- Email: [email protected]
Differential modulation of alpha-2-adrenoceptor subtypes by chronic antidepressant drugs
BEHAVIORAL A N D BIOCHENICAL EVIDENCES 01~ ANTIDEPRESSIVE ACTIVITY OF PINEAL NELATONIN i~.B. Arushanlan ,A.E. Arushanian ,K. S .Elbekian ~ o v ~edical Academy, ~ira str.310 355014 Stavropol, Russia
DIFFERENTIAL MODULATION OF ALPHA-2ADRENOCEPTOR SUBTYPES BY CHRONIC ANTIDEPRESSANT DRUGS L,F. Callado, J.J. Meana, A.M. Gabilondo. Department of Pharmacology, University of the Basque Country (UPV/EHU), E-48940 Leioa, Bizkaia, Spain.
In the recent years sedative and hypnotic properties of the melatonin which was released as a hormone from pineal gland have been described. As shown in three se" ties of our experiments on rats, it induce also an antidepressive effect. Melatonin (0,I mg/kg i.p.,]0 days) reorganized time course of forced swimming and decreased the rhythmological index of depression. On the contrary,after pinealectomy(PX) or administration of reserpine(1 mg/kg) it increased significantly. The reserpine depressogenic effect was intensified in PX animals, but was attenuated by melatonin. After REM sleep deprivation reorganization of time course of swimming with a decreased index of depression was observed. PX attenuated this behavioral shift unsignificantly and melatonin potentiated it. As in depressive patients, after reserpine administration plasma corticosterone level increased. Such endocrine response was intensified in PX rats and was limited by melatonin. These results suggest that pineal compounds(first of all melatonin) induces an antidepressive effect probably limiting some chronobiological disturbances.
In vitro studies suggest a subtype-selective desensitization of ct2adrenoceptors (~2) after the exposure to endogenous agonists. The [3H]RX821002(2-methoxy-idazoxan) binding to rat kidney m e m b r a n e s and c o m p e t i t i o n curves b y ( - ) a d r e n a l i n e , ARC239*(a2B/C-selective) and BRL44408**(a2A-selective) were evaluated after saline, desipramine (10 mg/kg x 2 x 7 days) or clorgyline (2mg/kg x 21 days) treatment. After desipramine, the competition curve of (-)adrenaline was shifted to the right (F[1,32]=76.1;p<0.001) whereas the competition curve was shifted to the left by clorgyline treatment (F[1,32]=17.4;p<0.001), The high-affinity c o m p o n e n t of ARC239 curves (Ct2B) was placed far to the left after desipramine (F[1,32]=4.37;p<0.05) or clorgyline (F[1,32]=8.84;p<0.01) treatment. The c o m p e t i t i o n curves by B R L 4 4 4 0 8 after desipramine were located to the right in the high-affinity component (~2A) (F[1,28]=15.7;p<0.001) and to the left in the low-affinity component (~2B) (F[1,28]=8.63;p<0.01) whereas in clorgyline group BRL4A.A.98 curves were aligned to the control group. The results indicate that desipramine induces a pronounced loss of affinity of the a2A together with a rise of the Ct2B in rat kidney. In contrast, clorgyline promotes in the same tissue an enhancement of affinity of the Ct2B. *ARC239 (2-[2-[4-(o-methoxyphenyl)-pipemzin-1-yl]-ethyl]-4,4-dimethyl1,3 (2H,4H)4soquinolindione); **BRL44408=2-[2H-(1-methyl-l,3dihydroisoindole)methyl]4,5-dihydroimidazole.
