Interação entre as vias de sinalização de receptores serotoninérgicos e Β-adrenérgicos em artéria femoral de ratos / Interaction between serotoninergic-and β-adrenergic receptors signaling pathways in rat femoral artery / Interacción entre las vías de señalización de receptores serotoninérgicos y β-adrenégicos en la arteria femoral de ratones

FUNDAMENTO: A doença coronária tem sido amplamente estudada em pesquisas cardiovasculares. No entanto, pacientes com doença arterial periférica (DAP) têm piores resultados em comparação àqueles com doença arterial coronariana. Portanto, os estudos farmacológicos com artéria femoral são altamente relevantes para a melhor compreensão das respostas clínicas e fisiopatológicas da DAP. OBJETIVO: Avaliar as propriedades farmacológicas dos agentes contráteis e relaxantes na artéria femoral de ratos. MÉTODOS: As curvas de resposta de concentração à fenilefrina contrátil (FC) e à serotonina (5-HT) e os agentes relaxantes isoproterenol (ISO) e forskolina foram obtidos na artéria femoral de ratos isolada. Para as respostas ao relaxamento, os tecidos foram contraídos com FC ou 5-HT. RESULTADOS: A potência de classificação na artéria femoral foi de 5-HT > FC para as respostas contráteis. Em tecidos contraídos com 5-HT, as respostas de relaxamento ao isoproterenol foram praticamente abolidas em comparação aos tecidos contraídos com FC. A forskolina, um estimulante da adenilil ciclase, restaurou parcialmente a resposta de relaxamento ao ISO em tecidos contraídos com 5-HT. CONCLUSÃO: Ocorre uma interação entre as vias de sinalização dos receptores β-adrenérgicos e serotoninérgicos na artéria femoral. Além disso, esta pesquisa fornece um novo modelo para estudar as vias de sinalização serotoninérgicas em condições normais e patológicas que podem ajudar a compreender os resultados clínicos na DAP.

BACKGROUND: Coronary heart disease has been widely studied in cardiovascular research. However, patients with peripheral artery disease (PAD) have worst outcomes compared to those with coronary artery disease. Therefore, pharmacological studies using femoral artery are highly relevant for a better understanding of the pathophysiologic responses of the PAD. OBJECTIVE: The aim of this study was to evaluate the pharmacologic properties of the contractile and relaxing agents in rat femoral artery. METHODS: Concentration response curves to the contractile phenylephrine (PE) and serotonin (5-HT) and the relaxing agents isoproterenol (ISO) and forskolin were obtained in isolated rat femoral artery. For relaxing responses, tissues were precontracted with PE or 5-HT. RESULTS: The order rank potency in femoral artery was 5-HT > PE for contractile responses. In tissues precontracted with 5-HT, relaxing responses to isoproterenol was virtually abolished as compared to PE-contracted tissues. Forskolin, a stimulant of adenylyl cyclase, partially restored the relaxing response to ISO in 5-HT-precontracted tissues. CONCLUSION: An interaction between β-adrenergic- and serotoninergic- receptors signaling pathway occurs in femoral artery. Moreover, this study provides a new model to study serotoninergic signaling pathway under normal and pathological conditions which can help understanding clinical outcomes in the PAD.

FUNDAMENTO: La enfermedad coronaria ha sido ampliamente estudiada en las investigaciones cardiovasculares. Sin embargo, los pacientes con enfermedad arterial periférica (EAP), tienen los peores resultados en comparación con aquellos con la enfermedad arterial coronaria. Por tanto, los estudios farmacológicos con la arteria femoral son extremadamente importantes para obtener una mejor comprensión de las respuestas clínicas y fisiopatológicas de la EAP. OBJETIVO: Evaluar las propiedades farmacológicas de los agentes contráctiles y relajantes en la arteria femoral de los ratones. MÉTODOS: Las curvas de concentración-respuesta a los agentes conctráctiles fenilefrina (FE) y a la serotonina (5-HT) y los agentes relajantes isoproterenol (ISO) y forskolina, se obtuvieron en la arteria femoral de ratones ya aislada. Para las respuestas a la relajación, los tejidos fueron contraídos con FE o 5-HT. RESULTADOS: La potencia de clasificación en la arteria femoral fue de 5-HT > FE para las respuestas contráctiles. En los tejidos contraídos con 5-HT, las respuestas de relajación al isoproterenol fueron prácticamente eliminadas en comparación con los tejidos contraídos con FE. La forskolina, un estimulante de la adenilil ciclasa, restauró parcialmente la respuesta de relajación al ISO en los tejidos contraídos con 5-HT. CONCLUSIÓN: Ocurre una interacción entre las vías de señalización de los receptores β-adrenérgicos y serotoninérgicos en la arteria femoral. Además, esa investigación suministra un nuevo modelo para estudiar las vías de señalización serotoninérgicas en condiciones normales y patológicas que puedan ayudar a comprender los resultados clínicos en la EAP.

