- Email: [email protected]
Effects of antidepressant drugs on a quickly-learned conditioned-suppression response in mice
OOZS-3908jS5 $3.00+ 0.00 Copyright (‘ 1985Pergamon Press Ltd
Neur~~p,phrrmtrrco/og~ Vol. 24. No. 4. pp. 285-290. 1985 Printed in Great Bntaln. All rights reserved
EFFECTS OF ANTIDEPRESSANT DRUGS ON A QUICKLY-LEARNED CONDITIONED-SUPPRESSION RESPONSE IN MICE T. KAMEYAMA,M. NAGASAKA and K. YAMADA Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University,
Nagoya
468, Japan (Accepted
12 July 1984)
Summary-Mice experienced to electric shock, exhibited a marked suppression of motor activity when placed in the same cage 24 hr after administration of shocks. Acute administration of imipramine-HCl (lOmg/kg, i.p.), desipramine-HCI (5 and 10 mg/kg, i.p.) and amitriptyline-HCl (5 and lOmg/kg, i.p.) caused marked reduction of the conditioned suppression of shocked mice, but reduced the motor activity of the non-shocked mice. Maprotiline, mianserin and dimetacrine did not cause reduction of the conditioned suppression. Nialamide (100 mg/kg, i.p.) and pargyline-HCl (100 and 200 mg/kg, i.p.) caused
marked reduction of the conditioned suppression but did not increase the motor activity of the non-shocked mice, and tranylcypromine-HCl (10 and 20mg/kg, i.p.) did not cause reduction of the conditioned suppression. Diphenhydramine-HCl (10 and 20 mg/kg, i.p.) reduced the conditioned suppression of shocked mice in a dose-related manner. Chronic administration of imipramine-HCl (1 and Smg/kg, i.p.) for 14 days significantly reduced the conditioned suppression but did not influence the motility rate of the non-shocked mice. Also, chronic administration of amitriptyline (1 mg/kg, i.p.), desipramine (5 mg/kg, Lp.) and dimetacrine (lOmg/kg, i.p.), for 10 days, significantly reduced the conditioned suppression, but did not influence the motility rate of the non-shocked mice. Chronic administration of maprotiline reduced the conditioned suppression. On the other hand, chronic administration of mianserin (5 mg/kg, i.p.) and diphenhydramine (10 mg/kg, i.p.) did not cause a reduction of the conditioned suppression. Key words: tricyclic pression, mice.
antidepressants,
tetracyclic
The effects of drugs on animal behavior which resembles human depression have been studied since the clinical application of iproniazide and imipramine (Kuhn, 1958; Loomer, Saunders and Kline, 1957). Reserpine-induced depression (Chen and Bohner, 1961; Chessin, Kramer and Scott, 1957; Costa, Garattini and Valzelli, 1960), learned helplessness (Seligman and Maier, 1967; Sherman, Sacquitne and Petty, 1982; Telner and Singhal, 1981), swimming (Kitada, Miyauchi, Satoh and Satoh, 1981; Porsolt, Pichon and Jalfre, 1977) and models of stress (Garzon and Rio, 1981; Hatotani, Nomura, Inoue and Kitayama, 1979) have been used. Animal behavior resembling human depression has provided useful means for studying antidepressant drugs which are applicable clinically and central nervous-system stimulants. There have been reports of studies concerning the monoamine-hypothesis of depression (Bunney and Daris, 1965; Coppen, 1967; Schildkraut, 1965). Most tricyclic antidepressant drugs block the neuronal reuptake of norepinephrine and/or serotonin (Glowinski and Axelrod, 1964). However, several weeks of treatment with tricyclic antidepressants are usually required for alleviating depression (Oswald, Brezinova and Dunleavy, 1972). Cocaine, however, an inhibitor of the uptake of monoamines, did not
antidepressants,
MAO-inhibitors,
conditioned
sup
relieve the symptoms of depression (Post, Kotin and Goodwin, 1974). Under the circumstances, these findings corroborate the view that there is a difference between acute and chronic effects of antidepressants. Previous studies have shown that animals exhibited a marked suppression of motor activity when placed in a chamber without shocks where they previously received shocks, whereas non-shocked animals did not exhibit such a suppression (Kameyama and Nagasaka, 1982a,1982b). The conditioned suppression is considered as a continuous conditioned emotional response (CER) to a situation associated with shocks. This conditioned suppression was reduced by pretreatment with apomorphine and methamphetamine, but not with diazepam, chlorpromazine and haloperidol (Kameyama and Nagasaka, 1983; Nagasaka and Kameyama, 1983). Thus, it is possible that conditioned suppression, studied in the present experiments, is related to the depression of motor activity caused by the motivational deficit to explore when animals were placed in the new situation, and that such a conditioned suppression resembles the clinical symptoms of human depression. The conditioned suppression paradigm may be useful for screening new antidepressant drugs, provided the suppression could be attenuated by pretreatment with clinicallyapplicable antidepressants. In the present study, an 285
286
T.
