Cardiovascular function alterations induced by acute paradoxical sleep deprivation in rats.

Sleep loss has been implicated in triggering the hypertension. The goal of the present study was investigated the possible mechanisms underlying cardiovascular alterations after acute paradoxical sleep deprivation (PSD). Male Wistar rats were assigned in two experimental groups: (1) control and (2) PSD for 24 h using the modified single platform method. Paradoxical sleep deprived rats exhibited higher blood pressure, heart rate (HR) and impaired baroreceptor sensitivity. After pharmacological autonomic double blockade (propranolol and methylatropine administration), intrinsic heart rate was decreased after PSD. The PSD rats showed a reduction in the vagal tone without affecting sympathetic tone. Isoproterenol administration (0.001, 0.01 and 1 µg/kg) induced an increase in ΔHR responses in PSD group. Electrocardiographic analysis in response to ß-adrenergic stimulation indicated that PSD contributed to ventricular cardiac arrhythmias. Our findings suggest that acute paradoxical sleep loss induce cardiovascular alterations, autonomic imbalance accompanied by impaired baroreflex sensitivity and increased arrhythmia susceptibility.

Acute effects of selective serotonin reuptake inhibitors on neuroleptic-induced catalepsy in mice.

Depression found in Parkinson disease (PD) usually responds to selective serotonin reuptake inhibitors (SSRIs). Drugs that modify experimental neuroleptic catalepsy (NC) might affect extrapyramidal symptoms in PD. Therefore, the effects of SSRIs on NC were tested in mice, 26-36 g, separated by sex. Catalepsy was induced with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals using a bar test. An SSRI (sertraline, ST; paroxetine, PX; fluoxetine) or vehicle (C) was injected ip 30 min before H. Dunnett's test was used for comparison of means. ST (1-5 mg/kg) or PX (1-5 mg/kg) attenuated NC, with a similar inhibition found in both sexes (5 mg/kg, 180 min: ST - males: 124 +/- 10 vs 714 +/- 15 s in C; females: 116 +/- 10 vs 718 +/- 6 s in C; PX - males: 106 +/- 10 vs 714 +/- 14 s in C; females: 102 +/- 10 vs 715 +/- 14 s in C). At 0.3 mg/kg, neither of these drugs affected NC. Fluoxetine (1-25 mg/kg) also inhibited catalepsy, although the effect was not dose-dependent; no differences were observed between males and females (5 mg/kg, 180 min: males, 185 +/- 14 vs 712 +/- 14 s in C; females, 169 +/- 10 vs 710 +/- 19 s in C). For these SSRIs, maximal inhibition of NC was obtained with 5 mg/kg, 180 min after H. These results are consistent with the hypothesis that serotonergic mechanisms modulate nigrostriatal transmission, and suggest that SSRIs are possibly safe in depressive PD patients.

Functional mapping of the cardiorespiratory effects of dorsal and median raphe nuclei in the rat.

The dorsal (DRN) and median (MRN) raphe nuclei are important sources of serotonergic innervation to the forebrain, projecting to sites involved in cardiovascular regulation. These nuclei have been mapped using electrical stimulation, which has the limitation of stimulating fibers of passage. The present study maps these areas with chemical stimulation, investigating their influence on cardiorespiratory parameters. Urethane-anesthetized (1.2 g/kg, iv) male Wistar rats (280-300 g) were instrumented for pulsatile and mean blood pressure (MBP), heart rate, renal nerve activity, and respiratory frequency recordings. Microinjections of L-glutamate (0.18 M, 50-100 nl with 1% Pontamine Sky Blue) were performed within the DRN or the MRN with glass micropipettes. At the end of the experiments the sites of microinjection were identified. The majority of sites within the MRN (86.1%) and DRN (85.4%) evoked pressor responses when stimulated (DRN: DeltaMBP = +14.7 +/- 1.2; MRN: DeltaMBP = +13.6 +/- 1.3 mmHg). The changes in renal nerve activity and respiratory rate caused by L-glutamate were +45 +/- 11 and +42 +/- 9% (DRN; P < 0.05%), +40 +/- 10 and +29 +/- 7% (MRN, P < 0.05), respectively. No significant changes were observed in saline-microinjected animals. This study shows that: a) the blood pressure increases previously observed by electrical stimulation within the raphe are due to activation of local neurons, b) this pressor effect is due to sympathoexcitation because the stimulation increased renal sympathetic activity but did not produce tachycardia, and c) the stimulation of cell bodies in these nuclei also increases the respiratory rate.

