Flat Body Posture Research Articles

Effects of chronic treatments with sm-9018, a potential atypical neuroleptic, on behavioral dopaminergic and serotonergic sensitivities in rats

1. 1. Changes in behavioral dopaminergic and serotonergic sensitivities were studied in rats after withdrawal of the chronic treatments with SM-9018 (0.1 mg/kg/day), a potential atypical neuroleptic, and with haloperidol (0.3 mg/kg/day) using continuous infusion pumps. 2. 2. Administration of SM-9018 inhibited the rat locomotor activities to an extent similar to that of haloperidol during the course of the 2 weeks treatment. 3. 3. The incidence of the apomorphine-induced stereotyped behaviors (e.g., sniffing, chewing, licking and biting) was negligibly affected by SM-9018 treatment, but was markedly enhanced by haloperidol treatment. 4. 4. The incidence of the 5-hydroxytryptophan-induced wet dog shakes and 8-hydroxy-2-(di-n-propyl-amino)tetralin-induced flat body posture was unaffected by either treatment with SM-9018 or haloperidol. 5. 5. These findings suggest that SM-9018 is weaker than haloperidol in inducing the behavioral dopaminergic hypersensitivity after its chronic treatment and has a lower propensity to cause tardive dyskinesia.

Serotoninergic behavioural effects induced by intrahippocampal infusion of 8-hydroxy-2-(DI-N-propylamino)tetralin (8-OH-DPAT) in the rat

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenolic or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat body posture) behavioural responses. The present study shows thats.c. administration of (R)-DPAT induces typical 5-HT1A receptor agonist behaviours. These effects are blocked by the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administration of (S)-DPAT induces dopaminergic behaviours, which are fully antagonised by raclopride, a dopamine D2 receptor antagonist. Both enantiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-hydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxylase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytryptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT1A receptor agonist and (S)-DPAT as a dopamine D2 receptor agonist. Presynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S)-DPAT for dopamine D2 receptors. Receptor binding studies, utilizing [3H]8-hydroxy-2-(di-n-propylamino)tetralin and [3H]quinpirole as radioligands for 5-HT1A and dopamine D2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A receptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT for dopamine D2 receptors. Thus, the results from receptor binding studies support the conclusion that (R)- and (S)-DPAT are agonists showing selectivity for 5-HT1A and dopamine D2 receptors, respectively. Taken together, these findings may explain previous controversies with regard to the pharmacology of racemic DPAT and re-emphasise the necessity to study pure enantiomers of chiral compounds.

Role of presynaptic and postsynaptic 5-HT1A receptors in spatial learning of rats with impaired hippocampal cholinergic transmission

Racemic 2-(di-n-propylamino)tetralin ((R,S)-DPAT), which lacks phenolic or other aromatic substituents, induces both dopaminergic (sniffing, licking and gnawing) and serotoninergic (forepaw treading and flat body posture) behavioural responses. The present study shows thats.c. administration of (R)-DPAT induces typical 5-HT1A receptor agonist behaviours. These effects are blocked by the 5-HT1A receptor antagonist (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)-UH-301). Administration of (S)-DPAT induces dopaminergic behaviours, which are fully antagonised by raclopride, a dopamine D2 receptor antagonist. Both enantiomers induce hypothermia, (R)-DPAT being antagonised by (S)-UH-301, whereas (S)-DPAT is antagonised by raclopride. The accumulation of 5-hydroxytryptophan and DOPA (3,4-dihydroxyphenylalanine) after decarboxylase inhibition that reflects presynaptic actions on 5-HT (5-hydroxytryptamine, serotonin) and dopamine neurons, respectively, are inhibited by both enantiomers of DPAT. (R)-DPAT is more potent than (S)-DPAT as an inhibitor of 5-hydroxytryptophan accumulation whereas (S)-DPAT is more potent than (R)-DPAT as an inhibitor of DOPA accumulation. Thus, in functional tests of postsynaptic actions (R)-DPAT behaves as a 5-HT1A receptor agonist and (S)-DPAT as a dopamine D2 receptor agonist. Presynaptically, (R)-DPAT shows selectivity for 5-HT1A receptors and (S)-DPAT for dopamine D2 receptors. Receptor binding studies, utilizing [3H]8-hydroxy-2-(di-n-propylamino)tetralin and [3H]quinpirole as radioligands for 5-HT1A and dopamine D2 receptors, respectively, showed (R)-DPAT to have a 3-fold higher affinity than (S)-DPAT for 5-HT1A receptors, whereas (S)-DPAT had a 6-fold higher affinity than (R)-DPAT for dopamine D2 receptors. Thus, the results from receptor binding studies support the conclusion that (R)- and (S)-DPAT are agonists showing selectivity for 5-HT1A and dopamine D2 receptors, respectively. Taken together, these findings may explain previous controversies with regard to the pharmacology of racemic DPAT and re-emphasise the necessity to study pure enantiomers of chiral compounds.