KAMEYA.MA et al
attempt was made to clarify the effects of three tricyclic and two tetracyclic antidepressants, three inhibitors of monoamine oxidase (MAO), ethanol and diphenhydramine, and the effects of the chronic administration of antidepressants and diphenhydramine, on the patterns of suppression within the conditioned emotional response paradigm of mice. METHODS
Male ddY mice, 8-10 weeks of age, were housed in cages in groups of 10 under constant environment conditions (22 f 0.5”C, 50 + 5% relative humidity) and given food and water ad libitum. The room lights were turned off between 8:00 p.m. and 8: 00 a.m. Experiments were carried out using a transparent acrylic rectangular cage (24.5 x 31 x 30cm), equipped with a metallic grid floor. The apparatus was located in a sound-attenuating room, illuminated with a 20-W bulb. Mice were tested between 9: 00 a.m. and 4: 00 p.m. On day 1, an animal was left in the test cage for 6 min and received brief electric shocks (l/l0 Hz, 150 V, d.c. for 200 msec). The resistance varied between 50 and 250 kohms; therefore, each animal received shocks in a range of 0.63.0 mA. On day 2, the animal was placed in the same cage without receiving shocks, and its motility was recorded automatically for 6 min by means of electronic digital counters with infra-red cell sensors placed on the walls (Opto-varimex, Columbus Instruments, U.S.A.). A total of 20 sensors, 2.5 cm apart, were mounted 1.O cm above the grid floor. Control animals (nonshocked animals) received the same treatment as shocked animals except for shocks on day 1. In studying the acute effects of the drugs, testing of motility began 30 min after the intraperitoneal injection of tricyclic and tetracyclic antidepressant drugs
Table
1. Effects of imipramine, motor activitv
and, 20 min after the intraperitoneal injection of ethanol and diphenhydramine. The MAO-inhibitors were injected intraperitoneally 16 hr before testing. In studying the chronic effects of the drugs, mice were given antidepressants and diphenhydramine for 10 or 14 consecutive days, beginning 24 hr after they had received shocks. They were kept in their home cages in groups of 7-10 during chronic administration. Motility testing began 30 min or 24 hr after the last administration of saline and drugs. Imipramine-HCl (Fujisawa Pharmaceutical Co. Osaka, Japan), amitriptyrine-HCl (Yamanouchi Pharmaceutical Co. Osaka, Japan), desipramine-HCl (Fujisawa Pharmaceutical Co. Japan), dimetacrinebitartrate (Nippon Chemiphar Co. Japan), maprotiline-HCl (Ciba-Geigy Japan Ltd), mianserinHCl (Sankyo Co. Japan), pargyline-HCl (Sigma Chemical Co. U.S.A.), tranylcypromine-HCl (Sigma Chemical Co. U.S.A.), diphenhydramine-HCl (Tokyo Chemical Ind. Co. Japan) and ethanol (Wako Pure Chemical Ind. Japan) were dissolved in a solution of 0.9% NaCl. Nialamide (Pfizer Taito Co. Tokyo Japan) was suspended in a vehicle of 0.3% sodium carboxymethyl cellulose. The volume of injection was 0.1 ml per 10 g of body weight. RESULTS
Effects qf tricyclic antidepressants on the conditioned emotional response As shown in Table 1, the mice exhibited a marked suppression of motor activity, when placed in the cage where they previously received electric shocks to the feet. Imipramine-HCl (10 mg/kg) caused attenuation of the conditioned emotional response. Imipramine-HCl (2.5-20 mg/kg) significantly decreased the motor activity of non-shocked animals, in a dose-related manner. Desipramine-HCl (5,
amitryptyline, desipramine and dimetacrine of shocked and non-shocked mice Motor
on the
activity
w/kg Compounds Saline Imipramine-HCl
Amitriptyline-HCl
Desipramine-HCl
(W 1 2.5 5 10 20 1 5 10 20 1 10 20
Dimetacrine-bitartrate
I 10
Shocked
mice
374.0 f 97.7 (10) 446.7 + 143.0 (10) 594.7 k 253.3 (10) 579.8 * 182.0 (10) 951.4i242.0(10)* 356.2 f 41.2(8) 620.4+ 150.1 (10) 1299.1 + 362.1 (lo)* 925.3 f 208.1 (lo)* 635.7 + 79.8 (8) 481.3+ 154.8(10) 1235.6 f 300.7(10)* 1118.3 & 232.3 (IO)? 503.6 _+48.7 (8) 447.5 * 149.5 (10) 584.2 + 206.4 (IO) 656.0 + 149.8 (10)
Non-shocked
mice
3067.2 + 234.1 (10) 2430.1 + 300.4 (10) 1726.4 i 210.9 (lO)f 1249.4 i 320.1 (10)f 1071.5~216.6(10)~ 1153.6 f 112.1 (7)f 1178.0 i_ 143.7 (1O)f 1006.9 & 192.5 (10)f 1086.0 f 177.3 (10)f 938.9 + 68.1 (7)f 2328.8 + 209.4 (lo)* 1196.9 f 216.4(10)$ 1200.2 rt. 132.4 (1O)f 1325.8 + 78.6 (7): 2618.1 &260.2(10) 2452.7 + 172.1 (10) 2643.7 + 240.6(10)
Motor activity (number of counts, mean + SE) was recorded 30 min after administering the drugs. The number of mice used is shown in parentheses. Levels of significance: *P < 0.05; tf’ < 0.01; fP < 0.001 as compared with respective saline-pretreated groups (Student’s t-test).
287
Antidepressants on suppression of motility Table 2. Effects of nialamide, pargyline and tranylcypromine shocked and non-shocked mice
Compounds Saline Nialamide Pargyline-HCl Tranylcypromine-HCl
Motor
mglkg (i.p.)
Shocked mice 374.0 693.4 1935.6 1329.9 1447.0 493.0 847.4
50 100 100 200 10 20
on the motor activity activity Non-shocked
f 97.7 (10) + 248.4(10) + 323.3 (1O)t * 448.2 (lo)* rfI 224.6 (lo)? f 115.1 (10) + 258.6(7)
of
3067.2 2103.4 2614.1 2341.6 1685.6 3009.5 2290.7
k + + + + + k
mice
234.1 (10) 260.2 (IO)* 156.4(10) 325.6 (8) 240.0 (IO)? 243.9 (10) 183.1 (8)*
Motor activity (number of counts, mean k SE) was recorded 16 hr after administering MAO-inhibitors. The number of mice used is shown in parentheses. Levels of significance: *P < 0.05; tP < 0.001 as compared with respective saline-pretreated groups (Student’s r-test).
10 mg/kg) and amitriptyline-HCl (5, 10 mg/kg) reduced the conditioned emotional response, and decreased motor activity of the non-shocked animals. The large dose (20 mg/kg) of these drugs, however, did not cause the reduction of the conditioned emotional response. The three drugs reduced activity of the non-shocked mice at doses that did not alter the activity of the shocked mice. Dimetacrine did not affect the motility of either the shocked or nonshocked mice. Effect of MAO-inhibitors on the conditioned emotional response
As shown in Table 2, nialamide (100 mg/kg) reduced the conditioned emotional response. Only the dose of 50 mg/kg of the same drug decreased motor activity of the non-shocked animals. Pargyline-HCI (100, 200 mg/kg) reduced the conditioned emotional response, and 200 mg/kg decreased the motor activity of the non-shocked animals. Tranylcypromine-HCl did not cause a reduction of the conditioned emotional response. A dose of 20mg/kg of tranylcypromine decreased the motor activity of the nonshocked animals, and caused the death of three out of ten shocked and two out of ten non-shocked, mice. Effects of tetracyclic antidepressants, ethanol and diphenhydramine on the conditioned emotional response
As shown in Table 3, maprotiline (10, 20mg/kg) and mianserin (10, 20 mg/kg) did not cause a reducTable 3. Effects of mianserin, activity
Compounds Saline Mianserin-HCl Maprotiline-HCI Ethanol
Effects of the chronic injection of imipramine on the conditioned emotional response
As shown in Fig. la, mice receiving injections of saline for two consecutive weeks exhibited a marked suppression of motor activity when placed in the cage where they previously received shocks. Chronic administration of imipramine-HCl (l,5 mg/kg) did not cause a reduction of the conditioned emotional response at 30 min after the last treatment, whereas a similar administration (5 mg/kg) caused a decrease in the motility rate of the non-shocked mice. When the mice shown in Fig. la were tested at 24 hr after the last administration of imipramine, the conditioned emotional response was attenuated, whereas the motility of the non-shocked mice was not affected by this administration (Fig. 1b).