L-arginine restores the effect of ouabain on baroreceptor activity and prevents hypertension.

In spontaneously hypertensive rats, ouabain exerts an excitatory effect on baroreceptor nerve activity (BNA). The aim of this study was to determine the effects of ouabain on BNA in other experimental models of hypertension and its interaction with nitric oxide. Rats were made hypertensive using the procedures for N(omega)-nitro-L-arginine methyl ester (L-NAME), deoxycorticosterone acetate (DOCA) salt, and 2-kidney, 1 clip (2K1C) hypertension models. In these groups, systolic arterial pressure was 195+/-7, 149+/-6, and 148+/-4 mm Hg, respectively, compared with 110+/-4 mm Hg in normotensive rats. Acute ouabain administration had an excitatory effect on BNA in normotensive rats (37+/-4%), an inhibitory effect in L-NAME hypertensive rats (-60+/-7%), and no effect in DOCA-salt and 2K1C hypertensive rats. The effects of ouabain were not related to arterial pressure levels, and no excitatory effect on BNA was observed in prehypertensive DOCA-salt rats. Long-term administration of L-arginine (3 g x kg(-1) x day(-1)) prevented DOCA-salt (121+/-8 mm Hg) and 2K1C (104+/-4 mm Hg) hypertension, markedly attenuated L-NAME (130+/-9 mm Hg) hypertension, and restored the excitatory effect of ouabain on BNA in these groups to levels similar to the normotensive rats and their respective control groups. We conclude that ouabain has a diverse effect on BNA in experimental models of hypertension, and it can be normalized by L-arginine. The data also indicate that nitric oxide may play a pivotal role in mediating the excitatory effect of ouabain on BNA, and we speculate that a therapeutic combination of ouabain and L-arginine may be beneficial in secondary hypertension.

Effects of 5-HT3 receptor antagonists on neuroleptic-induced catalepsy in mice.

Typical neuroleptics (e.g. haloperidol) can induce a cataleptic state in rodents by means of striatal DA receptor blockade. It has been shown that drugs which influence central serotonergic (5-HTergic) mechanisms can modify neuroleptic-induced catalepsy, suggesting that dopaminergic transmission is under 5-HTergic modulation. The aim of this study was to examine the effects of bemesetron and granisetron, two selective 5-HT3 receptor antagonists, on this catalepsy in mice. Catalepsy was induced with haloperidol (1.5 mg/kg, i.p.) and measured at 30-min intervals by means of a bar test. Drugs (or saline, for the controls) were injected i.p. 20 min before haloperidol, with each animal used only once. Bemesetron significantly reduced catalepsy at a dose of 1 mg/kg, whilst 10 mg/kg potentiated the phenomenon and 0.1 mg/kg was found to be without effect. Granisetron inhibited catalepsy at doses of 0.04 and 0.1 mg/kg while 4 mg/kg of the antagonist significantly increased the duration of catalepsy. These data suggest that 5-HT3 receptors play a role in neuroleptic-induced catalepsy. Considering the high affinities of both antagonists for 5-HT3 receptors, it is tempting to speculate that the potentiation of catalepsy by high doses of them is due to non 5-HT3 receptor mechanisms.

Changes in sympathetic activity to heart and blood vessels during desynchronized sleep.