The corticosterone-enhancing effects of the 5-HT 1A receptor antagonist, (S)-UH301, are not mediated by the 5-HT 1A receptor

We tried to antagonize the endocrine and behavioural changes induced by the selective 5-HT 1A receptor agonist, flesinoxan, with the putative 5-HT 1A receptor antagonist, (S)-UH301 (( S)-5-fluoro-8-hydroxy-2-(di- n-propylamino)tetralin). The interaction of (S)-UH301 (3 and 10 mg/kg s.c.) with flesinoxan (3 mg/kg s.c.) showed no antagonistic effects of (S)-UH301 on flesinoxan-induced corticosterone secretion. In fact, like flesinoxan (1 and 3 mg/kg s.c.), (S)-UH301 (3 and 10 mg/kg s.c.) itself dose dependently increased plasma corticosterone levels. Unlike flesinoxan, (S)-UH301 did not induce hyperglycemia, lower lip retraction and flat body posture. Moreover, flesinoxan-induced hyperglycemia and behavioural changes were effectively antagonized by (S)-UH301, showing potent 5-HT 1A receptor antagonistic effects of (S)-UH301. Therefore we conclude that (S)-UH301 is a potent 5-HT 1A receptor antagonist and that the (S)-UH301-induced corticosterone secretion is mediated by a non-5-HT 1A receptor mechanism.

Effects of repeated 2-deoxy- D-glucose administration on ingestive, psychological, and 5-HT-related behaviours in the rat

The effects of repeated treatment with the metabolic stressor 2-deoxy-D-glucose (2-DG: 500 mg/kg/day, 7 days) upon some ingestive and psychological behaviours were investigated, and compared with those elicited by repeated immobilization or cold exposure (2 hr/day, 7 days). Because all these stressors affect central serotonergic systems, 5-HT 1A and 5-HT 2A receptor-mediated behaviours were also analysed. Both 2-DG administration and immobilization decreased daily food intakes and increased the weight of the adrenals, while all stressors reduced body weight gain. In addition, 2-DG triggered hyperphagia (and reduced body weight loss) throughout the 7 light phases, and hypophagia (and reduced body weight gain) throughout the 7 dark phases. However, the other stressors had only temporary effects during the light phases. These results suggested that immobilized and cold exposed rats, but not 2-DG-treated rats had progressively adapted to their stressors. Furthermore, 2-DG-treated rats exhibited decreased ambulation when placed in the open field, but no change in social interaction. Forepaw treading and flat body posture responses to the 5-HT 1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were not altered by the stressors, but both of them slightly amplified 8-OH-DPAT-induced hypothermia. This change was associated with a decreased head shake response to the 5-HT 2A agonist 1-(4-iodo-2,5-dimethoxy-phenyl)-2-aminopropane (DOI) in 2-DG-treated rats, compared with that measured in the other groups. This study opens the possibility that alterations in feeding rhythms has functional consequences on 5-HT 2A receptors.