maprotiline, ethanol and diphenhydramine of shocked and non-shocked mice
mgikg (i.p.) 10 20 10 20 300
1000 Diphenhydramine-HCl
tion of the conditioned emotional response, although these drugs significantly decreased motor activity in the non-shocked mice. Ethanol also did not cause a reduction of the conditioned emotional response. The dose of 300 and 2000mg/kg of ethanol showed a decrease of motor activity in the non-shocked mice and a marked excitement of behavior in both the shocked and non-shocked mice, respectively. Diphenhydramine-HCl (10 and 20 mg/kg) reduced the conditioned emotional response in a dose-related manner. A dose of 20mg/kg of diphenhydramineHCl decreased the motor activity of the non-shocked animals and caused a slight convulsion in several shocked and non-shocked animals.
2000 10 20
Motor ~~
Shocked mice 150.7 165.6 192.0 150.4 170.0 249.5 230.9 109.7 295.5 1080.6
f f + f f f f + + +
36.8 (12) 56.9 (8) 69.4 (8) 34.8 (8) 50.5 (8) 65.6 (10) 32.8 (8) 33.2 (7) 63.5 (8)’ 173.8 (8)t
on the motor
activity Non-shocked 1855.9 755.3 442.1 1274.4 1163.7 1254.6 1397.6 1306.5 1671.3 1057.0
mice
f 135.9 (7) + 118.8 (7)f f 56.3 (7)$ k 153.3 (7)’ li_ 164.9 (7)t f 111.2 (7)* + 176.0(7) + 237.0 (7) + 130.7(7) * 154.1 (7)?
Motor activity (number of counts, mean f SE) was recorded 30 min after administering tetracyclic antidepressants and 20 min after other drugs. The number of mice used is shown in parentheses. Levels of significance: *P < 0.05; tP < 0.01; $P < 0.001 as compared with respective saline-pretreated groups (Student’s f-test).
T. KAMEYAMA et ul.
288 Shocked
group
Non-shocked
group
Shocked
group
Non-shocked
group
* l-i l_l lb)
d_L
1
5
s
Dose (mg/kg,
f
+
1
5
1
5
I p)
Fig. I The effect of chronic (2 week) administration of imipramine on the conditioned emotional response (CER). (a) Imipramine: motor activity was measured 30 min after the last administration. (b) Imipramine: motor activity was measured 24 hr after the last administration. S = saline-treated groups. The number of mice in each group consisted of 10 mice. Levels of significance: *P < 0.05, tP < 0.01, as compared with respective saline-treated groups (Student’s t-test).
Effects of the chronic injections of antidepressants and diphenhydramine on the conditioned emotional response As shown in Table 4, in the testing of motility at 24 hr after the last administration of saline and drugs, mice receiving saline for 10 consecutive days also exhibited a marked suppression of motor activity when placed in the cage where they previously received shocks. Chronic administration of amitriptyline, desipramine and dimetacrine for 10 days caused a marked reduction of the conditioned emotional response. The chronic treatment of maprotiline tended to reduce the conditioned emotional response (P < 0.1). Mianserin and diphenhydramine did not reduce the conditioned emotional response. The motility rate of the non-shocked mice was not affected by the chronic administration of any of these drugs. DISCUSSION
The present results that animals exhibited activity when placed in had previously received
confirmed previous findings a marked reduction of motor the environment in which they electric shocks. Acute admin-
Table 4. Effects of chronic
istration of imipramine, desipramine and amitriptyline, known as useful tricyclic antidepressants, induced attenuation of the conditioned emotional response in the middle dose of the range used, with desipramine showing the most effective attenuation. However, dimetacrine did not attenuate the conditioned emotional response. It is known that most tricyclic antidepressants block the neuronal reuptake of noradrenaline and/or serotonin in early phases of treatment (Glowinski and Axelrod, 1964). Desipramine blocks the reuptake of noradrenaline (NA) rather than serotonin (5HT). On the contrary, imipramine and amitriptyline block the reuptake of 5-HT rather than NA (Carlsson, Corrodi, Fuxe and Hukfelt, 1969; Ross and Renyi, 1967). Dimetacrine, tested on specific [3H]5-HT binding shows a similar inhibitory effect to that seen with imipramine (Segawa, Mizuta and Nomura, 1979). However, maprotiline, the most selective blocker of the reuptake of NA (Maitre, Waldmeier, Baumann and Stachelin, 1974), was found not to induce attenuation of the conditioned emotional response. These findings do not indicate that the block of the reuptake of NA is responsible for reducing the conditioned suppression.
treatment with antidepressants shocked and non-shocked mice Motor
w/kg Compounds Saline Amitnptyline-HCI Desipramine-HCI Dimetacrine-bitartrae Maprotiline-HCI Mianserin-HCI Diphenhydramine-HCI
(i.p.)
I 5 IO 5 5 IO
Shocked 73.3 k 316.3 + 244.3 + 194.6 f 229.0? 118.9 f 126.0 +
mice
17.6 (8) 125.2(6)* 64.7 (8); 39. I (8); 73.1 (8) 59.4 (8) 45.7 (7)
on the motor
activity
of
activity Non-shocked
mice
2106.2 k 196.2(7) 1951.2 & 389.5 (6) 1989.7 f 239.2 (7) 1974.0 i 268.7 (7) 1s94.5* 151.5(7) 1654.2 f 251.9 (7) 1787.3 + 313.4(7)
Mice were given antidepressants and diphenhydramine for 10 consecutive days, from 24 hr after they had been shocked. Motor activity (number of counts, mean + SE) was measured 24 hr after the last administration. The numbers in parentheses show the number of animals. Levels of significance: *P < 0.05 as compared with respective saline-treated groups (Student’s f-test).