An inhibitory compound against the interaction between Galpha(s) and the third intracellular loop region of serotonin receptor subtype 6 (5-HT(6)) disrupts the signaling pathway of 5-HT(6)

Serotonin receptor subtype 6 (5-HT(6)) is a neurotransmitter receptor, which is involved in various brain functions such as memory and mood. It mediates signaling via the interaction with a stimulatory G-protein. Especially, the third intracellular loop (iL3) of 5-HT(6) and the alpha subunit of stimulatory G protein (Galpha(s)) are responsible for the signaling process of 5-HT(6). Chemical compounds that could inhibit the interaction between the iL3 region of 5-HT(6) and Galpha(s) were screened from a chemical library consisted of 5,600 synthetic compounds. One of the identified compounds bound to Galpha(s) and effectively blocked the interaction between Galpha(s) and the iL3 region of 5-HT(6). The identified compound was further shown to reduce the serotonin-induced accumulation of cAMP in 293T cells transformed with 5-HT(6) cDNA. It also lowered the Ca2+ efflux induced by serotonin in cells expressing 5-HT(6) and chimeric Galpha(s5/q). These results indicate that the interaction between the iL3 of 5-HT(6) and Galpha(s) can be exploited for screening of regulatory compounds against the signaling pathway of 5-HT(6).

Study of the mechanism underlying the prokinetic action of erythromycin on lower esophageal sphincter pressure in dogs

Erythromycin [EM] and a number of its derivatives exhibit prokinetic properties. In particular, the drug increases the contractile activity of smooth muscles of esophagus and promotes gastric emptying in both health and disease. The drug enhances esophageal and gastric motility by acting as a motilin agonist. The aim of the study was to evaluate the effect of low dose of EM, as a prokinetic agent, on the lower esophageal sphincter pressure [LESP] and to study the receptors involved in the mediation of the prokinetic action of EM. The study was carried out on 30 adult healthy dogs [10-15 kg] divided into five groups, each group consisted of 6 dogs. The studied groups were: I: a control group [placebo treated], II: an erythromycin treated group [EM gp] [7 mg/kg b.w. by i.v.i], and three groups III, IV, V that were treated with EM [7 mg/kg b.w. i.v.L preceded by either atropine [a muscarinic blocker] in a dose of 40 micro ag/kg b.w. i.v.i., ondansetrone [5 HT3 antagonist] in a dose of 0.1 mg/kg b.w. i.v.i or metoclopramide [dopamine receptor type 2 antagonist] in a dose of 150 micro g/kg b.w. i.v.i. respectively. After an over night fasting, basal recording of LESP was carried out in each group by an esophageal manometer connected to a pressure transducer. LESP was recorded for all animals in all groups fifteen minutes after the end of the predescribed treatments. Data obtained showed that EM significantly increased the resting LESP. Pretreatment with either atropine or ondansetrone totally prevented the increase in LESP induced by EM. However, pretreatment with metoclopramide failed to prevent the increase in LESP induced by EM. The findings suggest that EM in a low, subantimicrobial dose has a prokinetic action on the lower esophageal sphincter. It was found that this prokinetic action is exerted most probably by stimulating cholinergic pathway and strongly suggested that 5 HT3 receptors are involved in this process. Meanwhile, the dopaminergic receptors seem to have no role in the mediation of this prokinetic action of EM. It is hoped that this prokinetic action of EM could be of a particular benefit in the improvement of GIT motility disorders. However this warrants further investigation to help more understanding of cellular mechanisms regarding that effect of EM

Serotonin/dopamine interaction--focus on 5-HT2C receptor, a new target of psychotropic drugs.

