Modulation of dopamine release in the nucleus accumbens by 5-HT1B agonists: involvement of the hippocampo-accumbens pathway

Changes in extracellular levels of dopamine (DA), DA metabolites DOPAC and HVA, and the serotonin metabolite 5-HIAA, were measured by microdialysis in the rat nucleus accumbens (n. acc) after treatments with serotonin (5-HT)1A (8-OH-DPAT) or 5-HT1B (RU 24969 and S-CM-GTNH2) receptor agonists. Subcutaneous injections of RU 24969 (0.02-2 mg/kg) dose-dependently decreased 5-HIAA levels (0 to -38%), and also induced long-lasting increases in DA levels (0 to +37%) and DOPAC (+11% at the dose 0.5 mg/kg) in the shell of the n. acc, whereas 8-OH-DPAT (0.25 and 0.5 mg/kg) reduced 5-HIAA levels (-25%) and very slightly increased DOPAC at the lower dose (+4%), but had no effect on DA levels. Three weeks after interruption of the subicular efferent projections, the increase in DA levels previously observed after systemic injections of RU 24969 was abolished. Microinjections of RU 24969 (10 micrograms/microliter) or S-CM-GTNH2 (3 micrograms/microliter) into the ventral subicular area reproduced the effects of systemic injections of RU 24969 cn DA levels and increased DOPAC (+13%; +19%, respectively) and HVA levels (+23%; +24%), with no significant change in 5-HIAA. It is concluded that: (1) serotonin interacts with the mesolimbic dopaminergic system through 5-HT1B, but not 5-HT1A, receptors: and (2) serotonin interaction with the mesolimbic dopaminergic system involves postjunctional 5-HT1B heteroreceptors located in the ventral subicular area, which modulate the activity of glutamatergic hippocampo-accumbens pathways and only secondarily alter DA levels in the n. acc. The possible relevance of these results for schizophrenia is discussed.     

Mycotic sinusitis

Previous drug discrimination studies have elucidated the importance of gamma-aminobutyric acidA (GABAA), N-methyl-D-aspartate (NMDA) glutamate, and serotonin (5-HT) receptor systems in mediating the discriminative stimulus effects of ethanol. The present study used a three-choice operant drug discrimination procedure in an attempt to determine if salient GABAergic effects could be separated from other stimulus effects of 2.0 g/kg ethanol. Adult male Long-Evans rats (n = 7) were trained to discriminate pentobarbital (10.0 mg/kg; intragastrically (i.g.) from ethanol (2.0 g/kg; i.g.) from water (4.7 ml; i.g.) using food reinforcement. Stimulus substitution tests were conducted following the administration of allopregnanolone (1.0-17.0 mg/kg; intraperitoneally (i.p.)), diazepam (0.1-7.3 mg/kg; i.p.), midazolam (0.0056-17.0 mg/kg; i.p.), dizocilpine (0.01-0.56 mg/kg; i.p.), phencyclidine (1.0-5.6 mg/kg; i.p.), CGS 12066B (3-30 mg/kg; i.p.), RU 24969 (0.1-5.6 mg/kg; i.p.) and morphine (1 or 3.0 mg/kg; i.p.). Within the group, allopregnanolone and midazolam completely substituted (> 80%), and diazepam partly substituted (67%) for the discriminative stimulus effects of pentobarbital. Dizocilpine and phencyclidine partly substituted (58 and 57%, respectively) for ethanol without substantial pentobarbital-appropriate responding. RU 24969, CGS 12066B and morphine did not result in complete substitution for either ethanol or pentobarbital, although RU 24969 resulted in partial (68%) pentobarbital substitution. The ability to train the present three-choice discrimination in rats indicates that the discriminative stimulus effects of 10.0 mg/kg pentobarbital were separable from those of 2.0 g/kg ethanol. The results suggest that the pharmacological effects of ethanol, which can control behavior, may seemingly be modified by training conditions (two-versus three-choice discrimination procedures), to the extent that a receptor system prominently linked to the behavioral activity of ethanol (i.e. GABAA) appears no longer to be involved in the interoceptive effects of the drug.     