In mid-collicular decerebrate cats, the activity in sympathetic nerves to the heart, kidney, gastro-intestinal tract, pelvic viscera and blood vessels of skeletal muscle was examined during periods of extensor rigidity and during desynchronized sleep-like periods (DSp) either occurring spontaneously or induced by physostigmine sulphate. During DSp the activity in sympathetic vasoconstricstor fibres to muscle increased whereas that in the other sympathetic nerves decreased. The changes were present in vagotomized and sino-aortic denervated animals as well as in paralyzed preparations. It was concluded that the differential pattern of sympathetic activity was a characteristic of the tonic stage of desynchronized sleep and originated from a site in the central nervous system independently of afferent input.

Desynchronized sleep-like pattern of sympathetic activity elicited by electrical stimulation of sites in the brainstem.

In unanaesthetized mid-collicular decrebrate cats, paralyzed and artificially respired, recordings were made of sympathetic activity in nerves to heart (CN), to kidney (RN) and in identified vasoconstrictor nerves to skeletal muscle (SFM), whilst stimulating electrically with monopolar electrodes at various sites throughout the pons and medulla. Comparing RN and SFM, 1 of 3 patterns of response was observed at any one site: an increase in RN and SFM activity, a reduction or abolition of activity in both or a reduction or abolition of RN activity with a simultaneous facilitation of SFM activity. The latter differential pattern of sympathetic activity is characteristic of desynchronized sleep-like periods and could only be elicited from a discrete region in the mid-line of the caudal brainstem. Stimulation in this same region produced a reduction or abolition of CN as well as RN. It was suggested that neurones within the caudal part of nucleus raphe obscurus can generate a pattern of sympathetic activity similar to that occurring naturally in desynchronized sleep.

Evidence that 5-HT3 receptors in the nucleus tractus solitarius and other brainstem areas modulate the vagal bradycardia evoked by activation of the von Bezold-Jarisch reflex in the anesthetized rat.

The effects of intracisternal (i.c.) application of the 5-HT3 receptor antagonist granisetron (0.016-0.16 microg kg-1) and the agonist phenylbiguanide (0.3-3 microg kg-1) on reflex bradycardia evoked by injection of phenylbiguanide (i.v.; 10 microg kg-1) were investigated in urethane anesthetized atenolol-pretreated rats. The effect of bilateral microinjection of granisetron (10 nmol per side, 100 nl) into the nucleus tractus solitarius (NTS) on the reflex was also investigated. Intracisternal administration of granisetron dose-dependently (0.016-0.16 microg kg-1) and significantly attenuated the reflex bradycardia whilst the highest dose given i.v. had no significant effect on the reflex bradycardia. Phenylbiguanide given i.c. only caused significant potentiation at the middle dose (1 microg kg-1), having no significant effects at the other doses. Neither granisetron nor phenylbiguanide given i.c. affected resting heart rate or blood pressure. Granisetron microinjected bilaterally into the NTS also significantly attenuated both reflex bradycardia and hypotension. It is concluded that excitation of cardiac vagal motoneurones evoked by cardiopulmonary afferents involves activation of 5-HT3 receptors located in the nucleus tractus solitarius and other brainstem areas.

Evidence for the ability of central 5-HT1A receptors to modulate the vagal bradycardia induced by stimulating the upper airways of anesthetized rabbits with smoke.

Cigarette smoke passed through the nasal cavity of atenolol pre-treated anesthetized spontaneously breathing rabbits caused a bradycardia which was significantly modified by intracisternal application of the 5-HT1A receptor ligands 8-OH-DPAT (50 micrograms.kg-1) and buspirone (200 micrograms.kg-1). 8-OH-DPAT attenuated while buspirone potentiated the bradycardia. These results support the view that 5-HT1A receptors play an important role in modulating the excitability of cardiac vagal motoneurones.

The involvement of serotonin neurones in the inhibition of renal nerve activity during desynchronized sleep.