Effects of FG 5893, a new compound with 5-HT 1A receptor agonistic and 5-HT 2 receptor antagonistic properties, on male rat sexual behavior

In the present study male rat sexual behavior was used to explore the functional properties of FG 5893, a newly developed diphenylbutylpiperazinepyridyl derivative which is a 5-HT 1A receptor agonist and a 5-HT 2 receptor antagonist. Treatment with FG 5893 (0.1–6.0 mg kg −1) stimulated male rat sexual behavior, as evidenced by a decrease in the number of mounts and intromissions to elicit ejaculation, and a shortening of the ejaculation latency. The stimulatory effects varied in a dose-dependent manner, reaching a maximum at 3.0 mg kg −1. Pretreatment with (±)-pindolol (0.5 mg kg −1 −30 min), a selective 5-HT 1A receptor antagonist, completely antagonized the stimulatory effects of FG 5893 (1 mg kg −1 −20 min) on male sexual behavior. In addition, the behavioral action of FG 5893 was investigated on various components of the ‘serotonin behavior syndrome’ including flat body posture, forepaw treading, and lower lip retraction. The effects obtained were compared with those induced by treatment with 8-hydroxy-2(di- n-propyl-amino)tetralin (8-OH-DPAT), the prototype of a 5-HT 1A receptor agonist. Compared to 8-OH-DPAT, a 100 times higher dose of FG 5893 (10 mg kg −1) was needed to elicit flat body posture while forepaw treading was never seen. Lower lip retraction was elicited by the lowest doses of FG 5893 (0.1 mg kg −1) and 8-OH-DPAT (0.03 mg kg −1). Treatment with (±)-pindolol reduced flat body posture elicited by 8-OH-DPAT and completely eradicated the flat body posture induced by FG 5893. The facilitatory effects of FG 5893 on ejaculatory behavior resembled those reported following treatment with typical 5-HT 1A receptor agonists and are suggested to be mediated by 5-HT 1A receptors. Since FG 5893 was inefficient in stimulating flat body posture, which is suggested to be a postsynaptically mediated syndrome, but readily stimulated lower lip retraction, which is assumed to be a presynaptically mediated behavior syndrome, it is concluded that FG 5893 may act as an agonist presynaptically.

Behavioural and neurochemical evidence for the decrease of brain extracellular 5-HT by the antidepressant drug tianeptine

The effects of the novel antidepressant tianeptine on behaviours induced by the serotonin (5-HT) precursor 5-hydroxytryptophan (5-HTP) and the 5-HT 1A agonist 8-hydroxy-2-(di- n-propylamino)-tetralin (8-OH-DPAT) were investigated. Tianeptine (10 mg/kg, i.p.) significantly attenuated wet dog shakes (WDS) induced by 5-HTP (75 mg/kg, i.p.; 30 min after carbidopa 25 mg/kg, i.p.). The effect was most marked when 5-HTP and tianeptine were given together. The main metabolite of tianeptine also attenuated WDS. Components of the 5-HT syndrome (i.e. reciprocal forepaw treading, hind limb abduction, flat body posture) induced by 8-OH-DPAT (0.5 mg/kg, s.c.) were unaffected by tianeptine and 5-HTP given both singly or together. However, tianeptine significantly reduced faecal pellet formation but not cage crossings resulting from 8-OH-DPAT administration. These cage crossings but not the associated faecal pellet formation were reduced by 5-HTP. This reduction was prevented by tianeptine. The increase of extracellular 5-HT in the frontal cortex following administration of 5-HTP was opposed and the concurrent increase of extracellular 5-hydroxyindoleacetic acid (5-HIAA) was enhanced by tianeptine. The above behavioral and neurochemical findings indicate that tianeptine opposes the increase of 5-HT at receptor sites due to 5-HTP administration.

WAY 100,135 and (−)-tertatolol act as antagonists at both 5-HT 1A autoreceptors and postsynaptic 5-HT 1A receptors in vivo

In binding studies, WAY 100,135 (N-tertiobutyl-3-[4-(2-methoxyphenyl)-piperazinyl]-2-phenylpropanamide) and (−)-tertatolol showed affinities (K i) of 29 nM and 10 nM, respectively, at 5-HT 1A receptors. In vivo, they both dose dependently blocked the flat-body posture and corticosterone secretion provoked by an action of the 5-HT 1A receptor agonist, S 14671 (1-[2-(2-thenoylamino)ethyl]-4-[1-(7-methoxynaphtyl)]piperazine), at postsynaptic 5-HT 1A receptors. Alone, they exerted little effect. The firing rate of dorsal raphe neurones, which bear inhibitory 5-HT 1A autoreceptors, was reduced by S 14671 whereas it was not affected by WAY 100,135 and was increased by (−)-tertatolol. Both WAY 100,135 and (−)-tertatolol blocked the ability of S 14671 to inhibit raphe firing. In conclusion, these data demonstrate that WAY 100,135 and (−)-tertatolol behave as antagonists at both 5-HT 1A autoreceptors and postsynaptic 5-HT 1A receptors in vivo.