Ex vivo inhibitory effect of the 5-HT uptake blocker citalopram on 5-HT synthesis

Serotonin (5-hydroxytryptamine, 5-HT) synthesis was determined in vivo by measuring the accumulation of 5-hydroxytryptophan (5-HTP) in rat frontal cortex after inhibition of aromatic amino acid decarboxylase by administrative of m-hydroxybenzylhydrazine (NSD 1015) (100 mg/kg, i.p.). The selective 5-HT reuptake inhibitor, citalopram, the 5-HT1A agonists, (+/-) 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), ipsapirone, gepirone and the 5-HT1A/B agonist, 7-trifluoromethyl-4(4-methyl-1-piperazinyl-pyrolo[1,2-a]-quinox ali ne (CGS 12066B), the 5-HT1A/B ligands and beta-adrenoceptor antagonists, (+/-) pindolol and (+/-) alprenolol, and the non-selective 5-HT ligands, m-chlorophenylpiperazine (mCPP) and metergoline, all inhibited the synthesis of 5-HT. The 5-HT1A/5-HT2 antagonist, spiperone, alone, had no effect on basal 5-HT synthesis, however it attenuated the effect of 8-OH-DPAT by 56% and CGS 12066B by 39% but only barely that of citalopram by 17%. The selective 5-HT1A antagonist, WAY 100635, which did not modify by itself 5-HT synthesis, had no effect on citalopram-induced reduction of 5-HT synthesis. Neither the 5-HT2 agonist, (+/-)1-(2,5-dimethoxy-4-indophenyl)-2-aminopropane (DOI) nor the 5-HT2 antagonist, ritanserin, had any effect on the synthesis of 5-HT. In addition, ritanserin did not modify the inhibitory effect of citalopram. Methiothepin was the only compound to increase 5-HT synthesis. These results suggest that the effect of citalopram on the synthesis of 5-HT is not mediated by 5-HT1A or 5-HT2 receptors and that other receptors may be involved.     

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.     

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.     

Serotonin regulation of aggressive behavior in male golden hamsters (Mesocricetus auratus).

These studies examined the neurochemistry and neuroanatomy of the serotonin (5-HT) system innervating the anterior hypothalamus (AH) and the interaction of 5-HT receptor agonists with arginine vasopressin (AVP) in the regulation of offensive aggression in golden hamsters. Because specific 5-HT1A, 5-HT1B, and AVP V1A binding sites were observed within the AH by in vitro autoradiography, the hamsters were tested for offensive aggression after microinjections of AVP in combination with either the 5-HT1A agonist 8-hydroxy-2-(di-n-propylarnino) tetraline (DPAT) or the 5-HT1B agonist CGS-12066A (CGS) directly within the AH. Though treatment with DPAT resulted in a dose-dependent inhibition of AVP-facilitated offensive aggression, CGS was ineffective. In addition, a retrograde tracer was injected within the AH to localize the distribution of 5-HT neurons projecting to the area. Retrogradely labeled 5-HT neurons were found within the dorsal, median, and caudal linear raphe nuclei and are suspected to inhibit AVP-facilitated offensive aggression by an activation of 5-HT1A receptors in the AH. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA receptor antagonists block stress-induced prolactin release in female rats at estrus