Several hypotheses regarding physiopathology of major psychiatric diseases exist. Attention has been focused on cerebral monoaminergic systems, the dysfunction of which is thought to underlie various aspects of their symptomatology. There are reports describing the involvement of serotonergic and dopaminergic systems in the mechanism of action of psychotropic drugs. This article reviews current knowledge on interaction between 5-hydroxytryptamine (5-HT), acting at 5-HT2C receptors in the central dopamine (DA) systems. Since 90s, a growing body of behavioural, neurochemical and electrophysiological evidence from animal studies have demonstrated a clear role for 5-HT2C receptors in modulation of activity of dopamine neurones. This evidence has led to the suggestion that drugs acting on 5-HT2C receptors have potential as novel antipsychotic and antidepressant agents and may also be used in the treatment of other neuropsychiatric disorders such as Parkinson's disease and psychoactive substance abuse.

Strain-dependent effects of diazepam and the 5-HT2B/2C receptor antagonist SB 206553 in spontaneously hypertensive and Lewis rats tested in the elevated plus-maze

The 5-HT2B/2C receptor antagonist SB 206553 exerts anxiolytic effects in rat models of anxiety. However, these effects have been reported for standard rat strains, thus raising the issue of SB 206553 effects in rat strains displaying different levels of anxiety. Herein, the effects of SB 206553 in a 5-min elevated plus-maze test of anxiety were compared to those of the reference anxiolytic, diazepam, in two rat strains respectively displaying high (Lewis rats) and low (spontaneously hypertensive rats, SHR) anxiety. Diazepam (0.37, 0.75, or 1.5 mg/kg; 30 min before testing) increased in a dose-dependent manner the behavioral measures in SHR, but not in Lewis rats. On the other hand, SB 206553 (1.25, 2.5, or 5 mg/kg; 30 min before testing) failed to alter the anxiety parameters in both strains, whereas it increased closed arm entries in Lewis rats, suggesting that it elicited hyperactivity in the latter strain. Accordingly, the hypolocomotor effect of the nonselective 5-HT2B/2C receptor agonist m-chlorophenylpiperazine (1.5 mg/kg ip 20 min before a 15-min exposure to an activity cage) was prevented by the 1.25 and 2.5 mg/kg doses of SB 206553 in Lewis rats and SHR, respectively. Compared with SHR, Lewis rats may display a lower response to benzodiazepine-mediated effects and a more efficient control of locomotor activity by 5-HT2B/2C receptors

Serotonergic mechanism in imipramine induced antinociception in rat tail flick test.

Substantial evidence has accumulated that spinally projecting serotonergic neurons modulate nociception. However, the exact receptor subtypes that mediate the antinociceptive response of serotonin within the spinal cord continue to be a subject of debate. Therefore, we explored the effect of serotonergic system on imipramine induced antinociception by using 5-Hydroxytryptamine-3 (5HT3) receptor antagonist ondansetron and 5-Hydroxytryptamine-2 (5HT2) receptor antagonist mianserine, and depletion of brain 5-Hydroxytryptamine (5HT) with p-chlorophenyl alanine (PCPA). Male wistar strain rats were pretreated with either ondansetron (0.5 mg/kg, i.p.) or mianserine (1 mg/kg, i.p.). After 15 minutes, rats received injection of imipramine (10 mg/kg). Nociception was assessed by tail-flick method. Imipramine (2 mg, 5 mg, 10 mg, and 20 mg/kg) produce antinociceptive response in the dose dependent manner. Prior treatment with 5HT3 antagonist, Ondansetron and 5HT2 antagonist, mianserine reduce the antinociceptive response of imipramine. In PCPA treated rats imipramine (10 mg/kg) failed to produce antinociception. These results indicate that the 5HT plays an important role in imipramine induced antinociception.