S 15535: a highly selective benzodioxopiperazine 5-HT 1A receptor ligand which acts as an agonist and an antagonist at presynaptic and postsynaptic sites respectively

The novel benzodioxopiperazine, S 15535 (4-(benzodioxan-5-yl)1-(indan-2-yl)piperazine), displayed high affinity for 5-HT 1A binding sites (1.8 nM) whereas its affinity was 100-fold lower at other 5-HT 1A receptor types, at α 1, α 2- and β-adrenoceptors dopamine D 1 and D 2 receptors. In vivo, S 15535 (0.16–10 mg/kg s.c.) acted as an antagonist at postsynaptic 5-HT 1A receptors in completely blocking the flat-body posture and hypothermia elicited by the 5-HT 1A receptor agonist, 8-OH-DPAT. It had no effect when applied alone. At presynaptic 5-HT 1A receptors, S 15535 acted as an agonist in inhibiting striatal accumulation of 5-hydroxytryptophan (0.04–0.63 mg/kg s.c.) and in spiperone reversibly reducing electrical activity of the dorsal raphe nucleus (0.004–0.031 mg/kg i.v.). At doses up to 40.0 mg/kg s.c., S 15535 neither inhibited methylphenidate-induced gnawing nor elicited ptosis suggesting a lack of antagonist properties at, respectively, dopamine D 2 receptors and α 1-adrenoceptors. In conclusion, S 15535 is a potent 5-HT 1A ligand which acts, in vivo, as a highly selective agonist and antagonist at presynaptic and postsynaptic 5-HT 1A receptors, respectively.

Serotonin receptor ontogeny: Effects of agonists in 1-day-old rats

Although numerous subtypes of serotonin [5-hydroxytryptamine (5-HT)] receptors have been identified in the newborn rat by radioligand binding studies, there have been few studies of the functional significance of these early receptors, most without the benefit of selective drugs. We performed acute dose-response and time course behavioral studies in 1-day-old rats with the putative selective agonists 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT) (5-HT 1A), 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1 H-indole (RU 24969) (5-HT 1B), and (±)1-(2,5-dimethoxy-4-iodo-phenyl aminopropane)-2 (DOI) (5-HT 2/1C). The agonists induced distinctive behavioral syndromes. The DOI syndrome mainly included rudiments of forepaw myoclonus and dystonic limb postures, but no shaking behavior (head shakes or wet-dog shakes) or spinal myoclonus, two key reference behaviors for its effects in adult rats. The most distinctive feature of the 8-OH-DPAT-induced syndrome was flat body posture. RU 24969 most significantly increased locomotor activity, inducing propulsive movements with episodic rests and sudden hindlimb jerks. These studies suggest that functional and differential activity of 5-HT 1A, 5-HT 1B, and 5-HT 2/1C receptors occurs much earlier in the rat than previously appreciated. The absence of DOI-induced shaking behavior and spinal myoclonus, however, suggests incomplete maturation at the level of the receptor or effector pathways for these behaviors.

Effects of cold stress on some 5-HT 1A, 5-HT 1C and 5-HT 2 receptor-mediated responses

The purpose of the present study was to analyze the influence of stress (24-h cold exposure) on presynaptic 5-HT 1A receptors, and on postsynaptic 5-HT 1A, 5-HT 1C and 5-HT 2 receptors. Cold exposure for 24 h affected neither pargyline-induced decreases in 5-hydroxyindoleacetic acid (5-HIAA) levels in midbrain and rest of brain, nor plasma glucose and corticosterone levels. Treatment with the 5-HT 1A receptor agonist, 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT; 0.5–1 mg/kg), 3–5 h after the end of cold exposure triggered less intense flat body posture and forepaw treading in cold-exposed rats than in controls. On the other hand, 15- and 30-min plasma glucose responses to 8-OH-DPAT (0.25–0.5 mg/kg, 3–5 h after cold) or to the α 2-adrenoceptor agonist, clonidine (0.025 mg/kg), were not affected by cold, while the 15-min, but not the 30 min, plasma corticosterone response to 8-OH-DPAT was slightly amplified in cold-exposed rats. Cold exposure affected neither the inhibitory effect of 8-OH-DPAT (0.25–0.5 mg/kg, 3–5 h after cold) on midbrain 5-HIAA levels, nor the hypothermic effect of 8-OH-DPAT (0.5–1 mg/kg, 3–5 h after cold). Lastly, the hypoactivity elicited by the 5-HT 1C recepor agonist, m-chlorophenyl-piperazine (1.5–3 mg/kg, 3–5 h after cold), or head shakes elicited by the 5-HT 2 receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1–2 mg/kg, 3–5 h after cold), were of similar intensities in control and in cold-exposed rats.