In order to evaluate the role of glutamate in prolactin secretion, we examined the effects of N-methyl-D,L-aspartic acid (NMDA) receptor antagonists on serum prolactin levels at both resting and restraint-stress conditions in female rats at estrus. NMDA increased basal serum prolactin levels. Administration of the selective NMDA receptor antagonist, cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755) (5 and 10 mg/kg i.p.), to rats under resting conditions enhanced basal prolactin levels. A low dose of CGS 19755 (3 mg/kg) was unable to modify the hormone serum level. Under stress conditions the pretreatment with CGS 19755 (3 and 5 mg/kg) prevented the increase in serum prolactin levels. This effect was reversed by NMDA (60 mg/kg s.c.). The NMDA receptor antagonist (5 mg/kg) decreased the median eminence concentration of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC), without modifying dopamine content. To examine the probable link between serotonin (5-HT) and glutamate in prolactin release, the 5-HT2A/5-HT2C receptor antagonist, ritanserin, was used. Under resting conditions, a dose of 5 mg/kg s.c. blocked the NMDA-induced prolactin release. In rats submitted to restraint, ritanserin decreased the prolactin response and NMDA was unable to correct the stress serum prolactin levels. The 5-HT1A receptor agonist, 8-hidroxypropyl-amino tetralin (8-OH-DPAT) (3 mg/kg s.c.), increased basal serum prolactin levels and restored serum prolactin in stressed animals pretreated with CGS 19755 (5 mg/kg). The present data strongly suggest that the glutamatergic system participates in the regulation of prolactin secretion. A stimulation tone seems to be exerted via the tuberoinfundibular dopaminergic system, and the prolactin release evoked by restraint apparently involves glutamate/NMDA receptors linked to a serotoninergic pathway.     

Role of renal interstitial pressure on chronic control of arterial blood pressure

We examined the modulatory effect of serotonergic activities on haloperidol-induced up-regulation of dopamine D2 receptors in rat striatum. Chronic treatment with haloperidol (0.1, 0.5 mg/kg, i.p., 3 weeks) increased the number of dopamine D2 receptors, while no increase was observed with atypical antipsychotic drugs clozapine (10 mg/kg) and ORG 5222 (0.25 mg/kg). Chronic treatment with MK 212, a serotonin (5-HT)2A/2C receptor agonist (2.5 mg/kg), or with citalopram, a 5-HT reuptake inhibitor (10 mg/kg), potentiated the haloperidol (0.1 mg/kg)-induced up-regulation of dopamine D2 receptor, while that with (+/-)-8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), a 5-HT1A receptor agonist (0.1 mg/kg), had no influence on the dopamine D2 receptor up-regulation. Co-administration of ritanserin (1 mg/kg), a 5-HT2A/2C receptor antagonist, with a low dose of haloperidol (0.1 mg/kg), but not with a high dose of the agent (0.5 mg/kg), attenuated the dopamine D2 receptor up-regulation. Drug occupation of 5-HT2A and dopamine D2 receptors in vivo examined with use of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) was 69.8% and 45.1%, respectively, after the acute administration of haloperidol (0.1 mg/kg) plus ritanserin (1 mg/kg). This profile that 5-HT2A receptors were highly occupied compared with dopamine D2 receptors was similar to that of clozapine or ORG 5222. These results suggest that potent 5-HT2A receptor antagonism versus weak dopamine D2 receptor blockade may be involved in the absence of up-regulation of dopamine D2 receptors after chronic treatment with clozapine or ORG 5222.     

Inhibition of trigeminal neurones after intravenous administration of naratriptan through an action at 5-hydroxy-tryptamine (5-HT(1B/1D)) receptors

1. The observation that 5-hydroxytryptamine (5-HT) is effective in treating acute attacks of migraine when administered intravenously resulted in a research effort that led to the discovery of the 5-HT(1B/1D) receptor agonist sumatriptan. 2. Clinical experience has shown sumatriptan to be an effective treatment with some limitations, such as relatively poor bioavailability, which naratriptan was developed to address. Increasing bioavailability has been achieved with greater lipophilicity and thus the potential for greater activity in the central nervous system. 3. In this study the increased access to central sites has been exploited in an attempt to characterize the pharmacology of those central receptors with the newer tools available. Trigeminovascular activation was examined in the model of superior sagittal sinus stimulation. 4. Cats were anaesthetized with alpha-chloralose (60 mg kg(-1), intraperitoneal), paralyzed (gallamine 6 mg kg(-1), intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation (250 micros pulses, 0.3 Hz, 100 V) by a mid-line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation. 5. Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.69+/-0.1 at a latency of 9.2+/-0.2 ms. Intravenous (i.v.) administration of naratriptan at clinically relevant doses (30 and 100 microg kg(-1)), inhibited neuronal activity in trigeminal neurones of the C2 dorsal horn, reducing probability of firing without affecting latency. 6. The effect of naratriptan could be reversed by administration of the selective 5-HT(1B/1D) receptor antagonist GR127935 (100 microg kg(-1), i.v.). 7. These data establish that naratriptan acts on central trigeminal neurones since sagittal sinus stimulation activates axons within the tentorial nerve and there are no inhibitory effects mediated within the trigeminal ganglion. Furthermore, given that this inhibition could be reversed by the relatively selective 5-HT(1B/1D) receptor antagonist GR127935, it is highly likely that the anti-migraine effects of drugs of this class with central nervous system access are mediated, at least in part, by 5-HT(1B/1D) receptors within the trigeminal nucleus.     

