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Antidepressantlike Effects of Chronic Nicotine on Learned Helplessness Paradigm in Rats
BRIEF REPORTS Antidepressantlike Effects of Chronic Nicotine on Learned Helplessness Paradigm in Rats Jun’ichi Semba, Chikage Mataki, Satoru Yamada, Masahiro Nankai, and Michio Toru Background: The association between smoking and depression has been widely investigated. Smoking cessation is known to induce depression to a variable extent, and patients with a history of depression are more likely to experience depressive symptoms. To investigate the hypothesis that nicotine may have an antidepressantlike effect, we used learned helpless rats as an animal model of depression. Methods: Learned helplessness was produced according to our previous method. Learned helpless rats were implanted with nicotine and escape test was performed at 7 and 14 days after the implantation. Results: The number of escape failure in the rats receiving 1.5 mg/kg/day of nicotine was significantly reduced (p , .05) compared to control at day 14. Furthermore, this effect was blocked when the nicotinic receptor antagonist mecamylamine was coadministered. Conclusions: These results suggest that chronic nicotine may act as an antidepressant, probably via nicotinic receptors. Biol Psychiatry 1998;43:389 –391 © 1998 Society of Biological Psychiatry Key Words: Antidepressant, animal model, depression, learned helplessness, nicotine
Introduction
N
umerous studies have been reported to show clinical association between smoking and depression (see review, Glassman 1993). Epidemiological studies demonstrated that psychiatric patients were more likely to smoke than the general population (Hughes et al 1991), and smokers with a history of major depression were less likely to quit smoking (Covey et al 1990; Glassman et al 1988). Also, smoking cessation often induced depression to a variable extent, and depression is considered to be one
From the Division of Health Sciences, University of the Air, Chiba, Japan (JS); Department of Biology, Faculty of Science, Toho University, Chiba, Japan (CM); Tokyo Metropolitan Umegaoka Hospital, Tokyo, Japan (SY); and Department of Neuropsychiatry, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan (SY, MN, MT). Address reprint requests to Dr. Jun’ichi Semba, Division of Health Sciences, University of the Air, 2-11 Wakaba, Mihama-ku, Chiba 261, Japan. Received May 20, 1997; revised August 9, 1997; accepted September 3, 1997.
© 1998 Society of Biological Psychiatry
of the symptoms of nicotine withdrawal (Covey et al 1990; Flanagan and Maany 1982). These depressive symptoms were reversed by resumption of smoking (Glassman 1993) or in antidepressant treatment (Dalack et al 1995; Lief 1996). Thus, we hypothesized that nicotine may act as an antidepressant for at least some types of depression. In this report we assessed antidepressantlike effects of chronic nicotine in rats using the learned helpless paradigm, which is widely accepted to be a useful animal model of depression (Maier and Seligman 1976). The appropriateness of this animal model is further emphasized by the fact that helpless behavior of learned helpless rats is known to be prevented by chronic administration of antidepressant drugs (Nankai et al 1995; Sherman et al 1982).