EFFECT OF Ca?+ IONS ON THE INHIBITION OF HISTAMINE AND SEROTONIN RELEASE CAUSED BY TRICYCLIC ANTIDEPRESSANTS. Ilonka Ferian, F. Erjavec Department of Pharmacology, Medical Faculty, Korytk0va 2, 61105 Ljubljana, Slovenia
ANTIDEPRESSANT EFFECTS OF BUSPIRONE IN A N E W M O D E L O F D E P R E S S I O N I N D U C E D BY SYSTEMIC 1-METHYL-4-PHENYL-1,2,5,6TETRAHYDROPYRIDINE (MPTP) ADMINISTRATION IN RATS N..A.Knlp_'ma.:,, I . N . O r l o v a , T . E . l o r d a n s k a y a , G . N . Kryzihemovsky Institute of General Pathology and Pathophysiology, R u s s i a n A c a d e m y o f M e d i c a l Sciences, 8 B a l t i y s k a y a Str. 125315 M o s c o w , R u s s i a
Supported by CICYT (SAF93/0459) and Basque Government (PI91/18). LFC was a recipient of a fellowship from Basque Government.
Tricyclic antidepressant amitryptiline inhil~s the release of histamine and serotonin (5-HT) induced by compound ,~/80 from rat peritoneal mast cells. The inhibition could be explained eithdr by an inhibitory effect of antidepressant on the release of both amines (1) or by a diffusion of amines back into mast cells after the secretion (2). Extracellular Ca2+ions could influence the mechanism of histamine and 5-HT secretion or Couldstabilize membrane permeability of mast cells and thus modify diffusion of released amines back into mast cells. Therefore, in our present work the mechanism of action of different antidepressants (amitryptiline, clomipramine) on histamine and 5-HT release was studied in the presence or in the absence of extracellular Ca2~ ions. Our results show: 1) antidepressants (amitryptiline, clomipramine) (>10"5mol/l) inhibit histamine and 5-HT release from rat mast cells in the presence or in the absence of extraceUular Ca2÷ions, 2) the inhibition is more pronounced in Ca2+-freemedium, 3) the percentage of released histamine and 5-HT is not changed between 1 and 30 minutes after the secretion. In c o n c l u s i o n : our findings indicate that the percentage of histamine and 5-HT in the medium is not changed during time of incubation after the secretion. This shows that the inhibition of the amines release is not due to diffusion of released amines back into mast cells. The inhibitory effect of antidepressantson the secretion of the amines could therefore be explained by the interference of antidepressants with Ca2+-bindingsites on mast cell membrane. This influences intracellular concentration of free Ca2+ions and thus the secretory mechanism of mast cells. References: 1) Theoharides T.C., Bondy P.K., Tsakalos N.D., Askenase 1a W ,Nature 297~229-231 (1982). 2) Purcell W.M., Cohen D.L., Han~ihoe T.H.p., Int Arch Allergy Appl Immunol 9~ 387-394 (1989).
--
Effects o f b u s p i r o n e , a p a r t i a l 5-HTIA a g o n i s t a n d a pat~iai Eh r e c e p t o r a g o n i s t l a n t a g o n i s t , were s t u d i e d usialg a n e w m o d e l o f a depression-like M P T P - i n d u e e d s y n d r o m e ha rats. P r e l i m i n a r y b u s p i r o n e a d m i n i s t r a t i o n (i mg/kg i n t r a p e r i t o n e a l l y ) 45-60 m i n u t e s before M P T P (20 m g / k g i n t r a p e r i t o n e a l l y ) daffy for 12 consecutive days p r e v e n t e d o r l o o s e n e d the d e v e l o p m e n t o f the signs o f M P T P - i n d u c e d d e p r e s s i o n i n rats n a m e l y : p r e v e n t e d decrease o f daily l i q u i d c o n s u m p t i o n , r e d u c e d l o w e r i n g o f preference for the sucrose over w a t e r a n d , to a less extent, r e d u c e d increase o f i n u n o b i l i t y t i m e in forced s w i m m i n g test b u t d i d n ' t influence o n decrease o f l o c o m o t i o n a n d i n v e s t i g a t i o n in depressed rats. It is supposed that b u s p h ' o n e ' s effect o n behavioral d e p r e s s i o n in rats is d u e to its i n t e r a c t i o n with p r e s y n a p t i c 5 - H ' r l A receptors o f d o r s a l r a p h e afferents m o d u l a t i n g the activity o f n i g r o s t r i a t a l d o p a m i n e system,
281
--
DIFFERENTIAL MODULATION OF ALPHA-2ADRENOCEPTOR SUBTYPES BY CHRONIC ANTIDEPRESSANT DRUGS L,F. Callado, J.J. Meana, A.M. Gabilondo. Department of Pharmacology, University of the Basque Country (UPV/EHU), E-48940 Leioa, Bizkaia, Spain.
