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The role of serotonin in compulsive behavior: an animal model
227
The role of serotonin in compulsive behavior: an animal model
W.H. Bridger, E. Friedman and E. Yadin Department of Psychiatry, Medical College of Penns3,1vania/Eastern Pennsylvania Psychiatric Institute, Philadelphia, PA 19129, USA Key words." Obsessive-compulsive disorder; Serotonin; Fluoxetine; Animal model Summary This report presents a possible animal model for compulsive disorders in humans, based on the principles of spontaneous alternation in rats. Challenge with a serotonin agonist disrupted spontaneous alternation, whereas a chronic course of treatment with a selective serotonin reuptake inhibitor prevented such a deficit. A modified version of the classic spontaneous alternation task, the four-arm maze, was used to assess the effects of changes in the serotonergic system on goal-directed choice behavior. Food-deprived rats were run in a black Plexiglas maze, with four identical arms, each baited with the same amount of chocolate milk. Each rat was placed in the center of the maze and allowed to explore the entire maze, until 12 arm entries were completed, or until a maximum time of l0 min had elapsed, whichever came first. Chocolate milk was replenished after each choice. The pattern of arm entries was recorded, as was the time spent at the choice point area and the total time to complete 12 choices. The non-selective serotonin agonist 5-MeODMT (1.25 mg/kg, i.p.) produced deficits in the four-arm maze behavior. Animals made significantly more repeated arm choices, spent more time in the choice area, and took longer to complete the session than did their control counterparts. A course of chronic treatment (10 mg/kg for 21 days) with the selective serotonin reuptake blocking agent fluoxetine had a protective effect on the 5-MeODMT-induced deficit. An acute dose of fluoxetine did not provide such protection, neither did a chronic course of the non-serotonergic antidepressant DMI (10 mg/kg, i.p.). The four-arm maze appears to be a sensitive tool for the assessment of serotonergic manipulations. Excess amounts of 5-HT at the synapse, as is the case with a single dose of fluoxetine, or by administration of an agonist, seem to produce spontaneous alternation impairments. Down-regulation of the system by chronic treatment with selective serotonin uptake blockers appears to protect against such an effect, whereas a chronic course of antidepressants that are not as effective clinically is ineffective in this animal model. Based on these results, the four-arm spontaneous alternation task may be used as one in a battery of animal models for compulsive disorders seen in humans. The evidence from the literature on OCD points largely to a serotonergic involvement in the pathophysiology of the disorder, although the precise nature of it is yet unclear. Platelet serotonin uptake capacity was shown to be significantly higher in OCD patients than in matched controls. Levels of the 5-HT metabolite 5hydroxyindoleacetic acid have been found to be elevated in patients with the disorder. Treatment with selective uptake inhibitors of serotonin has been consistently superior to other classes of agents with which they have been compared. Clinically controlled studies have clearly demonstrated reductions in the severity of obsessive-compulsive symptoms after a chronic course of clomipramine (e.g., De Veaugh-Geiss et al., 1989), fluoxetine (e.g., Fontaine and Chouinard, 1985), and fluvoxamine (Goodman et al., 1989). Clinical efficacy was poorer with other antidepressants (e.g., Foa et al., 1987), including monoamine oxidase inhibitors (Insel et al., 1983). The above cited evidence coupled with the finding that serotonin agonists such as m-chlorophenylpiperazine actually exacerbate OC symptoms (Zohar et al., 1987) suggests that the possible etiology of OCD may lie in part in an overactive serotonergic system. The fact that spontaneous alternation behavior in rats is adversely affected by serotonergic agonists, and that such disruptions are prevented after a chronic course of treatment with a selective serotonin uptake inhibitor and not with a tricyclic antidepressant that primarily inhibits the uptake of norepinephrine, makes this task a suitable tool for the screening of putative therapeutic agents for OCD. Unlike the acute administration of fluoxetine that results in excess serotonin at the synapse and therefore acts as an agonist, chronic administration of fluoxetine produces down-regulation of the serotonergic receptor. This animal behavioral model responds to chronic but not to acute regimens of treatment with the serotonin uptake inhibitor, a situation that is parallel to that seen clinically. The efficacy of agents other than the selective serotonin uptake inhibitors is limited in this paradigm as it has been in the clinic.
Acknowledgement: Supported by funds from the Department of Psychiatry/EPPl.