Sistema serotoninérgico: receptores e respostas funcionais / Brain serotonin system: receptors and functional response

A partir da síntese da serotonina, em 1951, iniciou-se a investigaçäo farmacológica dos receptores serotoninérgicos. A estimulaçäo dos mais variados tipos de receptores gera múltiplas respostas funcionais verificadas em nível de sistema nervoso central, terminaçöes nervosas serotoninérgicos em nível metabólico e fisiopatológico

Modelado molecular de n-isopropil lisergamidas analogas al LSD, utilizando calculos de mecanica molecular y mecanica cuantica / Molecular modeling of n-isopropyl lisergamides using molecular mechanisms and quantum mechanical calculations

Molecular mechanics and quantum mechanics were used to study the preferred conformations, electron densities and frontier orbitals of d-LSD and their analogs with the isopropyl amide group, compounds with reported activity over the serotonin receptor. Electron densities and frontier orbitals for isopropyl analogs were similar to d-LSD, so these properties can not be related with the changes in biological activity previously reported. It was found that isopropyl analogs have preferred conformations similar to d-LSD with small variation in the alkylamide group. The variation in the alkylamide group causes small variations in the orientation of the carbonyl amide group, our study suggests that this variation could affect the binding with the hydrophobic region of the receptor.

Preliminary experience with use of a selective 5HT3 receptor antagonist (ondansetron) to prevent high dose chemotherapy induced emesis.

Ondansetron was used as an antiemetic along with dexamethasone during 16 cycles of highly or moderately ematogenic chemotherapy. There was major control in two cycles and complete control in the remaining 14. Side effects were minor and did not require discontinuation of the drug. This combination, therefore, appears to be safe and effective in preventing chemotherapy induced emesis.

El droperidol interactúa con receptores serotonérgicos y adrenoceptores Ó- cardiovasculares / Droperidol interactions with serotonergic and cardiovascular Ó adrenoceptors

En este trabajo se investigó si los receptores cardiovasculares de la serotonina (5-HT) son antagonizados por el droperidol. Los efectos de este fármaco sobre la vasopresión y el cronotropismo positivo obtenidos con la infusión intravenosa de noradrenalina (NA; 1 µg.kg-1.min-1), angiotensina II (1 µg.kg-1.min-1) y quipazina (100 µg.kg-1.min-1) se estudiaron en ratas desmeduladas. El droperidol (0.01 - 1 mg.kg-1,i.v.) revirtió los efectos presores de la NA y la quipazina en forma dependiente de la dosis. El pretratamiento con propranolol, bromefeniramina o atropina (1 mg.kg-1, i.v.; cada uno), no previno los efectos del neuroléptico. Por otra parte, el droperidol no modificó la respuesta presora de la angiotensina II, ni el cronotropismo de las drogas estudiadas. Se observó que los efectos inhibitorios del droperidol (DI50 141 µg/kg; LC 105-191) y de la ketanserina (Di50 110 µg/kg; LC 91-132) sobre la vasopresión de la quipazina, son similares; sin embargo, esta última no fue modificada por la prazosina. Estos resultados indican una interacción del droperidol con los reeptores vasculares 5-HT y confirman su capacidad para bloquear Ó-adrenoceptores

D-fenfluramine reduces anxiety induced by simulated public speaking

To further explore the role of serotonin (5-HT) in anxiety, 28 healthy volunteers received in a double-blind study d-fenfluramine (30 mg, p.o.) or placebo, and were submitted to a simulated public speaking test (SPS), consisting of speaking in front of a video camera. The SPS induced significant increases in subjective anxiety evaluated by the visual analogue mood scale of Norris [MANCOVA, F(1.66,39.93) = 8.51, P < 0.001], as well as in systolic blood pressure [F(3,72) = 5.70, P = 0.001] and in heart rate [F(3,72) = 3.95, P = 0.012]. The drug decreased the anxiety factor [F(1,23) = 5.21, P = 0.032], without significantly affecting physical sedation, mental sedation or other feelings and attitudes. Also, the physiological measurements were not significantly changed by d-fenfluramine. Reported evidence shows that d-fenfluramine releases 5-HT from nerve endings and blocks 5-HT reuptake, indirectly stimulating postsynaptic 5-HT receptors. Therefore, the present results indicate that 5-HT inhibits the neural substrate of SPS-induced anxiety

Thyrotropin releasing hormone-induced potentiation of spinal monosynaptic reflex in rats in vitro.