Attenuation of chemically induced defence response by 5-HT1 receptor agonists administered into the periaqueductal gray.

The ability of 5-HT1 receptor agonists to modulate a chemically induced defence response has been studied in Lister hooded rats. Microinjections of the excitatory amino acid D,L-homocysteic acid (DLH) in both rostral and caudal dorsal periaqueductal gray matter (PAG) caused explosive motor behaviour characteristic of defence. This behaviour was quantified in terms of response duration, arena revolutions and number of defensive jumps. Direct administration into the PAG of either 5-carboxamidotryptamine (5-CT) or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced behaviours (decreased exploratory rearing, dose related onset of flat body posture) indicative of 5-HT1A receptor activation. Pretreatment with either 5-CT or 8-OHDPAT directly in the PAG caused a significant attenuation, and in some cases a complete abolition, of the DLH evoked response. These agonists share high affinity in vitro for the 5-HT1A receptor. Thus the results suggest that in vivo activation of 5-HT1A receptors mediates an antiaversive response with respect to defensive behaviour elicited by specific chemical stimulation of the dorsal PAG.

Repeated corticosterone treatment attenuates behavioural and neuroendocrine responses to 8-hydroxy-2-(di-n-propylamino) tetralin in rats

The effects of 5 day corticosterone treatment (50 mg/kg s.c.; 2 × daily) are investigated on the behavioural and neuroendocrine responses to 5-HT-1A selective agonist, 8-hydroxy -2-(di-n-propylamino) tetralin (8-OH-DPAT) in rats. Daily corticosterone treatment decreased body weight and food intake. After 5 day treatment a drug challenge of 0.25 and 0.5 mg/kg 8-OH-DPAT given on the sixth day produced smaller forepaw treading but comparable head waeving, flat body posture and also hypothermia in 5 day corticosterone than 5 day saline injected rats. Hyperphagic effects of only 0.25 mg/kg 8-OH-DPAT were attenuated in 5 day corticosterone injected animals. The effects of 8-OH-DPAT on the increases of plasma corticosterone were markedly attenuated in the 5 day corticosterone injected animals. The findings may help towards an understanding of steroid-induced affective changes and psychosis.

Effect of isolation rearing on 5-HT agonist-induced responses in the rat

Rats were reared from weaning (21 days of age) either in isolation or in social groups of five for 30 days and were then tested for spontaneous locomotor activity and 7 days later for 5-hydroxytryptamine (5-HT) agonist-induced behaviour. Isolation-reared animals displayed locomotor hyperactivity when placed in a novel environment. 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (2 mg/kg IP) and 8-hydroxy-2-(di-n-propyl-amino) tetralin (8-OH-DPAT) (0.32 mg/kg SC) elicited various components of the "5-HT behavioural syndrome" in both groups of animals, with forepaw treading and flat body posture being significantly more pronounced in isolation-reared animals. 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (2.5 mg/kg IP), a 5-HT2 selective agonist, produced a significantly greater number of back muscle contractions in isolation-reared animals but there was no difference between the two groups in the number of wet-dog shakes produced. Forepaw treading and flat body posture are thought to be mediated by 5-HT1A receptor activation, and stimulation of this receptor by either 5-MeODMT or 8-OH-DPAT produced greater responding in isolation-reared rats, suggesting supersensitivity of the post-synaptic 5-HT1A receptor. Wet-dog shakes are thought to be mediated by 5-HT2 and other (none-5-HT) receptors while back muscle contractions have been shown to be mediated by 5-HT2 receptors, indicating that there is also an increase in 5-HT2 receptor responsiveness in the socially-isolated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of the partial dopamine receptor agonists SDZ 208-911, SDZ 208-912 and terguride on central monoamine receptors