Risperidone inhibits 5-hydroxytryptaminergic neuronal activity in the dorsal raphe nucleus by local release of 5-hydroxytryptamine

1. The effects of risperidone on brain 5-hydroxytryptamine (5-HT) neuronal functions were investigated and compared with other antipsychotic drugs and selective receptor antagonists by use of single cell recording and microdialysis in the dorsal raphe nucleus (DRN). 2. Administration of risperidone (25-400 micrograms kg-1, i.v.) dose-dependently decreased 5-HT cell firing in the DRN, similar to the antipsychotic drug clozapine (0.25-4.0 mg kg-1, i.v.), the putative antipsychotic drug amperozide (0.5-8.0 mg kg-1, i.v.) and the selective alpha 1-adrenoceptor antagonist prazosin (50-400 micrograms kg-1, i.v.). 3. The selective alpha 2-adrenoceptor antagonist idazoxan (10-80 micrograms kg-1, i.v.), in contrast, increased the firing rate of 5-HT neurones in the DRN, whereas the D2 and 5-HT2A receptor antagonists raclopride (25-200 micrograms kg-1, i.v.) and MDL 100,907 (50-400 micrograms kg-1, i.v.), respectively, were without effect. Thus, the alpha 1-adrenoceptor antagonistic action of the antipsychotic drugs might, at least partly, cause the decrease in DRN 5-HT cell firing. 4. Pretreatment with the selective 5-HT1A receptor antagonist WAY 100,635 (5.0 micrograms kg-1, i.v.), a drug previously shown to antagonize effectively the inhibition of 5-HT cells induced by risperidone, failed to prevent the prazosin-induced decrease in 5-HT cell firing. This finding argues against the notion that alpha 1-adrenoceptor antagonism is the sole mechanism underlying the inhibitory effect of risperidone on the DRN cells. 5. The inhibitory effect of risperidone on 5-HT cell firing in the DRN was significantly attenuated in rats pretreated with the 5-HT depletor PCPA (p-chlorophenylalanine; 300 mg kg-1, i.p., day-1 for 3 consecutive days) in comparison with drug naive animals. 6. Administration of risperidone (2.0 mg kg-1, s.c.) significantly enhanced 5-HT output in the DRN. 7. Consequently, the reduction in 5-HT cell firing by risperidone appears to be related to increased availability of 5-HT in the somatodendritic region of the neurones leading to an enhanced 5-HT1A autoreceptor activation and, in turn, to inhibition of firing, and is probably only to a minor extent caused by its alpha 1-adrenoceptor antagonistic action.     

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.     

Pattern of synaptophysin immunoreactivity within mesencephalic grafts following transplantation in a parkinsonian primate model