Superfusion of thyrotropin-releasing hormone (TRH) in neonatal rat spinal cord in vitro produced dose (0.01-1.00 microM) dependent potentiation of monosynaptic reflex (MSR) which was maximum (44% of control) at 1 microM of TRH. But no ventral root depolarization was observed with TRH (1 microM) although potassium concentration out side ([K+]0) when increased produced a depolarization at the magnitude of 0.2 mV/mM of [K+]0. TRH-induced potentiation of MSR was not altered in spinal cords, obtained from the animals pretreated with 5,7-dihydroxytryptamine or 6-hydroxydopamine. Neither serotonin antagonists (spiperone, ketanserin, cyproheptadine or 3-troponyl-indole-3-carboxylate) nor adrenergic antagonists (phentolamine or haloperidol) could attenuate TRH-induced potentiation. Inhibition of MSR observed in the spinal cord elicited by stimulating the adjacent dorsal root was unaffected by TRH. The results suggest that, TRH potentiates MSR by directly acting on the motoneurons, without involving presynaptic serotonergic or catecholaminergic neuronal systems or the disinhibition of pre- or post-synaptic inhibition in the spinal cord.

Cortical and septal responses to dorsal raphe nucleus stimulation in the rat: long-term clomipramine actions

En la corteza cerebral y en el núcleo septal lateral coexisten diferentes subtipos de receptores serotoninérgicos. Así, se puede esperar una acción diferente sobre la descarga neuronal dependiendo del receptor activado. La estimulación del núcleo del rafé dorsal produce un aumento en la frecuencia de descarga en la capa cortical V, y en el núcleo septal lateral. Sin embargo, la frecuencia de descarga permanece sin modificarse en la capa cortical VI posterior a la estimulación del núcleo del refé dorsal. La clomipramina es un tricíclico que ejerce sus principales efectos sobre receptores serotoninérgicos y el tratamiento a largo plazo con este antidepresivo produce un aumento selectivo en la frecuencia de descarga de las neuronas septales laterales, pero no en las neuronas corticales. Desde el punto de vista electrofisiológico se concluye que las acciones excitatorias sobre la frecuencia de descarga evocadas por la estimulación del núcleo del rafé dorsal o por tratamiento con clomipramina son mediadas por la activación del subtipo de receptores 5-HT2 que pudiera actuar como un modulador 5-HT1A en los sitios donde coexisten ambos subtipos de receptores.

In vitro study of rat uterus after chronic formaldehyde exposure.

To measure cholinergic, adrenergic and tryptaminergic receptor activity of formaldehyde (HCHO) in rat uterus, albino rats were treated with 5 and 10 mg/kg, ip HCHO for 30 days. Acetylcholine (ACh) in doses 1.33, 2 and 3 micrograms/ml produced mild to moderate contraction of isolated rat uterus in control group. HCHO had no effect on isolated rat uterus per se, however it reduced ACh and carbachol induced contraction and presence of adrenaline influences in respect of ACh and carbachol activity. Adrenaline per se had no effect in control preparations, but reduced carbachol induced contraction. Propranolol had no effect on rat uterus; but its presence in the bathing medium increased activity of adrenaline. 5-Hydroxytryptamine (5-HT) had no effect of its own on isolated rat uterus but its presence in the bathing medium enhanced contractions of carbachol and oxytocin.

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 score 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

Effect of central administration of serotoninergic agonists on electrolyte excretion control