The partial dopamine receptor agonists SDZ 208-911 (N-[(8-alpha)-2,6-dimethylergoline-8-yl]-2,2-dimethylpropanamid e), SDZ 208-912 (N-[8-alpha)-2-chloro-6-methylergoline-8-yl]-2,2- dimethylpropanamide) and terguride (transdihydrolisuride; TDHL) were tested in biochemical, behavioral (locomotor activity) and electrophysiological assays in male rats. In reserpine-pretreated rats, SDZ 208-911 and terguride dose-dependently reduced striatal DOPA formation (NSD 1015 treatment) with similar efficacy (-80%) and potency as the selective D2 receptor agonist quinpirole (LY 171555). SDZ 208-912 only produced a partial reduction (-32%) at the highest dose tested. SDZ 208-911 and terguride partially reversed (by approximately 50%) the gamma-butyrolactone (GBL)-induced increase in striatal DOPA accumulation. Quinpirole produced a 100% reversal while SDZ208-912, per se, was inactive. While quinpirole decreased DOPA accumulation, all three partial agonists elevated striatal DOPA accumulation in non-pretreated rats with SDZ 208-912 being as potent and efficacious as haloperidol. The three partial agonists displayed comparatively high affinities in vitro for the dopamine D2 (3H-spiperone) receptor site and somewhat lower affinity for the 5-HT1A (3H-8-OH-DPAT) receptor site. SDZ 208-911 and SDZ 208-912 also showed high affinities for central alpha 2 (3H-idazoxane) receptors. In line with these findings, the partial ergoline agonists dose-dependently elevated the DOPA accumulation in the noradrenaline-rich cortical brain region and decreased the 5-HT synthesis rate (5-HTP accumulation) in the limbic brain region. Furthermore, high doses of SDZ 208-911 and terguride produced weak signs of the 5-HT behavioral syndrome (flat body posture) in reserpinized rats. In the locomotor activity studies in non-pretreated rats, SDZ 208-911, SDZ 208-912 and terguride reduced the activity to 10-20% of controls with SDZ 208-912 being approximately ten times less potent than the other two compounds. Weak postsynaptic dopamine receptor agonist effects of the partial agonists were demonstrated only in reserpine-pretreated rats; all three partial agonists tested produced occasional forward locomotion and the so-called "jerking" behavior. Extracellular single unit recordings were carried out in chloral hydrate-anesthetized rats to investigate the effects on firing rates of dopamine neurons located in the substantia nigra pars compacta. Intravenous administration of SDZ 208-911 and terguride depressed the firing rate by 42 and 53%, respectively, while apomorphine completely inhibited the cells. SDZ 208-912 only reduced the firing by 16% and some cells displayed a biphasic response with a weak depression at low doses that disappeared at high doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Characterization of the 5‐HT receptor subtypes involved in the motor behaviours produced by intrathecal administration of 5‐HT agonists in rats