Methods and Materials Male Wistar rats weighing 200 –220 g were used. The animals were housed with a 12-hour light– dark cycle (light on 7:00 hours, light off 19:00 hours) with free access to food and water. Learned helplessness was produced according to the method of Nankai et al (1995). All experimental animals were placed in an experimental chamber (18.5 cm long 3 20 cm high 3 9 cm wide) with an electrifiable grid floor. A disk was mounted from the ceiling 7 cm off the floor. In preshock escape testing, rats were administered pulsed (35 msec on and 35 msec off) 1-mA electric shocks. Shock onset began a trial, which was terminated either by pulling and releasing the disk or the end of 60 sec. Fifteen trials were given for a rat, and intertrial latency was set at 15 sec. On the next day, inescapable pulsed electric shocks were delivered for a single 60-min session. Two days after the inescapable shock, a postshock escape test was performed. Rats scoring fewer than 10 escape failures in the preshock test with an increase of more than five failures in the postshock test were used as learned helpless (LH) rats. Two days after the posttest session, the LH rats were anesthetized with pentobarbital and osmotic minipumps (Alzet model 2002; Alza Corp., Palo Alto, CA), filled with nicotine, were implanted subcutaneously behind the shoulder. (2)Nicotine di-tartrate or less active isomer, (1)nicotine di-p-toluoyltartrate (Sigma, St. Louis, MO), was dissolved with saline, and the pH was adjusted to 6 –7 with NaOH. The minipumps were designed to deliver nicotine at a constant rate (0.75 or 1.5 mg/kg/day as a free base) for 14 days. In a further experiment, mecamylamine (Sigma; 1.0 mg/kg/day) was coinfused with (2)nicotine (1.5 0006-3223/98/$19.00 PII S0006-3223(98)00477-0
390
J. Semba et al
BIOL PSYCHIATRY 1998;43:389 –391
Table 1. Effect of Chronic Nicotine Administration on the Number of Escape Failures in the Learned Helpless Rats n
Posttest
Day 7
Day 14
Control (2)Nicotine (0.75 mg/kg/day)
(7) (7)
13.3 6 0.7 13.4 6 0.9
11.9 6 1.9 9.7 6 1.7
10.6 6 2.5 8.7 6 1.8
Control (1)Nicotine (1.5 mg/kg/day)
(8) (7)
14.4 6 0.3 14.4 6 0.3
11.0 6 2.3 11.6 6 1.8
9.7 6 2.4 9.3 6 2.3
(15) (7) (6)
13.9 6 0.4 13.4 6 0.9 14.2 6 0.5
12.0 6 1.2 9.4 6 2.4 11.2 6 2.1
9.3 6 1.6 0.1 6 0.1a 8.3 6 2.9
Control (2)Nicotine (1.5 mg/kg/day) (2)Nicotine (1.5 mg/kg/day) 1 mecamylamine (1.0 mg/kg/day)
Data are expressed as mean 6 SEM. a p , .05, difference from control (nonparametric Kruskal–Wallis test followed by Dunnett’s test).
mg/kg/day). Control animals were implanted with a minipump filled with neutralized tartrate solution. At 7 and 14 days after the implantation each rat was subjected to an escape test, and the number of escape failures was recorded.
Results As shown in Table 1, a significant reversal of escape deficits was observed in the LH rats implanted with chronic (2)nicotine (1.5 mg/kg/day) on day 14. Neither the less active (1) isomer nor lower dose of (2)nicotine (0.75 mg/kg/day), however, reversed escape deficits. When mecamylamine was coinfused with (2)nicotine, the reversal of escape deficits induced by chronic nicotine was completely antagonized.
Discussion In this study, the maximal dose of nicotine was 1.5 mg/kg/day. This dose of nicotine was chosen because it has been shown to produce plasma levels of nicotine in rats similar to plasma levels of nicotine found in humans smoking one pack of cigarettes per day (Hill et al 1983). At this dose rats appeared to be healthy and no significant difference in body weight gain was observed between nicotine or control rats. Chronic (2)nicotine administration at 1.5 mg/kg/day for 2 weeks induced significant reduction in the number of escape failures, suggesting an antidepressantlike activity of chronic (2)nicotine. In our preliminary experiment, acute nicotine injection (1.0 mg/kg, SC) had no effect on escape failures determined 30 min after injection (data not shown). It is widely accepted that chronic but not acute treatment of antidepressants reduces escape failures in learned helpless rats (Nankai et al 1995; Sherman et al 1982). Thus, nicotine’s effect was observed only after chronic but not acute administration. We coadministered mecamylamine with nicotine to determine whether mecamylamine may antagonize nicotine, since mec-
amylamine has been shown to act as an antagonist to nicotine and reported to potentially antagonize many behavioral actions of nicotine (Malin et al 1994; Meltzer and Rosecrans 1989). Indeed, in the present study, coadministration with mecamylamine completely antagonized nicotine’s effect. The antagonism of mecamylamine suggests that the effect of nicotine on the reduction of escape failures was mediated via nicotinic receptors. This is also supported by the finding that less active isomer, (1)nicotine, was ineffective even at the same dose as (2)nicotine. The exact mechanism for nicotine’s effect on learned helplessness is not known; however, it is possible that nicotine influences several neurotransmitter systems that may play an etiological role in depression. For instance, enhancing the release into the synapse or the synthesis of norepinephrine (Smith et al 1991; Toth et al 1992) may reverse behavioral deficits in learned helplessness, since the involvement of the hypoactive noradrenergic system is well documented in learned helpless rats (Brannan et al 1995; Martin et al 1990; Petty et al 1993); however, we cannot exclude other possibilities that the reduction of the number of escape failures following chronic nicotine may be due to an enhancement of memory or an improvement of learning in the avoidance test (Sansone et al 1994; Decker et al 1992). Finally, our findings also suggest that certain nicotine receptor agonists may offer an innovative approach to the treatment of depression.
