after the injection. No effects were seen at the later time points (2-8 h). In the median raphe nucleus (B8) and the B9 cell group in the medial lemniscus, 8-OH-DPAT induced a marked decrease in labeling 30 min after injection. At 8 h following 8-OH-DPAT injection, the effect had shifted to an increase in 5-HT1A receptor labeling by 68% in the B8 area. Importantly 8-OH-DPAT had no significant effects on the expression of mRNA coding for TPH and galanin. The results suggest an important and differential mechanism for the regulation of 5-HT1A receptor mRNA levels in the dorsal and median raphe nuclei. This regulation may be of importance for the differential control of the activity of the ascending 5-HT neurons, and hence for mood regulation. The results also indicate a dissociation between the effects mediated by 5-HT1A receptor functions and those regulating the coexisting peptide galanin in the dorsal raphe.     

Dopamine receptor agonists, partial agonists and psychostimulant addiction

Despite the epidemic growth of psychostimulant addiction over the past years, few pharmacological means of intervention are available to date for clinical treatment. This is of importance since the withdrawal syndrome that follows abstinence from drugs such as cocaine and the amphetamines is characterized, among other symptoms, by intense craving for the abused drug, and this is considered a critical factor leading into relapse of drug use. In this article, Luigi Pulvirenti and George Koob focus on the modulatory role shown by drugs acting at the dopamine receptor on the various phases of psychostimulant dependence in preclinical models and in human studies, and suggest that a class of compounds with partial agonist properties at the dopamine receptor may have therapeutic potential.     

The 5-HT1A receptor antagonist p-MPPI blocks 5-HT1A autoreceptors and increases dorsal raphe unit activity in awake cats

The effects of the putative 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzam ide (p-MPPI) were examined on the activity of serotonergic dorsal raphe nucleus neurons in freely moving cats. Systemic administration of p-MPPI produced a dose-dependent increase in firing rate. This stimulatory effect of p-MPPI was evident during wakefulness (when serotonergic neurons display a relatively high level of activity), but not during sleep (when serotonergic neurons display little or no spontaneous activity). p-MPPI also blocked the ability of the 5-HT1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT) to inhibit serotonergic neuronal activity. This antagonism was evident both as a reversal of the neuronal inhibition produced by prior injection of 8-OH-DPAT and as a shift in the potency of 8-OH-DPAT following p-MPPI pretreatment. Overall, these results in behaving animals indicate that p-MPPI acts as an effective 5-HT1A autoreceptor antagonist. The increase in firing rate produced by p-MPPI supports the hypothesis that autoreceptor-mediated feedback inhibition operates under physiological conditions.     

Effects of 5-HT3 receptor agonists on voluntary ethanol intake in rats maintained on a limited access procedure

Catecholamines are a class of neurotransmitters involved in central nervous system autonomic control. Both acute and chronic hypoxia create alterations in ventilation and blood pressure via catecholamine release, although the mechanisms of these alterations are unknown. The enzymes tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT) catalyze the rate-limiting step in the catecholamine pathway and production of epinephrine, respectively. Both have been colocalized with Fos protein in metabolic mapping studies of the O2-chemosensory pathway of adult and early postnatal rat. Thus, catecholamines are putative neurotransmitters in a subset of second and higher order respiratory neurons. To characterize the effects of prenatal hypoxia on subsequent TH and PNMT gene and protein expression, pregnant rats were placed in moderate hypoxia (10% O2) from gestational d 18 until birth. Northern and Western analyses of dorsal (catecholaminergic/adrenergic cell group 2) and ventral (catecholaminergic/adrenergic cell group 1) medullary tissue of postnatal (P) age P0, P3, P7, P10, and P14 pups were then done to examine changes in TH and PNMT mRNA and protein compared with normoxia-reared controls. Compared with controls, pups exposed to maternal hypoxia during pregnancy had lower levels of TH mRNA and protein at birth in dorsal medulla and higher levels of TH mRNA the first postnatal week in the ventral medulla. Pups that had been hypoxic in utero showed significantly lower levels of PNMT protein during the second postnatal week in dorsal medulla than did controls. Prenatal hypoxia-induced changes in levels of enzymes responsible for catecholamine synthesis may later be manifest as developmental deficiencies in neuronal function. This may compromise responses to acute hypoxic challenges during early postnatal life and contribute to autonomic nervous system disorders of the newborn such as apnea and sudden infant death syndrome.     

The anxiolytic serotonin 5-HT1A receptor agonists buspirone, ipsapirone and gepirone are inhibitors of tyrosine hydroxylation in rat striatum

The anxiolytics buspirone (BUS), ipsapirone (IPSAP) and gepirone (GEP) were investigated as 5-HT1A receptor-mediated inhibitors of tyrosine hydroxylation (TH) in a synaptosome-rich preparation of rat striatum. BUS, IPSAP and GEP were moderately potent inhibitors of TH with EC50 values of 48.4 microM, 50 microM and 836 microM, respectively. By comparison, 8-OH-DPAT, a 5-HT1A receptor selective agonist, has been previously shown to be more potent with an EC50 value of 7.0 microM. Each of these agents demonstrated full agonist activity at the striatal 5-HT1A receptors regulating TH. The inhibitory effects of each agent were attenuated by prior exposure to the 5-HT1A antagonist NAN-190, (10 microM) (P < 0.05), but not by the dopamine D2 antagonist (-)-sulpiride (10 microM). The potencies of 8-OH-DPAT, BUS, IPSAP and GEP were correlated with their reported affinities for the 5-HT1A receptor (P < 0.01) but not the dopamine D2 receptor. These results support the hypothesis that BUS, IPSAP and GEP inhibit TH through activation of a striatal 5-HT1A heteroreceptor on dopamine nerve terminals.     