In the recent years sedative and hypnotic properties of the melatonin which was released as a hormone from pineal gland have been described. As shown in three se" ties of our experiments on rats, it induce also an antidepressive effect. Melatonin (0,I mg/kg i.p.,]0 days) reorganized time course of forced swimming and decreased the rhythmological index of depression. On the contrary,after pinealectomy(PX) or administration of reserpine(1 mg/kg) it increased significantly. The reserpine depressogenic effect was intensified in PX animals, but was attenuated by melatonin. After REM sleep deprivation reorganization of time course of swimming with a decreased index of depression was observed. PX attenuated this behavioral shift unsignificantly and melatonin potentiated it. As in depressive patients, after reserpine administration plasma corticosterone level increased. Such endocrine response was intensified in PX rats and was limited by melatonin. These results suggest that pineal compounds(first of all melatonin) induces an antidepressive effect probably limiting some chronobiological disturbances.
In vitro studies suggest a subtype-selective desensitization of ct2adrenoceptors (~2) after the exposure to endogenous agonists. The [3H]RX821002(2-methoxy-idazoxan) binding to rat kidney m e m b r a n e s and c o m p e t i t i o n curves b y ( - ) a d r e n a l i n e , ARC239*(a2B/C-selective) and BRL44408**(a2A-selective) were evaluated after saline, desipramine (10 mg/kg x 2 x 7 days) or clorgyline (2mg/kg x 21 days) treatment. After desipramine, the competition curve of (-)adrenaline was shifted to the right (F[1,32]=76.1;p<0.001) whereas the competition curve was shifted to the left by clorgyline treatment (F[1,32]=17.4;p<0.001), The high-affinity c o m p o n e n t of ARC239 curves (Ct2B) was placed far to the left after desipramine (F[1,32]=4.37;p<0.05) or clorgyline (F[1,32]=8.84;p<0.01) treatment. The c o m p e t i t i o n curves by B R L 4 4 4 0 8 after desipramine were located to the right in the high-affinity component (~2A) (F[1,28]=15.7;p<0.001) and to the left in the low-affinity component (~2B) (F[1,28]=8.63;p<0.01) whereas in clorgyline group BRL4A.A.98 curves were aligned to the control group. The results indicate that desipramine induces a pronounced loss of affinity of the a2A together with a rise of the Ct2B in rat kidney. In contrast, clorgyline promotes in the same tissue an enhancement of affinity of the Ct2B. *ARC239 (2-[2-[4-(o-methoxyphenyl)-pipemzin-1-yl]-ethyl]-4,4-dimethyl1,3 (2H,4H)4soquinolindione); **BRL44408=2-[2H-(1-methyl-l,3dihydroisoindole)methyl]4,5-dihydroimidazole.
EFFECT OF Ca?+ IONS ON THE INHIBITION OF HISTAMINE AND SEROTONIN RELEASE CAUSED BY TRICYCLIC ANTIDEPRESSANTS. Ilonka Ferian, F. Erjavec Department of Pharmacology, Medical Faculty, Korytk0va 2, 61105 Ljubljana, Slovenia
ANTIDEPRESSANT EFFECTS OF BUSPIRONE IN A N E W M O D E L O F D E P R E S S I O N I N D U C E D BY SYSTEMIC 1-METHYL-4-PHENYL-1,2,5,6TETRAHYDROPYRIDINE (MPTP) ADMINISTRATION IN RATS N..A.Knlp_'ma.:,, I . N . O r l o v a , T . E . l o r d a n s k a y a , G . N . Kryzihemovsky Institute of General Pathology and Pathophysiology, R u s s i a n A c a d e m y o f M e d i c a l Sciences, 8 B a l t i y s k a y a Str. 125315 M o s c o w , R u s s i a
Supported by CICYT (SAF93/0459) and Basque Government (PI91/18). LFC was a recipient of a fellowship from Basque Government.