This study was partly supported by a grant from the Smoking Research Foundation, Tokyo.
References Brannan SK, Miller A, Jones DJ, Kramer GL, Petty F (1995): Beta-adrenergic receptor changes in learned helplessness may depend on stress and test parameters. Pharmacol Biochem Behav 51:553–556. Covey LS, Glassman AH, Stetner F (1990): Depression and
Antidepressantlike Effects of Nicotine
depressive symptoms in smoking cessation. Compr Psychiatry 31:350 –354. Dalack GW, Glassman AH, Rivelli S, Covey L, Stetner F (1995): Mood, major depression, and fluoxetine response in cigarette smokers. Am J Psychiatry 152:398 – 403. Decker MW, Majchrzak MJ, Anderson DJ (1992): Effects of nicotine on spatial memory deficits in rats with septal lesions. Brain Res 572:281–285. Flanagan J, Maany I (1982): Smoking and depression. Am J Psychiatry 139:541. Glassman AH (1993): Cigarette smoking: Implications for psychiatric illness. Am J Psychiatry 150:546 –553. Glassman AH, Stetner F, Walsh BT, Raizman PS, Fleiss JL, Cooper TB, et al (1988): Heavy smokers, smoking cessation, and clonidine: Results of a double-blind, randomized trial. JAMA 259:2863–2866. Hill P, Haley NJ, Wynder EL (1983): Cigarette smoking: Carboxyhemoglobin, plasma nicotine, cotinine and thiocyanate vs self-reported smoking data and cardiovascular disease. J Chron Dis 36:439 – 449. Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW (1991): Symptoms of tobacco withdrawal: A replication and extension. Arch Gen Psychiatry 48:52–59. Lief HI (1996): Bupropion treatment of depression to assist smoking cessation. Am J Psychiatry 153:442. Maier SF, Seligman MEP (1976): Learned helplessness: Theory and evidence. J Exp Psychol 105:3– 46. Malin DH, Lake JR, Carter VA, Cunningham JS, Hebert KM,
BIOL PSYCHIATRY 1998;43:389 –391
391
Conrad DL, et al (1994): The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome in the rat. Psychopharmacology 115:180 –185. Martin JV, Edwards E, Johnson JO, Henn FA (1990): Monoamine receptors in an animal model of affective disorder. J Neurochem 55:1142–1148. Meltzer LT, Rosecrans J (1989): Investigations on the CNS sites of action of the discriminative stimulus effects of arecoline and nicotine. Pharmacol Biochem Behav 15:21–26. Nankai M, Yamada S, Muneoka K, Toru M (1995): Increased 5-HT2 receptor-mediated behavior 11 days after shock in learned helpless rats. Eur J Pharmacol 281:123–130. Petty F, Kramer G, Wilson L, Chae YL (1993): Learned helplessness and in vivo hippocampal norepinephrine release. Pharmacol Biochem Behav 46:231–235. Sansone M, Battaglia M, Castellano C (1994): Effect of caffeine and nicotine on avoidance learning in mice: Lack of interaction. J Pharm Pharmacol 46:765–767. Sherman AD, Sacquitne JL, Petty F (1982): Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16:449 – 454. Smith KM, Mitchell SN, Joseph MH (1991): Effects of chronic nicotine on tyrosine hydroxylase activity in noradrenergic and dopaminergic neurones in the rat brain. J Neurochem 57: 1750 –1756. Toth E, Sershen H, Hashim A, Vizi ES, Lajtha A (1992): Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: Role of glutamic acid. Neurochem Res 17:265–271.