Antidepressants on suppression of motility In addition, mianserin, which does not block the reuptake of NA and 5-HT (Goodlet, Mireylees and Sugrue, 1977), was found not to attenuate the conditioned emotional response. However, the present results indicated that the conditioned suppression could be attenuated by pretreatment with apomorphine, and that such a reduction of conditioned suppression may be related to activation of dopaminergic neurotransmission (Kameyama and Nagasaka, 1982a; Nagasaka and Kameyama, 1981). It is known, in general, that tricyclic and tetracyclic antidepressants do not affect the reuptake of dopamine, and that tricyclic antidepressants inhibit the reuptake of dopamine in the synaptic cleft (Yoshizaki and Tonda, 1981). Thus, it is possible that the reduction of the conditioned emotional response, found in the present study, was mediated by activation of dopaminergic neurotransmission in the brain. In the present study, tricyclic antidepressants, but not dimetacrine, significantly decreased motor activity of the nonshocked animals. These results correspond to the finding that the sedative effect of tricyclic antidepressants is related to the a-adrenaline blocking activity (U’Prichard, Greenberg, Sheehan and Snyder, 1978). Decreases of motility in the nonantishocked animals caused by tetracyclic depressants, as shown in the present experiment, were similar to those caused by tricyclic antidepressants. Ethanol, which has been reported to be a moodelevating agent, did not cause attenuation of the conditioned emotional response, even with a dose of 2000 mg/kg which is larger than that usually applied, although this dose in general causes marked excitement during testing of motility. Diphenhydramine, which reduces the duration of immobility as described by Porsolt (Kitada et al., 1981), caused the attenuation of conditioned suppression in a doserelated manner. A dose of 20 mg/kg of this drug induced a slight convulsion in several animals and decreased the motor activity of the non-shocked animals. It has been reported that histamine H, receptors are related to the sedative effects of tricyclic antidepressants (Langer and Raisman, 1983), and that H, receptors may be involved in the “wild fancy” phenomenon (Grimson, 1977). Thus, it may be that attenuation of the conditioned suppression, induced by acute administration of diphenhydramine, is mediated by the psychomotor mechanisms related to the “wild fancy” phenomenon. The present results showed that nialamide, a nonselective MAO-inhibitor, caused a reduction of the conditioned emotional response in a dose-related manner, and the smaller doses decreased the motor activity of the non-shocked animals. The patterns of these effects were similar to those of apomorphine. Pargyline, a B type MAO-inhibitor, (Johnston, 1968; Neff and Yang, 1974) caused a marked reduction of the conditioned emotional response in a dose-related manner, and decreased the motor activity of the non-shocked animals with the larger doses. These
289
effects may be related to the finding that acute administration of MAO inhibitors elevated levels of NA, dopamine and serotonin in the brain (Finberg and Youdim, 1983). However, the condition under which lethal doses of tranylcypromine, a nonselective MAO-inhibitor, has no effect on the conditioned emotional response, remains uncertain. The decrease of motor activity in the non-shocked animals may be less under the administration of an MAO-inhibitor than under tricyclic or tetracyclic antidepressants, probably due to the fact that an MAO-inhibitor has a limited blocking effect on E-adrenaline in the postsynaptic receptor sites. Tricyclic and tetracyclic antidepressants show, in general, anti-depressant effects in the clinical treatment of depression. In the present study, two weeks of chronic, but not acute, administration of imipramine (1, 5 mg/kg) caused a reduction of the conditioned emotional response at 24 hr, but not 30min, after the termination of this treatment. Administration of imipramine did not cause a decrease in the motility of the non-shocked mice. In most cases, the concentration of imipramine in plasma and brain falls to negligible values 24 hr after single or chronic administration (Daniel, Adamus and Melzacka, 1981; Dingell, Sulser and Gillette, 1964). Thus, the effect of imipramine at 30min after administration may have shown that the chronic action of the drug is overshadowed by the acute action. In addition, the effects of amitriptyline and desipramine produced similar effects to those imipramine in both the shocked and the non-shocked animals. Moreover, chronic, but not acute, administration of dimetacrine caused the reduction of the conditioned emotional response and maprotiline also tended to cause such an effect. On the other hand, the chronic administration of diphenhydramine did not cause a reduction of the conditioned emotional response, although acute administration did show a dose-dependent reduction. These results can be interpreted as follows: the effects of tricyclic and tetracyclic antidepressants on the conditioned emotional response are mediated by some neuronal mechanisms or some changes‘in the neuronal systems that developed during the repeated administration of the drugs, even after the effects of acute administration of tricyclic and tetracyclic antidepressants had disappeared. The chronic administration of antidepressants to reduce the conditioned emotional response in the present experiments is consistent with clinical treatment using these drugs, in that several weeks of administration are usually required for the treatment of depression. However, the chronic administration of mianserin, which was found to be effective in reducing emotional responses in a swimming test as described by Porsolt (Kitada et al., 1981) did not cause a reduction of the conditioned emotional response in the present study. This discrepancy may be related to methodological differences between the forced swimming and conditioned suppression. It may be that there is a certain similarity
290
T.
KAMEYAMA cf ul.
between the effects of tricyclic antidepressants, alleviating the depression or enhancing the motivation for everyday living in clinical cases, and those attenuating the conditioned emotional response or enhancing exploratory behavior in animals. Thus, the present finding that the conditioned emotional resDonse could be attenuated by the chronic administration of antidepressant drugs suggest that the conditioned ~rtXdXKd response paradigm is a USefUI means Of screening antidepressants. In conclusion, the common mechanism of action of tricyclic and tetracyclic antidepressants and inhibitors of MAO in reducing the
conditioned
emotional
response
in the
acute
administration paradigm remains uncertain. The chronic administration of antidepressants did produce the attenuation of the conditioned emotional response. REFERENCES
Kameyama T. and Nagasaka M. (1982a) Effects of apomorphine and diazepam on a quickly learned conditioned suppression in rats. Phormac. B&hem. Behav. 17: 59-63. Kameyama T. and Nagasaka M. (1982b) The effects of analgesics on a quickly learned conditioned suppression in mice. ~europharmac~l~g~~ 21: 1283-1289. Kameyama T. and Nagasaka M. (1983) Effects of apomorphine and methamphetamine on a quickly-learned condjtioned-suppression response in rats. Nelrropharmacology 22: 8 13-S 17. Kita& y.. Mivauchi T., Satoh A. and Satoh S. (1981) Effects antidepressants in the rat forced swimming test.
of
Eur. J. Pharmai. 72: 145-152.
Kuhn R. (1958) The treatment of depressive states with G-22355 (imipramine hydrochloride). Am. J. Ps_whiat. 115: 4S9-464.
Langer S. Z. and Raisman R. (f983) Binding of ()H)imipramine and (3H)desipramine as biochemical tools for studies in depression. Neuropharmacology 20:
407-413. Loomer H. P., Saunders J. C. and Kline N. S. (1957) A clinical and pharmacodynamic evaluation of iproniazid as a osvchic energizer. Psychiatric Research Reports (No. 8), ~0s;1;:;41, American Psychiatric Association, WashingI
Bunnev W. E. and Daris J. M. (1965) Norepinephrine in depressive reactions. Archs gen. Psychiut. l% 483494. Calsson A.. Corrodi H.. Fuxe K. and Hukfelt T. (1969) Effect of ‘antidepressant drugs on the depletion of ‘intra: neuronal brain 5-hydroxytryptamine stores caused by 4-methyl-a-ethyl-meta-tyramine. Eur. J. Pharmac. 5: 357-366.