The functional regulation by serotonin (5-HT) receptors of the 5-HT-enhanced dopamine (DA) release from the rat substantia nigra (SN) was investigated using in vivo microdialysis. Exogenously administered or extracellularly enhanced 5-HT (by means of intranigral citalopram perfusion) (both 1 microM for 1 h) significantly increased nigral DA efflux to 165% and 145%, respectively. Intranigral administration of pindolol (10 microM, 3 h), a 5-HT1A/1B receptor antagonist which is clinically used in order to block 5-HT1A/1B autoreceptors, did not affect DA levels but significantly increased nigral 5-HT levels to 135%. Co-perfusion of this antagonist with 5-HT (1 microM, 1 h) did not abolish the 5-HT-induced DA release from the SN as DA was increased to 166%. Local application of the 5-HT1A/1B receptor agonist, CP 93129 (1 microM, 1 h), increased DA release from the SN to 4770% whereas 5-HT release was significantly decreased to 75%. Co-perfusion of the 5-HT1A/1B receptor antagonist, pindolol, with this agonist only partly abolished the CP 93129-induced DA release whereas the CP 93129-induced decrease in nigral 5-HT release was completely abolished. Administration of the 5-HT2A/2C receptor antagonist, ketanserin (50 microM, 3 h), significantly increased DA to 143% and 5-HT release to 363%. Co-perfusion of this antagonist with 5-HT still caused an increase in nigral DA release to 214%. Intranigral perfusion of the 5-HT4 receptor antagonist, RS 39604 (10 microM, 3 h), did not affect DA levels but significantly decreased nigral 5-HT levels to 74%. Co-perfusion of this antagonist with 5-HT was able to prevent the 5-HT-enhanced DA efflux from the SN. From this study it can be concluded that the 5-HT-enhanced (and possibly the citalopram-induced) nigral DA release is 5-HT4 receptor mediated.     

5-HT1B receptor antagonist properties of novel arylpiperazide derivatives of 1-naphthylpiperazine

A new series of arylpiperazide derivatives of 1-naphthylpiperazine of general formula 4 has been prepared and evaluated as 5-HT1B antagonists. Binding experiments at cloned human 5-HT1A, 5-HT1B, and 5-HT1D receptors show that these derivatives are potent and selective ligands for 5-HT1B/1D subtypes with increased binding selectivity versus the 5-HT1A receptor when compared to 1-naphthylpiperazine (1-NP). Studies of inhibition of the forskolin-stimulated cAMP formation mediated by the human 5-HT1B receptor demonstrate that the nature of the arylpiperazide substituent modulates the intrinsic activity of these 1-NP derivatives. Among them, 2-[[8-(4-methylpiperazin-1-yl)naphthalen-2-yl]oxy] -1-(4-o-tolylpiperazin-1-yl)ethanone (4a) was identified as a potent neutral 5-HT1B antagonist able to antagonize the inhibition of 5-HT release induced by 5-CT (5-carbamoyltryptamine) in guinea pig hypothalamus slices. Moreover, 4a was found to potently antagonize the hypothermia induced by a selective 5-HT1B/1D agonist in vivo in the guinea pig following oral administration (ED50 = 0.13 mg/kg).     

Evidence for specific involvement of 5-HT1A and 5-HT2A/C receptors in the expression of patterns of spontaneous motor activity of the rat

The 5-HT1A and the 5-HT2A/C receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.006-0.4 mg kg-1 s.c.) and (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (0.05-4.0 mg kg-1 s.c.), respectively, produced a similar stereotyped forward locomotion in rats, although the intensity of the behavioral change was considerably less with DOI. The stereotyped forward locomotion was accompanied by a slight decrease in total activity, suppression of rearing behavior and an increased activity in the periphery of the open-field arena. In support of receptor specificity, the effects of 8-OH-DPAT and DOI could be antagonised by pretreatment with the 5-HT1A/B and the 5-HT2A/C receptor antagonists (-)-pindolol (2 mg kg-1 s.c.) and ritanserin (2 mg kg-1 s.c.), respectively. In addition, (-)-pindolol, but not the selective beta-adrenoceptor antagonist betaxolol, markedly enhanced the behavioral effects produced by DOI. The nature of these specific actions and interactions in terms of pre- and post-synaptic serotonergic mechanisms remains an important question.     