Introduction
N
umerous studies have been reported to show clinical association between smoking and depression (see review, Glassman 1993). Epidemiological studies demonstrated that psychiatric patients were more likely to smoke than the general population (Hughes et al 1991), and smokers with a history of major depression were less likely to quit smoking (Covey et al 1990; Glassman et al 1988). Also, smoking cessation often induced depression to a variable extent, and depression is considered to be one
From the Division of Health Sciences, University of the Air, Chiba, Japan (JS); Department of Biology, Faculty of Science, Toho University, Chiba, Japan (CM); Tokyo Metropolitan Umegaoka Hospital, Tokyo, Japan (SY); and Department of Neuropsychiatry, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan (SY, MN, MT). Address reprint requests to Dr. Jun’ichi Semba, Division of Health Sciences, University of the Air, 2-11 Wakaba, Mihama-ku, Chiba 261, Japan. Received May 20, 1997; revised August 9, 1997; accepted September 3, 1997.
© 1998 Society of Biological Psychiatry
of the symptoms of nicotine withdrawal (Covey et al 1990; Flanagan and Maany 1982). These depressive symptoms were reversed by resumption of smoking (Glassman 1993) or in antidepressant treatment (Dalack et al 1995; Lief 1996). Thus, we hypothesized that nicotine may act as an antidepressant for at least some types of depression. In this report we assessed antidepressantlike effects of chronic nicotine in rats using the learned helpless paradigm, which is widely accepted to be a useful animal model of depression (Maier and Seligman 1976). The appropriateness of this animal model is further emphasized by the fact that helpless behavior of learned helpless rats is known to be prevented by chronic administration of antidepressant drugs (Nankai et al 1995; Sherman et al 1982).
Methods and Materials Male Wistar rats weighing 200 –220 g were used. The animals were housed with a 12-hour light– dark cycle (light on 7:00 hours, light off 19:00 hours) with free access to food and water. Learned helplessness was produced according to the method of Nankai et al (1995). All experimental animals were placed in an experimental chamber (18.5 cm long 3 20 cm high 3 9 cm wide) with an electrifiable grid floor. A disk was mounted from the ceiling 7 cm off the floor. In preshock escape testing, rats were administered pulsed (35 msec on and 35 msec off) 1-mA electric shocks. Shock onset began a trial, which was terminated either by pulling and releasing the disk or the end of 60 sec. Fifteen trials were given for a rat, and intertrial latency was set at 15 sec. On the next day, inescapable pulsed electric shocks were delivered for a single 60-min session. Two days after the inescapable shock, a postshock escape test was performed. Rats scoring fewer than 10 escape failures in the preshock test with an increase of more than five failures in the postshock test were used as learned helpless (LH) rats. Two days after the posttest session, the LH rats were anesthetized with pentobarbital and osmotic minipumps (Alzet model 2002; Alza Corp., Palo Alto, CA), filled with nicotine, were implanted subcutaneously behind the shoulder. (2)Nicotine di-tartrate or less active isomer, (1)nicotine di-p-toluoyltartrate (Sigma, St. Louis, MO), was dissolved with saline, and the pH was adjusted to 6 –7 with NaOH. The minipumps were designed to deliver nicotine at a constant rate (0.75 or 1.5 mg/kg/day as a free base) for 14 days. In a further experiment, mecamylamine (Sigma; 1.0 mg/kg/day) was coinfused with (2)nicotine (1.5 0006-3223/98/$19.00 PII S0006-3223(98)00477-0
390
J. Semba et al
BIOL PSYCHIATRY 1998;43:389 –391
Table 1. Effect of Chronic Nicotine Administration on the Number of Escape Failures in the Learned Helpless Rats n
Posttest
Day 7
Day 14