Numerous 5-hydroxytryptamine (5-HT)-containing cell bodies were visualized by fluorescence microscopy in the caudal brainstem rostral to the decussation of the pyramids in a region from which a desynchronized sleep-like pattern of sympathetic activity was obtained in a previous study. In unanaesthetized mid-collicular decerebrated cats recordings were made of sympathetic activity in a renal nerve. The inhibition of renal nerve activity occurring during desynchronized sleep-like state induced by physostigmine was attenuated significantly by procedures which interfered with the pathways from the 5-HT-containing neurones. Small cuts in the dorsolateral funiculus of the cervical spinal cord reduced the inhibition from 43 +/- 6% to 14.0 +/- 3%. Microinjection of 5,7-dihydroxytryptamine into cervical spinal cord reduced the serotonin content of the thoracic cord by 22.4% and attenuated the desynchronized sleep-like state inhibition of renal nerve activity by a similar amount. Depletion of serotonin with p-chlorophenylalanine significantly reduced the inhibition of renal nerve activity during the desynchronized sleep-like state, from 42.5 +/- 5% to 10.0 +/- 2.0%. It was suggested that serotonin-containing neurones are likely to be involved in the inhibition of renal nerve activity occurring during desynchronized sleep.

Evidence suggesting that gonadal hormones influence benzodiazepine withdrawal-induced weight loss in rats.

1. In experimental animals, benzodiazepine (BZ) withdrawal syndrome includes anorexia and acute weight loss. The literature shows several sex-based differences in the expression of BZ dependence; however, the authors did not find studies dealing with the influence of gonadal hormones on BZ withdrawal-induced weight loss. Thus, this study was designed to investigate the effects of castration on diazepam (DZ) withdrawal-induced weight loss in rats. 2. Male (260-330 g) or female (220-260 g) Wistar rats were anesthetized with ether and submitted to surgical castration or sham-operation. Seven days later, recovered from the surgery, the animals were injected i.p. with DZ (4 mg kg-1 day-1) or appropriate vehicle (VEH; 2 ml kg-1 kg-1 day-1) for 28 days. In the next 7 days, the rats received the same doses of DZ (four groups) or VEH (eight groups). Weights of all animals were recorded daily to the nearest gram at 09:00 h. To assess the degree of weight loss and make statistical comparisons, weights over days 29-34 were expressed as percentage of those recorded in the morning of day 28. 3. Sham-operated female rats from the group DZ-VEH showed a small but statistically significant weight loss on days 29 and 30 (P < 0.05) when compared with groups VEH-VEH and DZ-DZ. Ovariectomized rats, however, did not show any significant change in body weight from days 29-34. 4. Sham-operated male rats did not exhibit any significant weight loss after DZ withdrawal. Orchidectomized animals, however, showed a small but statistically significant weight loss on day 31 (P < 0.05) when compared with groups VEH-VEH and DZ-DZ. 5. These results show a gonadal influence on DZ withdrawal-induced weight loss in Wistar rats; in particular, they also suggest that female hormones (progesterone and/or estrogen) facilitate whilst male hormones inhibit this phenomenon.

Evidence of sex related differences in the effects of calcium channel blockers on neuroleptic-induced catalepsy in mice.

1. Calcium channel blockers (CCBs) are reported to affect extrapyramidal motor behavior in mammals. Since sex related differences are a common feature in the pharmacological properties of several centrally active drugs, the authors decided to investigate the effects of verapamil (VER), flunarizine (FLU) and nimodipine (NIM), three pharmacologically different CCBs, on neuroleptic-induced catalepsy in male and female albino mice. 2. Catalepsy was induced with haloperidol (0.75 mg/kg, i.p.) and measured at 30-min intervals by means of a bar test. Drugs (or appropriate vehicle, for the controls) were injected i.p. 20 min before haloperidol, with each animal being used only once. 3. VER (1, 5 and 10 mg/kg) did not significantly affect catalepsy in male mice. In females, however, a significant attenuation of catalepsy was found at the two higher doses. 4. FLU (1, 5 and 10 mg/kg) did not significantly affect catalepsy in male mice, whilst a significant attenuation was observed in females with the doses of 1 and 5 mg/kg (but not with the dose of 10 mg/kg). 5. NIM (3, 10 and 30 mg/kg) potentiated neuroleptic-catalepsy in males at the doses of 10 and 30 mg/kg. In females, however, only the higher dose of NIM caused a potentiation of catalepsy. 6. These results demonstrate the existence of sex related differences in the extrapyramidal effects of CCBs in mice. Further, this sex related effect might depend, among other factors, on the particular channel involved.

