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Chronic antidepressants and GABA synapses
0028-3908;84 53.00 + 0.00 Pergamon Press Ltd
CHRONIC
ANTIDEPRESSANTS
AND GABA SYNAPSES
K.C. Lloyd and A. Pile (1) L.E.R.S
- SYNTHET,ABO, 31 Awe P V. Couturier, 92220 BAGNEUX - FRANSE Address : Department of Neurobiology, of Texas Medical School, ~~OUSTON, TX ,U S.A.
(1) Present University
Desipramine, amitryptyline, viloxazine, citalopram and pargyline were administered either acutely or chronically (18 days) to rats Chronic, but not acute, treatment resulted in a significant increase in 'H-GABA "B" binding (Bmax effect) for all compounds. Acute or chronic administration was without effect on GABA levels, glutarnic acid decarboxylase activity or ?H-GABA "A" receptor binding. These results strongly support a GARAergic contribution to the action of antidepressant drugs. In the different hypotheses oE the biochemical pathology of depression, and/or the mechanism acid (GABA), a major inhibitory neuroof action of antidepressant drugs, gamma-aminobutyric to affective 'II-transmitter, has not been studied In any depth and the data linking GABA ncss 3s very limited. Plasma and cerebrospinal fluid GARA levels are reportedly reduced in A’ I+ “‘3 i‘CrSpnii 1-,$ n--i- : 1Oq?3.dcoressed IlatFcnts (Bcrr,:tt:+ the following drug solutions : saline, amitryptyline viloxazine (10 me/kg/day), desipramine (5 mg/kg/day) or pargyline ('20 mg/kg/day). Animalswere killed 4 h after the removal of the minipumps (18 day-implantation). After decapitation the brains were immediately removed, dissected and stored at --80°C. Only the data for the frontal cortex will be reported here. The follot+ing assays were performed : 'H-GAB.4 "A" receptor biv 1977); 3H-GABA "8" receptor binding (Hill and Bowery , ding (Lloyd, Shenen and Hornykiewicz, i981), GAEA levels (Bohlen, Schechter, van Damme, Coquillat, Dosch and Koch-Weser , 1978 ). and L-glutamic acid decarboxylase (GAD) activity (Lloyd, MohLer, Heitz and Bartholini.1975) ?H-nipecotic acid binding to the GABA uptake recognition site (Lloyd and Vargas, 1982). (pargyline not tested: or 3F!-CAD? Bone of the treatments significantly altered GAD activity "A" receptor binding in the frontal cortex. GABA levels were enhanced by desipramine(38%)cira!opram (46%) and viloxazine (48%) but these changes were not statistically significantprobably due to the small number of animals used. After 18 days of continuous administration all compounds significantly enhanced 3H-CABAbinding to GABA "B" receptors in the frontal cortex. At 10 nM 3H-GABA the results were: acjltrgptyline = 155% control (p (0.01); desipramine : 151% control (p (0.05); citalopram = 173%control (p < 0.01): vlloxazine : 189% control (p (0.01); pargyline = 142% control (p (O.O5).After a single (intraperitoneal) administration, only viloxazine (136X control, p ~0.05) enhanced GABA "E" binding Upon Scatchard analysis these changes in the chronically treatpd animals ~*'aferelated to changes in Bmax rather than Kd values. Thus, Kd values were43.9 -6.7 nPl(n-3) for saline-tre;ied rats, snd+varied from 37.9 to 54.6 nM in the drug treatment groups, ;ncontrast Bmax values were 1269 - 113 fnol/mg protein in saline--treated rats and saried from1758 to 2112 fmol/mg protein in drug-treated animals. The binding of 'H-nipecotic acid (1 fluM),which labels GABA uptake recognition sites (Lioyd and Vargas, 1982), was significantly enhanced in the frontal cortex only after :hror.ic viloxazine (1603 control, ~(0.01) and citalopram (169X control, p< O.Ol), but not after amitryptylino (104% control) or desipramine, (104% control). "H-nipecotic acid bindingwas unaltered by a single administration of any of the com>cunds studied. However, preliminary results indicate that 'H-nipecotic acid binding in the hippocampus and amygdala, is increasedby all of tne antidepressants tested. This latter effect. appears to be related to a proconvulsant activity of the compounds, rather than their ant'd-*~--~~,~nt .C_-'uI)C. action (P?lc and Lloyd, unpublis!:ed results). ‘~‘lius, of the pzrnmnters which reflect GABA synaptic activity in the rat frontal cortex, the 841
842
K. G. LLOYU and A. Pnc