Chen G. and Bohner B. (1961) The anti-reserpine effects of certain centrally-acting agents. f. Pharma~. exp. Ther. 131: 179-184.
Chessin M., Kramer E. R. and Scott C. C. (1957) Modifications of the pharmacology of reserpine and serotonin by iproniazid. J. Phormac. exp. Ther. 11% 453-46t’.
Coppen A. (1967) The biochemistry of affective disorders. Br. J. Psychiut. 113: 1237-1264. Costa E., Garattini S. and Valzelli L. (1960) Interactions between reserpine, chlorpromazine, and imipramine. Experientia 16: 461-463.
Daniel W., Adamus A. and Meizacka M. (1981) Cerebral pharmaco-kinetics of imipramine in rats after single and multiple dosages. Nauqn -Schmiedeberg,r Arch. Pharmac. 317: 209-213.
Dingell J. V., Sulser F. and Gillette J. R. (1964) Species differences in the metabolism of imipramine and desmethylimipramine (DMI). J. Pharmac. exp. Ther. 143: 14-22. Finberg J. P. L. and Youdim M. B. H. (1983) Selective MAO A and B inhibitors: their mechanism of action and pharmacology. Neuropharmacology 22: 441-446. Garzon J. and Rio J. D. (1981) Hyperactivity induced in rats by long term isolation: Further studies in a new animal model for the detection of antidepressants. Eur. J. Pharmat. 74: 287-294.
Glowinski J. and Axelrod J. (1964) inhibition of uptake of tritiated noradrenaline in the intact rat brain by imipramine and structurally related compounds. Nature 204: 1318-1319. Goodlet S. E., Mireylees S. E. and Sugrue M. F. (1977) Effects of mianserin, a new antidepressant, on the in uivo and in vitro uptake of monoamines. Br. J. Pharmac. 61: 307-313. Grimson T. A. (1977) Reactions to cimetidine. Lancer 1: 858. Hatotani N., Nomura J., Inoue K. and Kitayama I. (1979) Psychoendocrine of depression. Psychonertroendocrirlology 4: 155-172.
Johnston J. P. (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem. Pharmac. 17: 1285-I 297.
,
1
,
Maitre L., Waldmeier P. C., Baumann P. A. and Stachelin M. (1974) Serotonin-new vistas. In: Histochemistry and Pharmacology, Vol. 10, p. 297. Raven Press, New York. Nagasaka M. and Kameyama T. (1981) Involvement of dopamine on the quickly learned conditioned suppression (OLCS) in rats. Jup. J. Pharmac. 31: Swol. 163 P. Nagisaka M. and Kameyama T. (1983) Effe% of diazepam, meprobamate, chlorpromazine and apomorphine on a quickly learned conditioned suppression in mice. 1. Pharmat. Dyn. 6: 523-526. Nefl’ N. H. and Yang H.-Y. T. (1974) Another look at the
monoamine oxidases and the monoamine oxidase inhibitor drugs. Life Sri. 14: 2061-2074. Oswald I., Brezinova V. and Dunleavy D. L. (1972) On the slowness of action of tricyclic antidepressant drugs. Br. J. Psych&.
120: 673-677.
Porsolt R. D., Pichon M. L. E. and Jalfre M. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730-732. Post R. M., Kotin J. and Goodwin F. K. (1974) The effect of cocaine on depressed patients. A!n. J. Psyrhint. 131: 51 I-517. Ross S. B. and Renyi A. L. (1967) Inhibition of the uptake of tritiated catecholamines by antidepressant and related agents. Eur. J. Pharmac. 2: 181.-186. Schildkraut J. J. (1965) The catecholamine hypothesis of affective disorders: A review of supporting evidence. An?. J. Psychiat. 122: 509-522.
Segawa T., Mizuta T. and Nomura Y. (1979) Modifications of central S-hydroxytryptamine binding sites in synaptic membranes from rat brain after long-term administration of tricyclic antidepressants. Eur. J. Pharmuc. 58: 75-83. Seligman M. E. P. and Maier S. F. (1967) Failure to escape traumatic shock. J. exp. Psychol. 74: l-9. Sherman A. D., Sacquitne J. L. and Petty F. (1982) Specificity of the learned helplessness model of depression. Pharmnc. Biochern. Behau. 16: 449-454. Telner J. I. and Singhai R. L. (1981) Effects of nortriptyline treatment on learned helplessness in the rat. Pharmac. Biochem. Behav. 14: 823-826. U’Prichard D. C., Greenberg D. A., Sheehan P. P. and Snvder S. H. (1978) Tricvclic antidepressants: therapeuric properties ani affinity fdr a-noradrenergic recepto; binding sites in the brain. Science 199: 1977198. Yoshizaki T. and Tonda K. (1981) Effects of tricyclic antidepressants on tetrabenazine-induced depletion of brain monoamines in rats. 2. Dopamine. Jap. J. Ph~rmac. 31: 433-449.
Neur~~p,phrrmtrrco/og~ Vol. 24. No. 4. pp. 285-290. 1985 Printed in Great Bntaln. All rights reserved
EFFECTS OF ANTIDEPRESSANT DRUGS ON A QUICKLY-LEARNED CONDITIONED-SUPPRESSION RESPONSE IN MICE T. KAMEYAMA,M. NAGASAKA and K. YAMADA Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, Meijo University,
Nagoya
468, Japan (Accepted
12 July 1984)
Summary-Mice experienced to electric shock, exhibited a marked suppression of motor activity when placed in the same cage 24 hr after administration of shocks. Acute administration of imipramine-HCl (lOmg/kg, i.p.), desipramine-HCI (5 and 10 mg/kg, i.p.) and amitriptyline-HCl (5 and lOmg/kg, i.p.) caused marked reduction of the conditioned suppression of shocked mice, but reduced the motor activity of the non-shocked mice. Maprotiline, mianserin and dimetacrine did not cause reduction of the conditioned suppression. Nialamide (100 mg/kg, i.p.) and pargyline-HCl (100 and 200 mg/kg, i.p.) caused
marked reduction of the conditioned suppression but did not increase the motor activity of the non-shocked mice, and tranylcypromine-HCl (10 and 20mg/kg, i.p.) did not cause reduction of the conditioned suppression. Diphenhydramine-HCl (10 and 20 mg/kg, i.p.) reduced the conditioned suppression of shocked mice in a dose-related manner. Chronic administration of imipramine-HCl (1 and Smg/kg, i.p.) for 14 days significantly reduced the conditioned suppression but did not influence the motility rate of the non-shocked mice. Also, chronic administration of amitriptyline (1 mg/kg, i.p.), desipramine (5 mg/kg, Lp.) and dimetacrine (lOmg/kg, i.p.), for 10 days, significantly reduced the conditioned suppression, but did not influence the motility rate of the non-shocked mice. Chronic administration of maprotiline reduced the conditioned suppression. On the other hand, chronic administration of mianserin (5 mg/kg, i.p.) and diphenhydramine (10 mg/kg, i.p.) did not cause a reduction of the conditioned suppression. Key words: tricyclic pression, mice.