Control (2)Nicotine (0.75 mg/kg/day)
(7) (7)
13.3 6 0.7 13.4 6 0.9
11.9 6 1.9 9.7 6 1.7
10.6 6 2.5 8.7 6 1.8
Control (1)Nicotine (1.5 mg/kg/day)
(8) (7)
14.4 6 0.3 14.4 6 0.3
11.0 6 2.3 11.6 6 1.8
9.7 6 2.4 9.3 6 2.3
(15) (7) (6)
13.9 6 0.4 13.4 6 0.9 14.2 6 0.5
12.0 6 1.2 9.4 6 2.4 11.2 6 2.1
9.3 6 1.6 0.1 6 0.1a 8.3 6 2.9
Control (2)Nicotine (1.5 mg/kg/day) (2)Nicotine (1.5 mg/kg/day) 1 mecamylamine (1.0 mg/kg/day)
Data are expressed as mean 6 SEM. a p , .05, difference from control (nonparametric Kruskal–Wallis test followed by Dunnett’s test).
mg/kg/day). Control animals were implanted with a minipump filled with neutralized tartrate solution. At 7 and 14 days after the implantation each rat was subjected to an escape test, and the number of escape failures was recorded.
Results As shown in Table 1, a significant reversal of escape deficits was observed in the LH rats implanted with chronic (2)nicotine (1.5 mg/kg/day) on day 14. Neither the less active (1) isomer nor lower dose of (2)nicotine (0.75 mg/kg/day), however, reversed escape deficits. When mecamylamine was coinfused with (2)nicotine, the reversal of escape deficits induced by chronic nicotine was completely antagonized.
Discussion In this study, the maximal dose of nicotine was 1.5 mg/kg/day. This dose of nicotine was chosen because it has been shown to produce plasma levels of nicotine in rats similar to plasma levels of nicotine found in humans smoking one pack of cigarettes per day (Hill et al 1983). At this dose rats appeared to be healthy and no significant difference in body weight gain was observed between nicotine or control rats. Chronic (2)nicotine administration at 1.5 mg/kg/day for 2 weeks induced significant reduction in the number of escape failures, suggesting an antidepressantlike activity of chronic (2)nicotine. In our preliminary experiment, acute nicotine injection (1.0 mg/kg, SC) had no effect on escape failures determined 30 min after injection (data not shown). It is widely accepted that chronic but not acute treatment of antidepressants reduces escape failures in learned helpless rats (Nankai et al 1995; Sherman et al 1982). Thus, nicotine’s effect was observed only after chronic but not acute administration. We coadministered mecamylamine with nicotine to determine whether mecamylamine may antagonize nicotine, since mec-
amylamine has been shown to act as an antagonist to nicotine and reported to potentially antagonize many behavioral actions of nicotine (Malin et al 1994; Meltzer and Rosecrans 1989). Indeed, in the present study, coadministration with mecamylamine completely antagonized nicotine’s effect. The antagonism of mecamylamine suggests that the effect of nicotine on the reduction of escape failures was mediated via nicotinic receptors. This is also supported by the finding that less active isomer, (1)nicotine, was ineffective even at the same dose as (2)nicotine. The exact mechanism for nicotine’s effect on learned helplessness is not known; however, it is possible that nicotine influences several neurotransmitter systems that may play an etiological role in depression. For instance, enhancing the release into the synapse or the synthesis of norepinephrine (Smith et al 1991; Toth et al 1992) may reverse behavioral deficits in learned helplessness, since the involvement of the hypoactive noradrenergic system is well documented in learned helpless rats (Brannan et al 1995; Martin et al 1990; Petty et al 1993); however, we cannot exclude other possibilities that the reduction of the number of escape failures following chronic nicotine may be due to an enhancement of memory or an improvement of learning in the avoidance test (Sansone et al 1994; Decker et al 1992). Finally, our findings also suggest that certain nicotine receptor agonists may offer an innovative approach to the treatment of depression.