GABA "B" binding site appears to be selectively responsive to prolonged antidepressant administration, a consistant finding with 4 different clinically used compounds and a monoamine oxydase Inhibitor. Another psychotropic compound, haloperidol, does not produce such changes These findings suggest that GABAergic mechanisms may be important for antidepressant drug action and may provide a link between the GABA and monoamine hypotheses ofdepression asreports indicate that GABA "B" receptors are located on central noradrenergic nerve terminals ( Hill and Bowery, 1981; Karbon, Duman and dnna, 1983; Arbilla and Langer, unpublished results). References Berrettini, W.H., Nurnberger, J.I., Hare, T.A., Simmons-Ailing, S. Gershon, E.S. and Post, R.M. (1983). Reduced plasma y-aminobutyric acid in affective illness : effect oflithiumcarbonate. Biol. Psychiat. 18 : 185-194. Bohlen, P., Schechter, P.J., van Damme, W., Coquillat, G., Dosch,J.C. andKoch-Weser, 5.(1978) Automated assay of y-aminobutyric acid in human cerebrospinal fluid. Clin. Chem. 24 : 256 260. Emrich, H.M., Zerssen, D.V., Kissling, W., Mohler, H.J. and Windorder, A. (1980). Effect of sodium valproate on mania : The GABA-hypothesis of affective disorders. Arch. Psychiat.Ner_ venkr. 229 : 1-16. Hill, D.R. and Bowery, N. (1981) 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA sites in rat brain. Nature. 290 : 149-152. KarbEn, E.W., Duman, R. and Enna, S.J. (1983). Biochemical identi~fication ofmultiple GABAB binding sites : association with noradrenergic terminals in rat forebrain. Brain Res. 274 : 393-396. Lloyd, K.G. and Vargas, F. (1982) 3H-nipecotic acid binding: Identification of CABA uptake sites in frozen tissue. In : Problems in GABA Research (Okada, Y. and Roberts, E Eds), PP. 355-365. Excerpta Medica, Amsterdam. Lloyd, K.G., Mohler, H., Hertz, Ph. and Bartholini, G. (1975). Distribution of choline acetyltransferase and glutamate decarhoxylase vthin the suhstnnt:? nigrn .~nd other bra;? regions from control and Parkinsonian patients. _:.__ J Neurochem. 25 : 789-795. Lloyd, K.G., Shemen, L. and Hornykiewicz, 0. (1977). Distribution of high affinity sodiumindependent (3H) gamma-aminobutyric acid c3H-GABA) binding in the human brain: Alterations in Parkinson's disease, Brain Res. 127 : 269-278 Lloyd, K.G., Morselli, P.L., Depoortere, H., Fournier, V., Zivkovic, B., Scatton, B., Broekkamp, C., Worms, P. and Bartholini, G. (1983). The potential use of GABA agonistsin psychiatric disorders : Evidence from studies with progabide in animals and clinical trials. Pharmacol. Biochem. Behav. 18 : 957-966, Sherman, A.D. and Petty, F. (1982). Additivity of neurochemical changes in learned helplessness and imipramine. Behav. Neural. Biol. 35 : 344-353
CHRONIC
ANTIDEPRESSANTS
AND GABA SYNAPSES
K.C. Lloyd and A. Pile (1) L.E.R.S
- SYNTHET,ABO, 31 Awe P V. Couturier, 92220 BAGNEUX - FRANSE Address : Department of Neurobiology, of Texas Medical School, ~~OUSTON, TX ,U S.A.
(1) Present University
Desipramine, amitryptyline, viloxazine, citalopram and pargyline were administered either acutely or chronically (18 days) to rats Chronic, but not acute, treatment resulted in a significant increase in 'H-GABA "B" binding (Bmax effect) for all compounds. Acute or chronic administration was without effect on GABA levels, glutarnic acid decarboxylase activity or ?H-GABA "A" receptor binding. These results strongly support a GARAergic contribution to the action of antidepressant drugs. In the different hypotheses oE the biochemical pathology of depression, and/or the mechanism acid (GABA), a major inhibitory neuroof action of antidepressant drugs, gamma-aminobutyric to affective 'II-transmitter, has not been studied In any depth and the data linking GABA ncss 3s very limited. Plasma and cerebrospinal fluid GARA levels are reportedly reduced in A’ I+ “‘3 i‘CrSpnii 1-,$ n--i- : 1Oq?3.dcoressed IlatFcnts (Bcrr,:tt:+ the following drug solutions : saline, amitryptyline viloxazine (10 me/kg/day), desipramine (5 mg/kg/day) or pargyline ('20 mg/kg/day). Animalswere killed 4 h after the removal of the minipumps (18 day-implantation). After decapitation the brains were immediately removed, dissected and stored at --80°C. Only the data for the frontal cortex will be reported here. The follot+ing assays were performed : 'H-GAB.4 "A" receptor biv 1977); 3H-GABA "8" receptor binding (Hill and Bowery , ding (Lloyd, Shenen and Hornykiewicz, i981), GAEA levels (Bohlen, Schechter, van Damme, Coquillat, Dosch and Koch-Weser , 1978 ). and L-glutamic acid decarboxylase (GAD) activity (Lloyd, MohLer, Heitz and Bartholini.1975) ?H-nipecotic acid binding to the GABA uptake recognition site (Lloyd and Vargas, 1982). (pargyline not tested: or 3F!