antidepressants,
tetracyclic
The effects of drugs on animal behavior which resembles human depression have been studied since the clinical application of iproniazide and imipramine (Kuhn, 1958; Loomer, Saunders and Kline, 1957). Reserpine-induced depression (Chen and Bohner, 1961; Chessin, Kramer and Scott, 1957; Costa, Garattini and Valzelli, 1960), learned helplessness (Seligman and Maier, 1967; Sherman, Sacquitne and Petty, 1982; Telner and Singhal, 1981), swimming (Kitada, Miyauchi, Satoh and Satoh, 1981; Porsolt, Pichon and Jalfre, 1977) and models of stress (Garzon and Rio, 1981; Hatotani, Nomura, Inoue and Kitayama, 1979) have been used. Animal behavior resembling human depression has provided useful means for studying antidepressant drugs which are applicable clinically and central nervous-system stimulants. There have been reports of studies concerning the monoamine-hypothesis of depression (Bunney and Daris, 1965; Coppen, 1967; Schildkraut, 1965). Most tricyclic antidepressant drugs block the neuronal reuptake of norepinephrine and/or serotonin (Glowinski and Axelrod, 1964). However, several weeks of treatment with tricyclic antidepressants are usually required for alleviating depression (Oswald, Brezinova and Dunleavy, 1972). Cocaine, however, an inhibitor of the uptake of monoamines, did not
antidepressants,
MAO-inhibitors,
conditioned
sup
relieve the symptoms of depression (Post, Kotin and Goodwin, 1974). Under the circumstances, these findings corroborate the view that there is a difference between acute and chronic effects of antidepressants. Previous studies have shown that animals exhibited a marked suppression of motor activity when placed in a chamber without shocks where they previously received shocks, whereas non-shocked animals did not exhibit such a suppression (Kameyama and Nagasaka, 1982a,1982b). The conditioned suppression is considered as a continuous conditioned emotional response (CER) to a situation associated with shocks. This conditioned suppression was reduced by pretreatment with apomorphine and methamphetamine, but not with diazepam, chlorpromazine and haloperidol (Kameyama and Nagasaka, 1983; Nagasaka and Kameyama, 1983). Thus, it is possible that conditioned suppression, studied in the present experiments, is related to the depression of motor activity caused by the motivational deficit to explore when animals were placed in the new situation, and that such a conditioned suppression resembles the clinical symptoms of human depression. The conditioned suppression paradigm may be useful for screening new antidepressant drugs, provided the suppression could be attenuated by pretreatment with clinicallyapplicable antidepressants. In the present study, an 285
286
T.
KAMEYA.MA et al
attempt was made to clarify the effects of three tricyclic and two tetracyclic antidepressants, three inhibitors of monoamine oxidase (MAO), ethanol and diphenhydramine, and the effects of the chronic administration of antidepressants and diphenhydramine, on the patterns of suppression within the conditioned emotional response paradigm of mice. METHODS
Male ddY mice, 8-10 weeks of age, were housed in cages in groups of 10 under constant environment conditions (22 f 0.5”C, 50 + 5% relative humidity) and given food and water ad libitum. The room lights were turned off between 8:00 p.m. and 8: 00 a.m. Experiments were carried out using a transparent acrylic rectangular cage (24.5 x 31 x 30cm), equipped with a metallic grid floor. The apparatus was located in a sound-attenuating room, illuminated with a 20-W bulb. Mice were tested between 9: 00 a.m. and 4: 00 p.m. On day 1, an animal was left in the test cage for 6 min and received brief electric shocks (l/l0 Hz, 150 V, d.c. for 200 msec). The resistance varied between 50 and 250 kohms; therefore, each animal received shocks in a range of 0.63.0 mA. On day 2, the animal was placed in the same cage without receiving shocks, and its motility was recorded automatically for 6 min by means of electronic digital counters with infra-red cell sensors placed on the walls (Opto-varimex, Columbus Instruments, U.S.A.). A total of 20 sensors, 2.5 cm apart, were mounted 1.O cm above the grid floor. Control animals (nonshocked animals) received the same treatment as shocked animals except for shocks on day 1. In studying the acute effects of the drugs, testing of motility began 30 min after the intraperitoneal injection of tricyclic and tetracyclic antidepressant drugs
Table
1. Effects of imipramine, motor activitv
and, 20 min after the intraperitoneal injection of ethanol and diphenhydramine. The MAO-inhibitors were injected intraperitoneally 16 hr before testing. In studying the chronic effects of the drugs, mice were given antidepressants and diphenhydramine for 10 or 14 consecutive days, beginning 24 hr after they had received shocks. They were kept in their home cages in groups of 7-10 during chronic administration. Motility testing began 30 min or 24 hr after the last administration of saline and drugs. Imipramine-HCl (Fujisawa Pharmaceutical Co. Osaka, Japan), amitriptyrine-HCl (Yamanouchi Pharmaceutical Co. Osaka, Japan), desipramine-HCl (Fujisawa Pharmaceutical Co. Japan), dimetacrinebitartrate (Nippon Chemiphar Co. Japan), maprotiline-HCl (Ciba-Geigy Japan Ltd), mianserinHCl (Sankyo Co. Japan), pargyline-HCl (Sigma Chemical Co. U.S.A.), tranylcypromine-HCl (Sigma Chemical Co. U.S.A.), diphenhydramine-HCl (Tokyo Chemical Ind. Co. Japan) and ethanol (Wako Pure Chemical Ind. Japan) were dissolved in a solution of 0.9% NaCl. Nialamide (Pfizer Taito Co. Tokyo Japan) was suspended in a vehicle of 0.3% sodium carboxymethyl cellulose. The volume of injection was 0.1 ml per 10 g of body weight. RESULTS