Electrophysiological evidence for a large receptor reserve for inhibition of dorsal raphe neuronal firing by 5-HT1A agonists

Previous studies [Meller et al. (1990) Mol. Pharmacol., 37:231-237] have shown that a large receptor reserve exists for the inhibition of serotonin synthesis in rat cortex and hippocampus by the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT), whereas little or no reserve exists for the lower efficacy agonists ipsapirone and BMY 7378. The current studies were undertaken to determine if the above drugs exhibit similar relative efficacies and receptor reserves in an electrophysiological model of 5-HT1A receptor activation, i.e., the inhibition of dorsal raphe cell firing. Intravenous dose-response curves were constructed in untreated control rats, or in rats which received an injection of the irreversible receptor inactivator N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 6 mg/kg, s.c.) 24 hours before recording. All three drugs fully inhibited dorsal raphe cell firing in control rats (ED50's: 1.5 micrograms/kg, 8-OH-DPAT; 30.0 micrograms/kg, ipsapirone; 17.5 micrograms/kg, BMY 7378). However, unlike effects on serotonin synthesis, EEDQ treatments caused no depression of the maximal inhibitory response for any of the agonists, although all dose-response curves were shifted to the right (ED50's: 10.1 micrograms/kg, 6.7-fold shift, 8-OH-DPAT; 139.9 micrograms/kg, 4.7-fold shift, ipsapirone; 53.8 micrograms/kg, 3.1-fold shift, BMY 7378). Although the order of agonist efficacies was similar for both inhibition of serotonin synthesis and dorsal raphe cell firing (8-OH-DPAT > ipsapirone > BMY 7378), a large (> 50%) receptor reserve was estimated for all three drugs in this electrophysiological system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of association between neuroleptic malignant syndrome and polymorphisms in the 5-HT1A and 5-HT2A receptor genes

OBJECTIVE: The molecular basis of neuroleptic malignant syndrome is unclear, but studies suggest that genetic factors are involved in its pathogenesis. Considering possible involvement of the serotonergic system in neuroleptic malignant syndrome, the authors examined the association between neuroleptic malignant syndrome and polymorphisms of the 5-HT1A and 5-HT2A receptor genes. METHOD: The authors examined the frequencies of gene polymorphisms in the 5-HT1A (Arg219Leu) and 5-HT2A (Thr25Asn and His452Tyr) receptor genes in 29 patients previously diagnosed with neuroleptic malignant syndrome, 94 neuroleptic-treated patients with schizophrenia who had no history of neuroleptic malignant syndrome, and 94 healthy comparison subjects. Polymerase chain reaction and restriction fragment length polymorphism analyses were used to screen gene mutations. RESULTS: No polymorphic allele was detected in the patients who had experienced the neuroleptic malignant syndrome. CONCLUSIONS: The authors cannot conclude that polymorphisms in the 5-HT1A and 5HT2A receptor genes are factors determining susceptibility to the neuroleptic malignant syndrome.     

Role of 5-HT1b receptor in the pressure-induced behavioral and neurochemical disorders in rats

When human divers and experimental animals are exposed to increasing environmental pressure, they develop the high-pressure neurologic syndrome (HPNS) that has been recently demonstrated to include an increase in striatal dopamine (DA) release. This increase has been correlated with enhanced locomotor and motor activity (LMA). In the present study, we investigated the effect of the 5-HT1b receptor antagonist (+/-)cyanopindolol, which has been shown to block at normal pressure the increase in striatal DA release induced by the administration of the 5-HT1b receptor agonist CGS 12066B. Our data clearly showed that the administration of (+/-)cyanopindolol partially blocked both the pressure-induced increase in striatal DA release and the development of LMA. These results suggest the contribution of the 5-HT neurotransmission in the DA-related neurochemical and behavioral disorders that occur in rats exposed to high pressure.     

Long-term sequential determination of behavioral ontogeny of 5-HT1A and 5-HT2 receptor functions in the rat

Activation of 5-hydroxytryptamine1A (5-HT1A) receptors in rats produces hypothermia and a number of behaviors [hindleg abduction (HLA), lateral head-weaving (LHW), forepaw treading (FPT), flat body posture (FBP), rollover (RO), tremor (T), and straub tail (ST)] known collectively as the serotonin syndrome (SS). Stimulation of 5-HT2A receptors produces wet-dog shakes (WDS), whereas 5-HT2C sites induce back muscle contraction (BMC). We investigated the functional ontogeny of the cited receptors in rat pups on postnatal days (PD) 7, 14, 18, 22, 28, 35, 60, and 120 by using (1) the 5-HT1A agonist 8-hydroxy-2-dipropylaminotetralin (0, 1.25, and 5 mg/kg) to induce the SS and hypothermia and (2) the 5-HT2A/C agonist (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane (0, 0.5, and 4 mg/kg) to produce both WDS and BMC. The age of onset for most symptoms of SS [FBP, HLA, RO, and T] was the first week of life. They attained maximal intensities at ages 7 to 14 days, after which their maxima either reduced or dissipated to zero. Per contra, the onset of LHW and FPT required 14 to 18 days, and their maxima developed later. The onset of (+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane-induced WDS occurred after PD 14, and by PD 18, it reached its maximal intensity, which persisted up to PD 60, after which it declined. The onset of BMC was evident on PD 28 and attained its maximal frequency at ages 90 to 120 days. The results show that different components of SS appear within 14 days of birth, but they mature differentially, whereas the hypothermic effect of 5-HT1A receptors remains relatively constant during aging. The times of onset and maturation of WDS were intermediate (between the second and third weeks of life), whereas BMC required 1 to 2 months for its appearance and maturation.