The participation of different central serotoninergic (5HT) receptors in the mediation of Na+ excretion (UNaV), K+ excretion (UKV) and urine output (UV) was evaluated. Male wistar rats weighing 220-280 g were used in each group of 9-18 animals. The rats were injected intracerebroventricularly (icv) with the 5 HT agonists MK212 (1.5, 15.0 and 30.0 *g), 8-OH-DPAT (5.0 and 15.0 *g) 5HT (2.5, 12.5 and 25.0 *g) and DOI (10.0 and 25.0 *g). At the lowest MK212 dose, UNaV was significantly reduced (0.18 ñ 0.04 *Eq/min vs 0.35 ñ 0.04 *Eq/min for saline) at 20 min. At the highest dose, MK212 provoked a significant increase in UNaV (0.60 ñ 0.06 *Eq/min vs 0.34 ñ 0.03 *Eq/min for saline) at 40 min UKV values were significantly modified only at the 1.5-*g dose (0.18 ñ 0.04 *Eq/min vs 0.04 *Eq/min for saline) at 20 min. Icv injection of 8-OH-DPAT provoked a significant reduction in UNaV (0.16 ñ 0.05 *Eq/min vs 0.35 ñ 0.03 Eq/min for saline) and UKV (0.15 ñ0.05 *Eq/min vs 0.34 * ñ 0.02 *Eq?min for saline) at 40 min at both doses. Icv injection of 5HT at the highest dose provoked a signficant increase in UNaV (0.92 ñ 0.10 *Eq/min vs 0.33 ñ 0.04 *Eq/min for saline) and in UKV (0.55 ñ 0.08 *Eq/min vs 0.24 ñ 0.07 *Eq/min for saline) at 40 min. Icv administration of DOT caused a natriuretic response (0.69 ñ 0.12 *Eq/min vs 0.31 ñ 0.04 *Eq/min for saline) at 40 min, with no significant effect on UKV. All the 5HT agonists induced a rapid antidiuretic response (35 to 75% below control levels), which was notably more intense and longer lasting at the highest 8-OH-DPAT dose. The results appear to indicate the involvement of both receptor families (5HT2) in the expression of the antidiuretic response. The present evidence indicates an opposite participation of the different receptor families in elicing the antinatriuretic (5HT1) and natriuretic (5HT2) responses

Excitatory and inhibitory behavioral responses to the pharmacological stimulation of serotonergic function in dorsalis raphe lesioned rats

La lesion de neuronas 5-HT median te neurotoxinas induce supersensibilidad de receptores 5-HT1 sin afectar el "binding" de receptores 5-HT2. Este modelo fue utilizado en el presente trabajo para analizar el papel de ambos subtipos de receptores 5-HT en el mecanismo de control de las respuestas comportamentales excitatorias e inhibitorias provocadas por la estimulación farmacológica del sistema 5-HT. Las lesiones del rafe dorsales (RD) fueron hechas mediante inyección estereotáxica de ác. kaínico. Treinta días después las ratas RD y sus controles mostraron una actividad basal similar en "testes" de "hole board". Tres días después las ratas RD y sus controles fueron inyectadas ip con fluoxetina (5 y 10 mg/Kg) y 30 m después con 50HTP (15 y 30 mg/Kg). Imediatamente antes y después de cada inyección ip la respuesta excitatoria (síndrome mioclónico) fue evaluada. Las ratas RD y sus controles mostraron similares valores de mioclonías en respuesta a fluoxetina-5-HTP. La respuesta inhibitoria fue investigada en sesiones de "holeboard" a los 30 m de la segunda inyección ip. La lesión del RD potenció el efecto depresor de fluoxetina-5-HTP sobre el comportamiento. En concordancia con la literatura, la lesión del RD produjo una caída del 74.9% de la 5-HT del cerebro anterior y un incremento del 75% en el "bilding" de 3H-5HT en membranas corticales. En conclusión, los componentes de la respuesta excitatoria, que no se modificó por la lesión del RD, estarían relacionados principalmente con receptores 5-HT2. El aumento de la respuesta inhibitoria a la estimulación 5-HT observado en las rata lesionadas en RD estaría vinculado a la supersensibilidad de receptores 5-HT1

Effect of restraint stress on cannabis-induced catalepsy in rats.

The effect of restraint stress (1, 2 and 4 hr) on cannabis-induced catalepsy, was investigated in rats. Restraint stress produced a time-related-potentiation of the cataleptic effect of a sub-cataleptic dose of cannabis. Stress (4 hr)-induced potentiation of cannabis catalepsy was attenuated after pretreatment of the animals with drugs known to decrease central 5-HT and prostaglandin activity, but was unaffected by metyrapone, an inhibitor of endogenous corticoid synthesis. The results suggest the involvement of 5-HT and prostaglandins in restraint stress-cannabis interaction. The results have been discussed in the light of earlier investigations, from this laboratory, indicating increased rat brain 5-HT and prostaglandin activity, following restraint stress, and possible 5-HT mediation in central effects of prostaglandins. It is suggested that restraint stress first enhances rat brain prostaglandins, which in its proposed role as the first mediator' of stress, activates the serotonergic system in this species. This prostaglandin 5-HT link, thus mediates the observed potentiating effect of restraint stress on cannabis catalepsy.