Effects qf tricyclic antidepressants on the conditioned emotional response As shown in Table 1, the mice exhibited a marked suppression of motor activity, when placed in the cage where they previously received electric shocks to the feet. Imipramine-HCl (10 mg/kg) caused attenuation of the conditioned emotional response. Imipramine-HCl (2.5-20 mg/kg) significantly decreased the motor activity of non-shocked animals, in a dose-related manner. Desipramine-HCl (5,
amitryptyline, desipramine and dimetacrine of shocked and non-shocked mice Motor
on the
activity
w/kg Compounds Saline Imipramine-HCl
Amitriptyline-HCl
Desipramine-HCl
(W 1 2.5 5 10 20 1 5 10 20 1 10 20
Dimetacrine-bitartrate
I 10
Shocked
mice
374.0 f 97.7 (10) 446.7 + 143.0 (10) 594.7 k 253.3 (10) 579.8 * 182.0 (10) 951.4i242.0(10)* 356.2 f 41.2(8) 620.4+ 150.1 (10) 1299.1 + 362.1 (lo)* 925.3 f 208.1 (lo)* 635.7 + 79.8 (8) 481.3+ 154.8(10) 1235.6 f 300.7(10)* 1118.3 & 232.3 (IO)? 503.6 _+48.7 (8) 447.5 * 149.5 (10) 584.2 + 206.4 (IO) 656.0 + 149.8 (10)
Non-shocked
mice
3067.2 + 234.1 (10) 2430.1 + 300.4 (10) 1726.4 i 210.9 (lO)f 1249.4 i 320.1 (10)f 1071.5~216.6(10)~ 1153.6 f 112.1 (7)f 1178.0 i_ 143.7 (1O)f 1006.9 & 192.5 (10)f 1086.0 f 177.3 (10)f 938.9 + 68.1 (7)f 2328.8 + 209.4 (lo)* 1196.9 f 216.4(10)$ 1200.2 rt. 132.4 (1O)f 1325.8 + 78.6 (7): 2618.1 &260.2(10) 2452.7 + 172.1 (10) 2643.7 + 240.6(10)
Motor activity (number of counts, mean + SE) was recorded 30 min after administering the drugs. The number of mice used is shown in parentheses. Levels of significance: *P < 0.05; tf’ < 0.01; fP < 0.001 as compared with respective saline-pretreated groups (Student’s t-test).
287
Antidepressants on suppression of motility Table 2. Effects of nialamide, pargyline and tranylcypromine shocked and non-shocked mice
Compounds Saline Nialamide Pargyline-HCl Tranylcypromine-HCl
Motor
mglkg (i.p.)
Shocked mice 374.0 693.4 1935.6 1329.9 1447.0 493.0 847.4
50 100 100 200 10 20
on the motor activity activity Non-shocked
f 97.7 (10) + 248.4(10) + 323.3 (1O)t * 448.2 (lo)* rfI 224.6 (lo)? f 115.1 (10) + 258.6(7)
of
3067.2 2103.4 2614.1 2341.6 1685.6 3009.5 2290.7
k + + + + + k
mice
234.1 (10) 260.2 (IO)* 156.4(10) 325.6 (8) 240.0 (IO)? 243.9 (10) 183.1 (8)*
Motor activity (number of counts, mean k SE) was recorded 16 hr after administering MAO-inhibitors. The number of mice used is shown in parentheses. Levels of significance: *P < 0.05; tP < 0.001 as compared with respective saline-pretreated groups (Student’s r-test).
10 mg/kg) and amitriptyline-HCl (5, 10 mg/kg) reduced the conditioned emotional response, and decreased motor activity of the non-shocked animals. The large dose (20 mg/kg) of these drugs, however, did not cause the reduction of the conditioned emotional response. The three drugs reduced activity of the non-shocked mice at doses that did not alter the activity of the shocked mice. Dimetacrine did not affect the motility of either the shocked or nonshocked mice. Effect of MAO-inhibitors on the conditioned emotional response
As shown in Table 2, nialamide (100 mg/kg) reduced the conditioned emotional response. Only the dose of 50 mg/kg of the same drug decreased motor activity of the non-shocked animals. Pargyline-HCI (100, 200 mg/kg) reduced the conditioned emotional response, and 200 mg/kg decreased the motor activity of the non-shocked animals. Tranylcypromine-HCl did not cause a reduction of the conditioned emotional response. A dose of 20mg/kg of tranylcypromine decreased the motor activity of the nonshocked animals, and caused the death of three out of ten shocked and two out of ten non-shocked, mice. Effects of tetracyclic antidepressants, ethanol and diphenhydramine on the conditioned emotional response
As shown in Table 3, maprotiline (10, 20mg/kg) and mianserin (10, 20 mg/kg) did not cause a reducTable 3. Effects of mianserin, activity
Compounds Saline Mianserin-HCl Maprotiline-HCI Ethanol
Effects of the chronic injection of imipramine on the conditioned emotional response
As shown in Fig. la, mice receiving injections of saline for two consecutive weeks exhibited a marked suppression of motor activity when placed in the cage where they previously received shocks. Chronic administration of imipramine-HCl (l,5 mg/kg) did not cause a reduction of the conditioned emotional response at 30 min after the last treatment, whereas a similar administration (5 mg/kg) caused a decrease in the motility rate of the non-shocked mice. When the mice shown in Fig. la were tested at 24 hr after the last administration of imipramine, the conditioned emotional response was attenuated, whereas the motility of the non-shocked mice was not affected by this administration (Fig. 1b).
maprotiline, ethanol and diphenhydramine of shocked and non-shocked mice
mgikg (i.p.) 10 20 10 20 300
1000 Diphenhydramine-HCl
tion of the conditioned emotional response, although these drugs significantly decreased motor activity in the non-shocked mice. Ethanol also did not cause a reduction of the conditioned emotional response. The dose of 300 and 2000mg/kg of ethanol showed a decrease of motor activity in the non-shocked mice and a marked excitement of behavior in both the shocked and non-shocked mice, respectively. Diphenhydramine-HCl (10 and 20 mg/kg) reduced the conditioned emotional response in a dose-related manner. A dose of 20mg/kg of diphenhydramineHCl decreased the motor activity of the non-shocked animals and caused a slight convulsion in several shocked and non-shocked animals.
2000 10 20
Motor ~~
Shocked mice 150.7 165.6 192.0 150.4 170.0 249.5 230.9 109.7 295.5 1080.6
f f + f f f f + + +
36.8 (12) 56.9 (8) 69.4 (8) 34.8 (8) 50.5 (8) 65.6 (10) 32.8 (8) 33.2 (7) 63.5 (8)’ 173.8 (8)t
on the motor
activity Non-shocked 1855.9 755.3 442.1 1274.4 1163.7 1254.6 1397.6 1306.5 1671.3 1057.0
mice
f 135.9 (7) + 118.8 (7)f f 56.3 (7)$ k 153.3 (7)’ li_ 164.9 (7)t f 111.2 (7)* + 176.0(7) + 237.0 (7) + 130.7(7) * 154.1 (7)?