1. The motor behavioural effects of intrathecal injections of 5-hydroxytryptamine (5-HT) and a variety of 5-HT receptor agonists were examined in adult Wistar rats to establish; (a) which 5-HT receptor subtype/s elicit each behaviour and (b) whether these receptors are located within the spinal cord. 2. Intrathecal injection of 5-methoxy-N,N'-dimethyltryptamine (5-MeODMT), (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) or 2,5-dimethoxy-alpha,4-dimethylbenzene ethamine hydrochloride (DOM) produced dose-related back muscle contractions (BMC) and wet dog shakes (WDS) which were both markedly attenuated by intraperitoneal pretreatment with either ritanserin (1 mg kg-1), ketanserin (0.16 mg kg-1) or mianserin (0.6 mg kg-1) indicating the involvement of 5-HT2 receptors in both these motor behaviours. Both fluoxetine (1-20 mg kg-1, i.p.) and high doses of 5-HT (50 micrograms) following fluoxetine (5 mg kg-1, i.p.) also elicited BMC, further confirming the involvement of 5-HT in this behaviour. 3. Intrathecal 5-carboxamidotryptamine (5-CT) evoked a marked wet-dog shake response without producing any BMC. Intrathecal pretreatment with 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) enhanced, while in contrast 2-methyl-5-HT pretreatment attenuated, 5-HT agonist-induced BMC without affecting WDS. These data suggest that the spinal 5-HT2 receptors mediating BMC are positively modulated by 5-HT1A but negatively influenced by 5-HT3 receptor activation and may be of a different subtype to the supra-spinal 5-HT2 receptors which elicit WDS. 4. A contrast, reciprocal forepaw treading, lateral head weaving, flat body posture and Straub-tail were evoked by 5-MeODMT, 8-OH-DPAT or 5-CT but not by DOI or DOM indicating that these behaviours were not produced by 5-HT2 receptor activation alone. Ritanserin (1 mg kg- 1, i.p.) or ketanserin (0.16mgkg-1, i.p.) pretreatment reduced the reciprocal forepaw treading induced by high intrathecal doses of either 5-MeODMT (25.pg) or 5-CT (50,ug) suggesting that this behaviour may be facilitated by 5-HT2 receptor activation. 5. Intrathecal injection of 5-HT (0.05-50pg, after systemic fluoxetine, 5mg kg 1, i.p.), or 1-(3-chlorophenyl) piperazine (mCPP) produced dose-related forepaw-licking and grooming, neither of which were attenuated by ketanserin (0.16 mgkg-1, i.p.) pretreatment suggesting these behaviours may be mediated by 5-HT1c receptors. In contrast, 2-methyl-5-HT (50 and 100pg) produced sideward tail-flicks, not evoked by any other 5-HT agonist and could therefore be mediated by spinal 5-HT3 receptor activation. 6. These data provide behavioural evidence for the existence of spinal 5-HT2 receptors which produce a novel motor behaviour, BMC. Ligand binding studies and dose-response studies with a range of selective 5-HT antagonists are required to establish whether BMC and WDS are mediated by different subtypes of 5-HT2 receptors.

Region-selective inhibition of male rat sexual behavior and motor performance by localized forebrain 5-HT injections: a comparison with effects produced by 8-OH-DPAT

The local application of 5-HT (0-40 micrograms side-1) into the nucleus accumbens was found to inhibit male rat sexual behavior, as evidenced by an increase in number of mounts and intromissions preceding ejaculation and in time to ejaculation. There were no effects on male rat sexual behavior after similar 5-HT injections into other striatal areas, including the dorsolateral, the ventromedial and the posterior neostriatum, as well as the olfactory tubercle. The same groups of animals were also scored for motor activity and body posture after the injection of 5-HT, and only animals injected into the nucleus accumbens showed a statistically significant decrease in motor activity and an increase in the display of a flat body posture. 8-OH-DPAT (0-5 micrograms side-1), injected into the nucleus accumbens, produced a facilitation of the male rat sexual behavior, as evidenced by a decrease in number of mounts and intromissions to ejaculation, as well as in the postejaculatory interval. 8-OH-DPAT injections into the nucleus accumbens produced a decrease in motor activity and an increase in the per cent animals with a flat body posture. Injections into the olfactory tubercle had no effects on the sexual behavior or on the motor activity, whereas the per cent flat body posture was increased. Local application of 8-OH-DPAT (0-5 micrograms) into the median raphe nucleus, facilitated male rat sexual behavior, as evidenced by a decrease in number of intromissions preceding ejaculation and in time to ejaculation. The same doses of 8-OH-DPAT injected into the dorsal raphe had no effects on the sexual behavior. In an additional experiment, 3 groups of animals were injected with 5-HT (40 micrograms) or 8-OH-DPAT (5 micrograms) into the nucleus accumbens, the dorsal and the median raphe nuclei and thereafter observed for treadmill performance. No statistically significant effects were found after injections in any of these brain areas. The present results strongly suggest an inhibitory role of ventral forebrain 5-HT in the mediation of male rat sexual behavior. The facilitation produced by 8-OH-DPAT is possibly due to a blockade of 5-HT2 receptors. Facilitation by 8-OH-DPAT of the male rat copulatory performance after median raphe injections is probably due to stimulation of 5-HT1A autoreceptors in this brainstem region. In contrast to their opposite effects on sexual behavior, both compounds produced a decrease in motor activity and an increased display of flat body posture after accumbens injections.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential behavioural activation following intra-raphe infusion of 5-HT 1A receptor agonists