228 References
De Veaugh-Geiss, J., Landau, P. and Katz, R. (1989) Treatment of obsessive-compulsive disorder with clomipramine. Psychiat. Ann. 19, 97- 101. Foa, E.B., Steketee, G., Kozak, M.J. and Dugger, D. (1987) Efl'ects of imipramine on depression and obsessive-compulsive symptoms. Psychiat. Res. 21, 123 126. Fontaine, R. and Chouinard, G. (1985) Fluoxetine in the treatment of obsessive-compulsive disorder. Prog. Neuropsychopharm. Biol. Psychiatry 9, 605 608. Goodman, W.K., Price, L.H., Rassmussen, S.A., Delgado, P.L., Heninger, G.R. and Charney, D.S. (1989) Efficacy of fluvoxamine in obsessive-compulsive disorder: a double blind comparison with placebo. Arch. Gen. Psychiatry 46, 36 44. lnsel, T.R., Mueller, E.A., Alterman, I., Linnoila, M. and Murphy, D.L. (1985) Obsessive-compulsive disorder and serotonin: Is there a connection? Biol. Psychiatry 20, 1174 1188. Zohar, J., Mueller, E.A., |nsel, T.R., Zohar-Kadouch, R.C. and Murphy, D.L. (1987) Serotonergic responsivity in obsessivecompulsive disorder: Comparisons of patients and healthy controls. Arch. Gen. Psychiatry 44, 946 951.
Molecular biology of serotonin receptors: relation to psychiatric disease states
R.D. Ciaranello Nam T Pritzker Laborator 3' o1 Developmental and Molecular Neurobiolog.l', Department qf P.~3,chiatrr. 5"lw!/~wd Uniter.rift School of Medicine, Stanlbrd, CA 94305-5485, USA Ker word. Serotonin receptor regulation
In recent years, much has been learned about the structure of serotonin receptors derived from knowledge of the cloned cDNAs. This information is being actively used in a number of industrial and academic laboratories to develop new generations of receptor selective agonists and antagonists. However, there is a great deal of information to be derived from sequences of cDNAs, as well as the genes themselves, which is just now beginning to tell us how serotonin receptors are regulated in vivo. This information is of great value in providing clues relevant to particular psychiatric diseases in which serotonin is implicated, as well as providing additional targets of focused drug design. This presentation will focus on three examples of serotonin receptor regulation based on knowledge of the structure of the receptor protein and on the genes encoding specific receptors. As an example of how knowledge about protein structure can be used to examine models of receptor regulation, we will discuss the 5HT~=~receptor. The 5HTh, receptor has several consensus sites for phosphorylation by protein kinase A and protein kinase C. We will describe studies showing how exposure to low concentrations of agonist activate several transduction pathways, ultimately shutting down the expression of 5HT~, receptors in cultured cells. As an example of genomic regulation, data on the organization of the promoter region of the 5HT: receptor will be presented, and the concept of negative regulation of serotonin receptor gene expression by hormones introduced. Finally, as an example of how information in the noncoding regions of receptor messenger RNAs is used in regulation of receptor activity, data on the 5HT~, receptor will be presented.
The role of serotonin in compulsive behavior: an animal model
W.H. Bridger, E. Friedman and E. Yadin Department of Psychiatry, Medical College of Penns3,1vania/Eastern Pennsylvania Psychiatric Institute, Philadelphia, PA 19129, USA Key words." Obsessive-compulsive disorder; Serotonin; Fluoxetine; Animal model Summary This report presents a possible animal model for compulsive disorders in humans, based on the principles of spontaneous alternation in rats. Challenge with a serotonin agonist disrupted spontaneous alternation, whereas a chronic course of treatment with a selective serotonin reuptake inhibitor prevented such a deficit. A modified version of the classic spontaneous alternation task, the four-arm maze, was used to assess the effects of changes in the serotonergic system on goal-directed choice behavior. Food-deprived rats were run in a black Plexiglas maze, with four identical arms, each baited with the same amount of chocolate milk. Each rat was placed in the center of the maze and allowed to explore the entire maze, until 12 arm entries were completed, or until a maximum time of l0 min had elapsed, whichever came first. Chocolate milk was replenished after each choice. The pattern of arm entries was recorded, as was the time spent at the choice point area and the total time to complete 12 choices. The non-selective serotonin agonist 5-MeODMT (1.25 mg/kg, i.p.) produced deficits in the four-arm maze behavior. Animals made significantly more repeated arm choices, spent more time in the choice area, and took longer to complete the session than did their control counterparts. A course of chronic treatment (10 mg/kg for 21 days) with the selective serotonin reuptake blocking agent fluoxetine had a protective effect on the 5-MeODMT-induced deficit. An acute dose of fluoxetine did not provide such protection, neither did a chronic course of the non-serotonergic antidepressant DMI (10 mg/kg, i.p.). The four-arm maze appears to be a sensitive tool for the assessment of serotonergic manipulations. Excess amounts of 5-HT at the synapse, as is the case with a single dose of fluoxetine, or by administration of an agonist, seem to produce spontaneous alternation impairments. Down-regulation of the system by chronic treatment with selective serotonin uptake blockers appears to protect against such an effect, whereas a chronic course of antidepressants that are not as effective clinically is