Absence of fenfluramine-induced anorexia and reduced c-Fos induction in the hypothalamus and central amygdaloid complex of serotonin 1B receptor knock-out mice

Fenfluramine, a serotonin releaser and uptake inhibitor, has been widely prescribed as an appetite suppressant. Despite its popular clinical use, however, the precise neural pathways and specific 5-HT receptors that account for its anorectic effect have yet to be elucidated. To test the hypothesis that stimulation of 5-HT1B receptors is required for the anorectic effect of fenfluramine, we assessed food intake in wild-type and 5-HT1B knock-out mice. Next, to determine possible brain structures and pathways that may contribute to the 5-HT1B-mediated effects of fenfluramine, we studied by immunohistochemistry the induction of the immediate early gene c-fos. Although the effect of fenfluramine on locomotion was indistinguishable between both wild-type and 5-HT1B knock-out mice, the anorectic effect of the drug was absent in only the knock-out mice. Furthermore, the induction of c-Fos immunoreactivity found in the paraventricular nucleus of the hypothalamus (PVN) of wild-type mice was substantially reduced in the knock-outs. Induction in the central amygdaloid nucleus (CeA) and in the bed nucleus of the stria terminalis (BNST), although robust in wild-type animals, was completely absent in knock-out animals. The mixed 5-HT1A/1B agonist RU24969 was able to mimic both the hypophagia and c-fos induction elicited by fenfluramine in wild-type mice, but not in the 5-HT1B knock-out mice. Our results thus demonstrate that stimulation of 5-HT1B receptors is required for fenfluramine-induced anorexia and suggest a role for the PVN, CeA, and BNST in mediating this effect.     

Importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity: an in vivo microdialysis study in the freely-moving guinea-pig

The importance of h5-HT1B receptor selectivity for 5-HT terminal autoreceptor activity was investigated with the selective h5-HT1B receptor ligands SB 219085, SB 220272, SB 224289 and SB 216641. The studies employed measurement of compound affinity and efficacy in vitro and the measurement of extracellular 5-HT in the frontal cortex of the freely-moving guinea-pig using in vivo microdialysis. All compounds had high affinity and selectivity for the h5-HT1B receptor, with SB 224289 the most selective for h5-HT1B over h5-HT1D receptors. Compounds exhibited a range of efficacies at both receptors: SB 224289 and SB 219085 were inverse agonists, SB 220272 was an antagonist and SB 216641 was a partial agonist. SB 220272, SB 216641 and SB 224289 had no effect on extracellular 5-HT following systemic administration, however, SB 219085 produced a significant increase. The SB 219085-induced increase in extracellular 5-HT was attributed to the compounds non-specific releasing properties as it was also demonstrated to increase basal release of [3H]5-HT from pre-loaded guinea-pig cortical slices. The lack of effect of the above h5-HT1B receptor selective compounds and the decrease in extracellular 5-HT elicited by the non-selective compounds GR 127935, GR125743 and methiothepin suggest that antagonism of 5-HT1D receptors may mediate this decrease in 5-HT levels. It is plausible that blockade of 5-HT1D receptors increases 5-HT levels in the raphe, this activates 5-HTtA receptors which results in an overall decrease in terminal 5-HT release. Definitive proof now awaits elucidation of the action of a selective 5-HT1D receptor antagonist.     

Dose dependent of sister chromatid exchanges in humans lymphocytes induced by in vitro alpha-particle irradiation

AIM: To study the effect of (-)-stepholidine (SPD) on serum prolactin (PRL) level and elucidate its pharmacological action on dopamine D2 receptors. METHOD: After i.p. administration of dopamine receptor agonist, antagonist, or SPD, the serum PRL levels were determined by radioimmunoassay. RESULTS: SPD (24 mg.kg-1, i.p.) caused a rapid rise in serum PRL level, lasting more than 1 h. SPD 0.2-40 mg.kg-1 raised serum PRL level in a dose-dependent manner with ED50 of 3.7 mg.kg-1 (95% confidence limits, 2.6-4.3 mg.kg-1) and PRL maximal level of 448 +/- 64 micrograms.L-1. Pergolide 2 mg.kg-1 i.p. caused a decrease (P < 0.01 vs saline) of PRL level, which was partially attenuated by SPD of 5 mg.kg-1 and completely abolished by 10 mg.kg-1. CONCLUSION: SPD is a dopamine D2 receptor antagonist.     