-CAD? Bone of the treatments significantly altered GAD activity "A" receptor binding in the frontal cortex. GABA levels were enhanced by desipramine(38%)cira!opram (46%) and viloxazine (48%) but these changes were not statistically significantprobably due to the small number of animals used. After 18 days of continuous administration all compounds significantly enhanced 3H-CABAbinding to GABA "B" receptors in the frontal cortex. At 10 nM 3H-GABA the results were: acjltrgptyline = 155% control (p (0.01); desipramine : 151% control (p (0.05); citalopram = 173%control (p < 0.01): vlloxazine : 189% control (p (0.01); pargyline = 142% control (p (O.O5).After a single (intraperitoneal) administration, only viloxazine (136X control, p ~0.05) enhanced GABA "E" binding Upon Scatchard analysis these changes in the chronically treatpd animals ~*'aferelated to changes in Bmax rather than Kd values. Thus, Kd values were43.9 -6.7 nPl(n-3) for saline-tre;ied rats, snd+varied from 37.9 to 54.6 nM in the drug treatment groups, ;ncontrast Bmax values were 1269 - 113 fnol/mg protein in saline--treated rats and saried from1758 to 2112 fmol/mg protein in drug-treated animals. The binding of 'H-nipecotic acid (1 fluM),which labels GABA uptake recognition sites (Lioyd and Vargas, 1982), was significantly enhanced in the frontal cortex only after :hror.ic viloxazine (1603 control, ~(0.01) and citalopram (169X control, p< O.Ol), but not after amitryptylino (104% control) or desipramine, (104% control). "H-nipecotic acid bindingwas unaltered by a single administration of any of the com>cunds studied. However, preliminary results indicate that 'H-nipecotic acid binding in the hippocampus and amygdala, is increasedby all of tne antidepressants tested. This latter effect. appears to be related to a proconvulsant activity of the compounds, rather than their ant'd-*~--~~,~nt .C_-'uI)C. action (P?lc and Lloyd, unpublis!:ed results). ‘~‘lius, of the pzrnmnters which reflect GABA synaptic activity in the rat frontal cortex, the 841
842
K. G. LLOYU and A. Pnc
GABA "B" binding site appears to be selectively responsive to prolonged antidepressant administration, a consistant finding with 4 different clinically used compounds and a monoamine oxydase Inhibitor. Another psychotropic compound, haloperidol, does not produce such changes These findings suggest that GABAergic mechanisms may be important for antidepressant drug action and may provide a link between the GABA and monoamine hypotheses ofdepression asreports indicate that GABA "B" receptors are located on central noradrenergic nerve terminals ( Hill and Bowery, 1981; Karbon, Duman and dnna, 1983; Arbilla and Langer, unpublished results). References Berrettini, W.H., Nurnberger, J.I., Hare, T.A., Simmons-Ailing, S. Gershon, E.S. and Post, R.M. (1983). Reduced plasma y-aminobutyric acid in affective illness : effect oflithiumcarbonate. Biol. Psychiat. 18 : 185-194. Bohlen, P., Schechter, P.J., van Damme, W., Coquillat, G., Dosch,J.C. andKoch-Weser, 5.(1978) Automated assay of y-aminobutyric acid in human cerebrospinal fluid. Clin. Chem. 24 : 256 260. Emrich, H.M., Zerssen, D.V., Kissling, W., Mohler, H.J. and Windorder, A. (1980). Effect of sodium valproate on mania : The GABA-hypothesis of affective disorders. Arch. Psychiat.Ner_ venkr. 229 : 1-16. Hill, D.R. and Bowery, N. (1981) 3H-baclofen and 3H-GABA bind to bicuculline-insensitive GABA sites in rat brain. Nature. 290 : 149-152. KarbEn, E.W., Duman, R. and Enna, S.J. (1983). Biochemical identi~fication ofmultiple GABAB binding sites : association with noradrenergic terminals in rat forebrain. Brain Res. 274 : 393-396. Lloyd, K.G. and Vargas, F. (1982) 3H-nipecotic acid binding: Identification of CABA uptake sites in frozen tissue. In : Problems in GABA Research (Okada, Y. and Roberts, E Eds), PP. 355-365. Excerpta Medica, Amsterdam. Lloyd, K.G., Mohler, H., Hertz, Ph. and Bartholini, G. (1975). Distribution of choline acetyltransferase and glutamate decarhoxylase vthin the suhstnnt:? nigrn .~nd other bra;? regions from control and Parkinsonian patients. _:.__ J Neurochem. 25 : 789-795. Lloyd, K.G., Shemen, L. and Hornykiewicz, 0. (1977). Distribution of high affinity sodiumindependent (3H) gamma-aminobutyric acid c3H-GABA) binding in the human brain: Alterations in Parkinson's disease, Brain Res. 127 : 269-278 Lloyd, K.G., Morselli, P.L., Depoortere, H., Fournier, V., Zivkovic, B., Scatton, B., Broekkamp, C., Worms, P. and Bartholini, G. (1983). The potential use of GABA agonistsin psychiatric disorders : Evidence from studies with progabide in animals and clinical trials. Pharmacol. Biochem. Behav. 18 : 957-966, Sherman, A.D. and Petty, F. (1982). Additivity of neurochemical changes in learned helplessness and imipramine. Behav. Neural. Biol. 35 : 344-353