ineffective in this animal model. Based on these results, the four-arm spontaneous alternation task may be used as one in a battery of animal models for compulsive disorders seen in humans. The evidence from the literature on OCD points largely to a serotonergic involvement in the pathophysiology of the disorder, although the precise nature of it is yet unclear. Platelet serotonin uptake capacity was shown to be significantly higher in OCD patients than in matched controls. Levels of the 5-HT metabolite 5hydroxyindoleacetic acid have been found to be elevated in patients with the disorder. Treatment with selective uptake inhibitors of serotonin has been consistently superior to other classes of agents with which they have been compared. Clinically controlled studies have clearly demonstrated reductions in the severity of obsessive-compulsive symptoms after a chronic course of clomipramine (e.g., De Veaugh-Geiss et al., 1989), fluoxetine (e.g., Fontaine and Chouinard, 1985), and fluvoxamine (Goodman et al., 1989). Clinical efficacy was poorer with other antidepressants (e.g., Foa et al., 1987), including monoamine oxidase inhibitors (Insel et al., 1983). The above cited evidence coupled with the finding that serotonin agonists such as m-chlorophenylpiperazine actually exacerbate OC symptoms (Zohar et al., 1987) suggests that the possible etiology of OCD may lie in part in an overactive serotonergic system. The fact that spontaneous alternation behavior in rats is adversely affected by serotonergic agonists, and that such disruptions are prevented after a chronic course of treatment with a selective serotonin uptake inhibitor and not with a tricyclic antidepressant that primarily inhibits the uptake of norepinephrine, makes this task a suitable tool for the screening of putative therapeutic agents for OCD. Unlike the acute administration of fluoxetine that results in excess serotonin at the synapse and therefore acts as an agonist, chronic administration of fluoxetine produces down-regulation of the serotonergic receptor. This animal behavioral model responds to chronic but not to acute regimens of treatment with the serotonin uptake inhibitor, a situation that is parallel to that seen clinically. The efficacy of agents other than the selective serotonin uptake inhibitors is limited in this paradigm as it has been in the clinic.
Acknowledgement: Supported by funds from the Department of Psychiatry/EPPl.
228 References
De Veaugh-Geiss, J., Landau, P. and Katz, R. (1989) Treatment of obsessive-compulsive disorder with clomipramine. Psychiat. Ann. 19, 97- 101. Foa, E.B., Steketee, G., Kozak, M.J. and Dugger, D. (1987) Efl'ects of imipramine on depression and obsessive-compulsive symptoms. Psychiat. Res. 21, 123 126. Fontaine, R. and Chouinard, G. (1985) Fluoxetine in the treatment of obsessive-compulsive disorder. Prog. Neuropsychopharm. Biol. Psychiatry 9, 605 608. Goodman, W.K., Price, L.H., Rassmussen, S.A., Delgado, P.L., Heninger, G.R. and Charney, D.S. (1989) Efficacy of fluvoxamine in obsessive-compulsive disorder: a double blind comparison with placebo. Arch. Gen. Psychiatry 46, 36 44. lnsel, T.R., Mueller, E.A., Alterman, I., Linnoila, M. and Murphy, D.L. (1985) Obsessive-compulsive disorder and serotonin: Is there a connection? Biol. Psychiatry 20, 1174 1188. Zohar, J., Mueller, E.A., |nsel, T.R., Zohar-Kadouch, R.C. and Murphy, D.L. (1987) Serotonergic responsivity in obsessivecompulsive disorder: Comparisons of patients and healthy controls. Arch. Gen. Psychiatry 44, 946 951.
Molecular biology of serotonin receptors: relation to psychiatric disease states
R.D. Ciaranello Nam T Pritzker Laborator 3' o1 Developmental and Molecular Neurobiolog.l', Department qf P.~3,chiatrr. 5"lw!/~wd Uniter.rift School of Medicine, Stanlbrd, CA 94305-5485, USA Ker word. Serotonin receptor regulation
In recent years, much has been learned about the structure of serotonin receptors derived from knowledge of the cloned cDNAs. This information is being actively used in a number of industrial and academic laboratories to develop new generations of receptor selective agonists and antagonists. However, there is a great deal of information to be derived from sequences of cDNAs, as well as the genes themselves, which is just now beginning to tell us how serotonin receptors are regulated in vivo. This information is of great value in providing clues relevant to particular psychiatric diseases in which serotonin is implicated, as well as providing additional targets of focused drug design. This presentation will focus on three examples of serotonin receptor regulation based on knowledge of the structure of the receptor protein and on the genes encoding specific receptors. As an example of how knowledge about protein structure can be used to examine models of receptor regulation, we will discuss the 5HT~=~receptor. The 5HTh, receptor has several consensus sites for phosphorylation by protein kinase A and protein kinase C. We will describe studies showing how exposure to low concentrations of agonist activate several transduction pathways, ultimately shutting down the expression of 5HT~, receptors in cultured cells. As an example of genomic regulation, data on the organization of the promoter region of the 5HT: receptor will be presented, and the concept of negative regulation of serotonin receptor gene expression by hormones introduced. Finally, as an example of how information in the noncoding regions of receptor messenger RNAs is used in regulation of receptor activity, data on the 5HT~, receptor will be presented.