Tricyclic antidepressant amitryptiline inhil~s the release of histamine and serotonin (5-HT) induced by compound ,~/80 from rat peritoneal mast cells. The inhibition could be explained eithdr by an inhibitory effect of antidepressant on the release of both amines (1) or by a diffusion of amines back into mast cells after the secretion (2). Extracellular Ca2+ions could influence the mechanism of histamine and 5-HT secretion or Couldstabilize membrane permeability of mast cells and thus modify diffusion of released amines back into mast cells. Therefore, in our present work the mechanism of action of different antidepressants (amitryptiline, clomipramine) on histamine and 5-HT release was studied in the presence or in the absence of extracellular Ca2~ ions. Our results show: 1) antidepressants (amitryptiline, clomipramine) (>10"5mol/l) inhibit histamine and 5-HT release from rat mast cells in the presence or in the absence of extraceUular Ca2÷ions, 2) the inhibition is more pronounced in Ca2+-freemedium, 3) the percentage of released histamine and 5-HT is not changed between 1 and 30 minutes after the secretion. In c o n c l u s i o n : our findings indicate that the percentage of histamine and 5-HT in the medium is not changed during time of incubation after the secretion. This shows that the inhibition of the amines release is not due to diffusion of released amines back into mast cells. The inhibitory effect of antidepressantson the secretion of the amines could therefore be explained by the interference of antidepressants with Ca2+-bindingsites on mast cell membrane. This influences intracellular concentration of free Ca2+ions and thus the secretory mechanism of mast cells. References: 1) Theoharides T.C., Bondy P.K., Tsakalos N.D., Askenase 1a W ,Nature 297~229-231 (1982). 2) Purcell W.M., Cohen D.L., Han~ihoe T.H.p., Int Arch Allergy Appl Immunol 9~ 387-394 (1989).
--
Effects o f b u s p i r o n e , a p a r t i a l 5-HTIA a g o n i s t a n d a pat~iai Eh r e c e p t o r a g o n i s t l a n t a g o n i s t , were s t u d i e d usialg a n e w m o d e l o f a depression-like M P T P - i n d u e e d s y n d r o m e ha rats. P r e l i m i n a r y b u s p i r o n e a d m i n i s t r a t i o n (i mg/kg i n t r a p e r i t o n e a l l y ) 45-60 m i n u t e s before M P T P (20 m g / k g i n t r a p e r i t o n e a l l y ) daffy for 12 consecutive days p r e v e n t e d o r l o o s e n e d the d e v e l o p m e n t o f the signs o f M P T P - i n d u c e d d e p r e s s i o n i n rats n a m e l y : p r e v e n t e d decrease o f daily l i q u i d c o n s u m p t i o n , r e d u c e d l o w e r i n g o f preference for the sucrose over w a t e r a n d , to a less extent, r e d u c e d increase o f i n u n o b i l i t y t i m e in forced s w i m m i n g test b u t d i d n ' t influence o n decrease o f l o c o m o t i o n a n d i n v e s t i g a t i o n in depressed rats. It is supposed that b u s p h ' o n e ' s effect o n behavioral d e p r e s s i o n in rats is d u e to its i n t e r a c t i o n with p r e s y n a p t i c 5 - H ' r l A receptors o f d o r s a l r a p h e afferents m o d u l a t i n g the activity o f n i g r o s t r i a t a l d o p a m i n e system,
281
--