Effects of physostigmine on the activity of medullary raphe neurons in anesthetized rats.

Medullary raphe neurons are involved in the control of sympathetic activity during desynchronized sleep. To determine if cholinergic stimulation of these sites has any effect on raphe unit activity, we administered physostigmine to urethane-anesthetized rats. Most of the neurons (68%) were excited by physostigmine, suggesting the existence of cholinergic synapses which are excitatory for the majority of medullary raphe neurons.

Responses of neurons of the nucleus raphe obscurus to noxious stimuli.

Extracellular recordings were made from neurons located in the nucleus raphe obscurus (NRO), raphe magnus (NRM), and raphe pallidus (NRP) of urethane-anesthetized rats. Noxious cutaneous stimuli had excitatory, inhibitory or no effect on neurons of the raphe nuclei. Most of the neurons were excited by noxious stimuli. The distribution of responses of noxiously activated units in the NRO is similar to that observed in the NRM. It is suggested that the NRO is also a component of the endogenous pain suppression system that originates in the NRM.

Are 5-HT1A receptors involved in the control of reflex bradycardia induced by intracoronary injection of contrast medium in humans?

Transient vagal bradycardia occurring during coronary arteriography (CA) immediately following intracoronary injection of ionic contrast medium is believed to be a component of the von Bezold-Jarisch reflex (BJ). Data obtained from experimental animals using buspirone (BSP) and other 5-HT1A receptor ligands suggest that these serotonergic receptors modulate the excitability of cardiac vagal motoneurones (CVM). This is a preliminary investigation of the possible effects of BSP in altering the bradycardia of patients submitted to CA for diagnostic purposes. Patients were divided into two age- and race-matched groups: control (C:N = 45, age 58.6 +/- 1.6 years, mean arterial blood pressure (MAP) 109 +/- 2.4 mmHg, heart rate (HR) 79 +/- 2.9 bpm) and BSP-treated (B:N = 14, age 58.9 +/- 2.1 years, MAP 111 +/- 4.5 mmHg, HR 76 +/- 3.4 bpm). The prevalent underlying pathology was coronary artery disease. Patients with acute angina, congestive heart failure, symptomatic arrhythmia and patients requiring atropine were excluded. CA was performed by a standard procedure using diatrizoate (MD-76) as contrast agent. The left and then the right coronary ostia were selectively catheterized and 8 ml of contrast medium was injected (over a period of 3 sec). HR was measured from ECG tracings before and after contrast injection into the left (LC) and right (RC) coronary arteries. Peak bradycardia was measured as the longest R-R interval during the first 15 sec after the injection minus the pre-injection R-R value, and reported as delta R-R. Group B patients received BSP tablets 48 and 24 h before the examination (30 mg/day po). There was no statistically significant difference (P > 0.05) in bradycardia between groups (C:LC = -147 +/- 23, RC = -155 +/- 25; B: LC = -143 +/- 44, RC = -234 +/- 56 msec). These results suggest that, in contrast to experimental animals, the central 5-HT1A receptors of humans are not relevant for modulating the excitability of CVM in the BJ reflex. However, since drugs and diseases can affect the responses, further studies are necessary to clarify this issue.

Effects of losartan on neuroleptic-induced catalepsy in mice.