This study was partly supported by a grant from the Smoking Research Foundation, Tokyo.
References Brannan SK, Miller A, Jones DJ, Kramer GL, Petty F (1995): Beta-adrenergic receptor changes in learned helplessness may depend on stress and test parameters. Pharmacol Biochem Behav 51:553–556. Covey LS, Glassman AH, Stetner F (1990): Depression and
Antidepressantlike Effects of Nicotine
depressive symptoms in smoking cessation. Compr Psychiatry 31:350 –354. Dalack GW, Glassman AH, Rivelli S, Covey L, Stetner F (1995): Mood, major depression, and fluoxetine response in cigarette smokers. Am J Psychiatry 152:398 – 403. Decker MW, Majchrzak MJ, Anderson DJ (1992): Effects of nicotine on spatial memory deficits in rats with septal lesions. Brain Res 572:281–285. Flanagan J, Maany I (1982): Smoking and depression. Am J Psychiatry 139:541. Glassman AH (1993): Cigarette smoking: Implications for psychiatric illness. Am J Psychiatry 150:546 –553. Glassman AH, Stetner F, Walsh BT, Raizman PS, Fleiss JL, Cooper TB, et al (1988): Heavy smokers, smoking cessation, and clonidine: Results of a double-blind, randomized trial. JAMA 259:2863–2866. Hill P, Haley NJ, Wynder EL (1983): Cigarette smoking: Carboxyhemoglobin, plasma nicotine, cotinine and thiocyanate vs self-reported smoking data and cardiovascular disease. J Chron Dis 36:439 – 449. Hughes JR, Gust SW, Skoog K, Keenan RM, Fenwick JW (1991): Symptoms of tobacco withdrawal: A replication and extension. Arch Gen Psychiatry 48:52–59. Lief HI (1996): Bupropion treatment of depression to assist smoking cessation. Am J Psychiatry 153:442. Maier SF, Seligman MEP (1976): Learned helplessness: Theory and evidence. J Exp Psychol 105:3– 46. Malin DH, Lake JR, Carter VA, Cunningham JS, Hebert KM,
BIOL PSYCHIATRY 1998;43:389 –391
391
Conrad DL, et al (1994): The nicotinic antagonist mecamylamine precipitates nicotine abstinence syndrome in the rat. Psychopharmacology 115:180 –185. Martin JV, Edwards E, Johnson JO, Henn FA (1990): Monoamine receptors in an animal model of affective disorder. J Neurochem 55:1142–1148. Meltzer LT, Rosecrans J (1989): Investigations on the CNS sites of action of the discriminative stimulus effects of arecoline and nicotine. Pharmacol Biochem Behav 15:21–26. Nankai M, Yamada S, Muneoka K, Toru M (1995): Increased 5-HT2 receptor-mediated behavior 11 days after shock in learned helpless rats. Eur J Pharmacol 281:123–130. Petty F, Kramer G, Wilson L, Chae YL (1993): Learned helplessness and in vivo hippocampal norepinephrine release. Pharmacol Biochem Behav 46:231–235. Sansone M, Battaglia M, Castellano C (1994): Effect of caffeine and nicotine on avoidance learning in mice: Lack of interaction. J Pharm Pharmacol 46:765–767. Sherman AD, Sacquitne JL, Petty F (1982): Specificity of the learned helplessness model of depression. Pharmacol Biochem Behav 16:449 – 454. Smith KM, Mitchell SN, Joseph MH (1991): Effects of chronic nicotine on tyrosine hydroxylase activity in noradrenergic and dopaminergic neurones in the rat brain. J Neurochem 57: 1750 –1756. Toth E, Sershen H, Hashim A, Vizi ES, Lajtha A (1992): Effect of nicotine on extracellular levels of neurotransmitters assessed by microdialysis in various brain regions: Role of glutamic acid. Neurochem Res 17:265–271.