In vivo electrophysiological characterization of 5-HT receptors in the guinea pig head of caudate nucleus and orbitofrontal cortex

The aim of the present study was to characterize in vivo the 5-HT receptor subtypes which mediate the effect of microiontophoretic applied 5-HT in the guinea pig head of caudate nucleus and orbitofrontal cortex. 5-HT and the preferential 5-HT2A receptor agonist DOI and the preferential 5-HT2C receptor agonist mCPP, suppressed the quisqualate (QUIS)-induced activation of neurons in both structures. The inhibitory effect of DOI and mCPP was not prevented by acute intravenous administration of the 5-HT1/2 receptor antagonist metergoline (2 mg/kg) and the 5-HT2A/2C receptor antagonist ritanserin (2 mg/kg) in the two regions nor by the selective 5-HT2A receptor antagonist MDL100907 (1 mg/kg) in the head of caudate nucleus. However, the inhibitory effect of DOI, but not that of mCPP, was antagonized by a 4-day treatment with metergoline and ritanserin (2 mg/kg/day; using minipumps implanted subcutaneously) in head of caudate nucleus, but not in orbitofrontal cortex. Microiontophoretic ejection of the 5-HT1A/7 receptor agonist 8-OH-DPAT and of the 5-HT1A receptor antagonist WAY100635 both suppressed the spontaneous and QUIS-activated firing activity of orbitofrontal cortex neurons. At current which did not affect the basal discharge activity of the neuron recorded, microiontophoretic application of WAY100635 and BMY7378 failed to prevent the inhibitory effect of 8-OH-DPAT. The inhibitory effect of gepirone, which is a 5-HT1A receptor agonist but devoid of affinity for 5-HT7 receptors, was also not antagonized by WAY100635. Altogether, these results suggest the presence of atypical 5-HT1A receptors in the orbitofrontal cortex. The present results also indicate that the suppressant effect of DOI may be mediated by 5-HT2A receptors in head of caudate nucleus and atypical 5-HT2 receptors in orbitofrontal cortex.     

Pharmacological characterization of in vivo properties of putative mixed 5-HT1A agonist/5-HT2A/2C antagonist anxiolytics. I. Antipunishment effects in the pigeon

A conflict procedure in pigeons was used to characterize the antipunishment effects of the putative mixed 5-hydroxytryptamine (5-HT)1A agonist/5-HT2A/2C antagonists WY 50,324, CGS 18102A, LEK 8804 and FG 5974 and to further investigate interactions between the antipunishment effects of the 5-HT1A agonists buspirone and 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] administered in combination with the mixed 5-HT2A/2C antagonist ritanserin and the alpha 1 antagonist prazosin. The 5-HT1A agonists, buspirone and 8-OH-DPAT, which lack affinity for 5-HT2A/2C receptors, produced dose-related increases in punished responding. Of the compounds with a mixed binding profile, only WY 50,324 showed effects that were comparable to those observed after 8-OH-DPAT, whereas FG 5974 and CGS 18102A exhibited limited effects on punished responding, and LEK 8804 was ineffective. Administration of a relatively low, behaviorally active dose of ritanserin (0.16 mg/kg) significantly enhanced the potency of 8-OH-DPAT and buspirone to increase punished responding from 8 to 50-fold without altering their effects on unpunished responding. Importantly, ritanserin failed to increase the number of doses of 8-OH-DPAT that significantly increased punished responding. In contrast, prazosin (2.5 mg/kg) significantly enhanced the potency and increased the number of doses of buspirone exerting significant effects on punished responding, but did not alter the effects of 8-OH-DPAT. Taken together, the results neither explain the suggested greater efficacy in producing anxiolytic effects of compounds with putative mixed 5-HT1A agonist and 5-HT2A/2C antagonist properties, nor confirm a proposed interaction between alpha1 adrenoreceptors and 5-HT1A agonists in preclinical tests of anxiolytic activity.