Neuroleptic-induced catalepsy remains a useful method to study central dopaminergic function in rodents. Evidence obtained in several studies indicates that this phenomenon can be modified by cholinergic, histaminergic and serotonergic manipulation. Angiotensin II is a central neurotransmitter acting through AT1 and AT2 receptors. There are few data on the effect of angiotensinergic drugs on dopaminergic transmission. We investigated the effect of losartan, a nonpeptide antagonist of central and peripheral AT1 receptors, on neuroleptic-induced catalepsy. Adult male albino mice, 26-35 g, were used. Catalepsy was induced with haloperidol (H; 1 mg/kg, ip) and measured at 30-min intervals by means of a bar test. Losartan (10 or 100 ng/kg) or saline (control; 0.13 ml) was injected intraperitoneally 20 min before H, with each animal (7 per group) being used only once. Losartan (10 and 100 ng/kg) significantly (P < 0.05) potentiated the cataleptic effect of H in comparison to the control group (e.g. 264 +/- 26 and 299 +/- 68 sec, respectively, vs 89 +/- 24 sec for the control group, 90 min after H). No differences were demonstrable 120, 150 or 180 min after H. Considering the high selectivity and the pharmacokinetic properties of losartan, these data suggest that central angiotensin AT1 receptors play a role in neuroleptic-induced catalepsy. However, further studies are necessary to confirm this hypothesis and to clarify the mechanism(s) involved in this process.

Pressor effects elicited by stimulation within the medullary raphe nuclei of the golden hamster (Mesocricetus auratus).

The medullary raphe nuclei are involved in central autonomic regulation. In all species investigated, electrical stimulation of the raphe nuclei causes cardiovascular responses, although these changes vary between species. The present study was designed to investigate the participation of these nuclei in cardiovascular regulation in the hamster. We studied the effect on arterial blood pressure (BP) and heart rate (HR) of electrical stimulation (isolated cathodal square wave pulses for 10 sec at 100 Hz, 40-100 microA and 1-msec pulse duration) within the medullary raphe nuclei in urethane-anesthetized (1.2 g/kg, iv, after ether induction) golden hamsters (Mesocricetus auratus, 130 to 150 g, either sex). Electrical stimulation of the same sites was performed on a group of paralyzed (Flaxedil, 1 mg/kg, iv) and artificially ventilated animals. Stimulation sites were histologically defined and maps of the stimuli were obtained for the effect of electrical stimulation on arterial blood pressure. In another series of experiments L-glutamate (0.18 M) was microinjected (75 to 150 nl) into the nucleus raphe obscurus. Electrical stimulation of the raphe nuclei produced predominantly pressor responses (delta = +12 to +100 mmHg; 49.3% of the stimulated sites). Hypotension (delta = -5 to -20 mmHg; 14.6% of the stimulated sites) and no change in BP (35.3%) were evoked from fewer stimulation sites. Pressor responses were also predominant in paralyzed animals (delta = +15 to +95 mmHg; 62.5% of the stimulated sites), and after microinjection of L-glutamate into the raphe obscurus (delta = +35 to +135 mmHg). The present results demonstrate that in the hamster the stimulation of these nuclei evokes mainly pressor responses. These responses are similar to those obtained in the rat and guinea pig but opposite to those observed in the cat and rabbit.

Dorsal raphe nucleus lesions have no effect on neuroleptic-induced catalepsy and on the anticataleptic activity of buspirone.

The anxiolytic drug buspirone (BUS) and other central 5-HT-1A receptor ligands are capable of reducing neuroleptic-induced catalepsy in rodents. The dorsal raphe nucleus (DRN) is reported to be an important source of serotonergic projections to the basal ganglia, the site of neuroleptic action. The present study was designed to evaluate the participation of the DRN in the anticataleptic effect of BUS on male Wistar rats. Rats were submitted to electrolytic or sham DRN lesion under barbiturate anesthesia. Ten days later, the animals were injected with BUS (5 mg/kg, ip) or saline (1 ml, ip) and catalepsy was induced 20 min later with haloperidol (1 mg/kg, ip). Saline-injected DRN-lesioned and sham-lesioned rats displayed similar catalepsy scores and BUS significantly and similarly reduced the catalepsy scores in both groups. The results suggest that, in producing anticataleptic effects, BUS interacts at sites other than the DRN. The participation of other raphe nuclei in the anticataleptic effect of BUS is currently under investigation.