Microinfusion of the selective 5-HT 1A receptor agonist, 8-hydroxy-(di-N-propylamino)tetralin (8-OHDPAT), into the dorsal raphe nucleus (DRN) produced a marked behavioural hypoactivity and flat body posture. Injections of similar doses into the median raphe nucleus (MRN) elicited hyperactivity but no postural change. Reductions in rearing and grooming were also observed after DRN and MRN infusion of 8-OHDPAT. The behavioural profiles of other 5-HT 1A selective compounds, gepirone and BMY7378 were found to be similar to 8-OHDPAT. The contrasting behavioural profiles of the 5-HT 1A agents observed after DRN or MRN microinfusions are probably related to the differential innervation of forebrain structures by each raphe nucleus. Thus, the present data confirms and extends previous results illustrating the influence of 5-HT systems on motor behaviour in the rat and identifies unique behavioural profiles following activation of the DRN and MRN.

Cardiovascular effects of 5-HT 1A receptor agonists injected into the dorsal raphe nucleus of conscious rats

The aim of this study was to investigate the cardiovascular effects of the 5-HT 1A receptor agonists, 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), flesinoxan and 5-carboxamidotryptamine (5-CT) following injection into the dorsal raphe nucleus of conscious rats. 8-OH-DPAT (0.5–2.5 μg), flesinoxan (2.5–5.0 μg) and 5-CT (0.05 μg) caused hypotension, bradycardia and flat body posture. In contrast, injection of 8-OH-DPAT (0.5 μg) into the median raphe nucleus caused no cardiovascular changes or flat body posture. (−)Pindolol (0.5 μg dorsal raphe nucleus) had little effect on cardiovascular parameters, but significantly attenuated the cardiovascular effects of 8-OH-DPAT (0.5 μg dorsal raphe nucleus). N-Methylatropine (1 mg/kg i.v.) antagonised the cardiovascular effects of 8-OH-DPAT (0.5 μg dorsal raphe nucleus), suggesting these were vagally mediated. Both pretreatments also appeared to reduce 8-OH-DPAT-induced flat body posture. The results suggest that 8-OH-DPAT activates 5-HT 1A receptors in the dorsal raphe nucleus to cause hypotension and bradycardia.

The behavioural, but not the hypothermic or corticosterone, response to 8-hydroxy-2-(di-n-propylamino)-tetralin, is antagonized by nan-190 in the rat

The 5-HT1A receptor antagonistic properties of 1-(2-methoxyphenyl)-4-[4-(2-phthalimmido)butyl] piperazine (NAN-190) were studied in rats: its effect on the 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT)-induced behavioural syndrome (flat body posture and reciprocal forepaw treading), hypothermia and secretion of corticosterone, i.e. responses mediated by 5-HT1A receptors, were examined. The drug NAN-190 (1-8 mg/kg) antagonized dose-dependently behavioural effects of 8-OH-DPAT (in both non-reserpinized and reserpine-pretreated animals); however, when administered in doses of 0.5-4 mg/kg, it did not affect the hypothermic or the hormonal response to 8-OH-DPAT. However, NAN-190 (1-8 mg/kg) given alone, produced hypothermia and increased the concentration of corticosterone in serum. The latter effects of NAN-190 were not reduced by (-)pindolol or spiperone. Moreover, the NAN-190-induced secretion of corticosterone was not affected by ketanserin, prazosin or yohimbine. The above results indicate that NAN-190 acts as a 5-HT1A receptor antagonist, only in the model of the 8-OH-DPAT-induced behavioural syndrome. The lack of effect of NAN-190 on the hypothermic or corticosterone response to 8-OH-DPAT most probably results from its own action which mimics the effects of 8-OH-DPAT. The mechanisms responsible for the NAN-190-induced hypothermia and secretion of corticosterone are still unknown, though stimulation of 5-HT1A receptors (either effect), 5-HT2 receptors and alpha 1- and alpha 2-adrenoceptors (corticosterone response) seems to be excluded.