Role of the rostral ventrolateral medulla in the pressor response to stimulation of the nucleus raphe obscurus.

1. Electrical stimulation of the nucleus raphe obscurus (NRO) in urethane-anesthetized rats increases arterial blood pressure (BP) between 20 and 95 mmHg (mean, 61.14 +/- 6.57; N = 30). 2. Unilateral electrolytic destruction of the rostral ventrolateral medulla (RVLM) did not reduce BP or heart rate (HR) but significantly reduced the pressor response to NRO stimulation (control, delta 76.0 +/- 5.4 mmHg; after lesion, delta 26.0 +/- 13.9 mmHg; P < 0.01, N = 5). 3. Bilateral destruction of the RVLM reduced basal BP (control, 104.1 +/- 11.4 mmHg; after lesion, 58.0 +/- 5.7 mmHg; P < 0.01) and the pressor response to NRO stimulation (control, delta 71.6 +/- 7.3; after lesion, delta 12.5 +/- 3.8 mmHg; P < 0.01, N = 6). 4. When topically applied to or microinjected into the RVLM, pentobarbital sodium (200 nl/1 microliters, 10 nmol) decreased BP, HR and the pressor response to NRO stimulation (control, delta 56.2 +/- 6.7 mmHg; after pentobarbital, delta 11.2 +/- 3.1 mmHg; P < 0.01, N = 13). Similar effects were obtained when glycine (200 nl, 50 nmol) was microinjected into RVLM (control, delta 40.5 +/- 5.9 mmHg; after glycine, delta 18.1 +/- 4.9 mmHg; P < 0.01, N = 6). 5. We conclude that RVLM is essential for the pressor response to NRO stimulation.

5-HT2 receptor blockade by ICI 170,809 does not affect the inhibitory effect of the 5-HT1A receptor ligand gepirone on neuroleptic-induced catalepsy.

Considerable experimental evidence suggests that central dopaminergic (DA) transmission is under serotonergic (5-HTergic) modulation. For instance, neuroleptic-induced catalepsy (NIC) in rodents, a behavior mainly due to blockade of DA receptors in the striatum, can be affected by 5-HTergic manipulation. It has been shown that ligands of 5-HT1A receptors (e.g. buspirone, gepirone) reduce NIC, while 5-HT2 receptor antagonists (e.g. ritanserin) do not affect this phenomenon. However, the role of 5-HT2 receptors in the modulation of NIC is still controversial and there is evidence from behavioral models other than NIC suggesting the existence of functional interaction between the two subtypes of 5-HT receptors. The present study was designed to evaluate the effect of ICI 170,809 (a selective 5-HT2 receptor antagonist) on NIC and to test the possible effect of this drug on the anticataleptic effect of gepirone (GP). Male Wistar rats weighing 300-350 g were used, and each animal (7 per group, 4 groups) was used only once. Catalepsy was induced with haloperidol (H; 1 mg/kg, i.p.) and measured at 30-min intervals by means of a bar test. Animals received either ICI 170,809 (3 mg/kg, i.p.) or 0.9% saline (SL; 0.8 ml, i.p.) 30 min before H. At 110 min after H, the rats received GP (1 mg/kg, i.p.) or SL (0.8 ml, i.p.). GP significantly attenuated NIC (e.g. 739 +/- 106 s vs 1009 +/- 85 s for controls, at 150 min after H), while ICI 170,809 did not significantly affect the phenomenon (e.g. 978 +/-89 s vs 1009 +/- 85 s for controls, at 150 min after H). Pretreatment with ICI 170,809 did not significantly modify the anticataleptic effect of GP (e.g. 617 +/- 90 s vs 739 +/- 106 s for SL-pretreated animals, at 150 min after H). These results confirm reports of the anticataleptic effect of GP and the lack of effect of 5-HT2 receptor antagonists on NIC. Moreover, these data also suggest the absence of functional interactions between central 5-HT1A and 5-HT2 receptors in this model of DA transmission.