Motor activity (number of counts, mean f SE) was recorded 30 min after administering tetracyclic antidepressants and 20 min after other drugs. The number of mice used is shown in parentheses. Levels of significance: *P < 0.05; tP < 0.01; $P < 0.001 as compared with respective saline-pretreated groups (Student’s f-test).
T. KAMEYAMA et ul.
288 Shocked
group
Non-shocked
group
Shocked
group
Non-shocked
group
* l-i l_l lb)
d_L
1
5
s
Dose (mg/kg,
f
+
1
5
1
5
I p)
Fig. I The effect of chronic (2 week) administration of imipramine on the conditioned emotional response (CER). (a) Imipramine: motor activity was measured 30 min after the last administration. (b) Imipramine: motor activity was measured 24 hr after the last administration. S = saline-treated groups. The number of mice in each group consisted of 10 mice. Levels of significance: *P < 0.05, tP < 0.01, as compared with respective saline-treated groups (Student’s t-test).
Effects of the chronic injections of antidepressants and diphenhydramine on the conditioned emotional response As shown in Table 4, in the testing of motility at 24 hr after the last administration of saline and drugs, mice receiving saline for 10 consecutive days also exhibited a marked suppression of motor activity when placed in the cage where they previously received shocks. Chronic administration of amitriptyline, desipramine and dimetacrine for 10 days caused a marked reduction of the conditioned emotional response. The chronic treatment of maprotiline tended to reduce the conditioned emotional response (P < 0.1). Mianserin and diphenhydramine did not reduce the conditioned emotional response. The motility rate of the non-shocked mice was not affected by the chronic administration of any of these drugs. DISCUSSION
The present results that animals exhibited activity when placed in had previously received
confirmed previous findings a marked reduction of motor the environment in which they electric shocks. Acute admin-
Table 4. Effects of chronic
istration of imipramine, desipramine and amitriptyline, known as useful tricyclic antidepressants, induced attenuation of the conditioned emotional response in the middle dose of the range used, with desipramine showing the most effective attenuation. However, dimetacrine did not attenuate the conditioned emotional response. It is known that most tricyclic antidepressants block the neuronal reuptake of noradrenaline and/or serotonin in early phases of treatment (Glowinski and Axelrod, 1964). Desipramine blocks the reuptake of noradrenaline (NA) rather than serotonin (5HT). On the contrary, imipramine and amitriptyline block the reuptake of 5-HT rather than NA (Carlsson, Corrodi, Fuxe and Hukfelt, 1969; Ross and Renyi, 1967). Dimetacrine, tested on specific [3H]5-HT binding shows a similar inhibitory effect to that seen with imipramine (Segawa, Mizuta and Nomura, 1979). However, maprotiline, the most selective blocker of the reuptake of NA (Maitre, Waldmeier, Baumann and Stachelin, 1974), was found not to induce attenuation of the conditioned emotional response. These findings do not indicate that the block of the reuptake of NA is responsible for reducing the conditioned suppression.
treatment with antidepressants shocked and non-shocked mice Motor
w/kg Compounds Saline Amitnptyline-HCI Desipramine-HCI Dimetacrine-bitartrae Maprotiline-HCI Mianserin-HCI Diphenhydramine-HCI
(i.p.)
I 5 IO 5 5 IO
Shocked 73.3 k 316.3 + 244.3 + 194.6 f 229.0? 118.9 f 126.0 +
mice
17.6 (8) 125.2(6)* 64.7 (8); 39. I (8); 73.1 (8) 59.4 (8) 45.7 (7)
on the motor
activity
of
activity Non-shocked
mice
2106.2 k 196.2(7) 1951.2 & 389.5 (6) 1989.7 f 239.2 (7) 1974.0 i 268.7 (7) 1s94.5* 151.5(7) 1654.2 f 251.9 (7) 1787.3 + 313.4(7)
Mice were given antidepressants and diphenhydramine for 10 consecutive days, from 24 hr after they had been shocked. Motor activity (number of counts, mean + SE) was measured 24 hr after the last administration. The numbers in parentheses show the number of animals. Levels of significance: *P < 0.05 as compared with respective saline-treated groups (Student’s f-test).
Antidepressants on suppression of motility In addition, mianserin, which does not block the reuptake of NA and 5-HT (Goodlet, Mireylees and Sugrue, 1977), was found not to attenuate the conditioned emotional response. However, the present results indicated that the conditioned suppression could be attenuated by pretreatment with apomorphine, and that such a reduction of conditioned suppression may be related to activation of dopaminergic neurotransmission (Kameyama and Nagasaka, 1982a; Nagasaka and Kameyama, 1981). It is known, in general, that tricyclic and tetracyclic antidepressants do not affect the reuptake of dopamine, and that tricyclic antidepressants inhibit the reuptake of dopamine in the synaptic cleft (Yoshizaki and Tonda, 1981). Thus, it is possible that the reduction of the conditioned emotional response, found in the present study, was mediated by activation of dopaminergic neurotransmission in the brain. In the present study, tricyclic antidepressants, but not dimetacrine, significantly decreased motor activity of the nonshocked animals. These results correspond to the finding that the sedative effect of tricyclic antidepressants is related to the a-adrenaline blocking activity (U’Prichard, Greenberg, Sheehan and Snyder, 1978). Decreases of motility in the nonantishocked animals caused by tetracyclic depressants, as shown in the present experiment, were similar to those caused by tricyclic antidepressants. Ethanol, which has been reported to be a moodelevating agent, did not cause attenuation of the conditioned emotional response, even with a dose of 2000 mg/kg which is larger than that usually applied, although this dose in general causes marked excitement during testing of motility. Diphenhydramine, which reduces the duration of immobility as described by Porsolt (Kitada et al., 1981), caused the attenuation of conditioned suppression in a doserelated manner. A dose of 20 mg/kg of this drug induced a slight convulsion in several animals and decreased the motor activity of the non-shocked animals. It has been reported that histamine H, receptors are related to the sedative effects of tricyclic antidepressants (Langer and Raisman, 1983), and that H, receptors may be involved in the “wild fancy” phenomenon (Grimson, 1977). Thus, it may be that attenuation of the conditioned suppression, induced by acute administration of diphenhydramine, is mediated by the psychomotor mechanisms related to the “wild fancy” phenomenon. The present results showed that nialamide, a nonselective MAO-inhibitor, caused a reduction of the conditioned emotional response in a dose-related manner, and the smaller doses decreased the motor activity of the non-shocked animals. The patterns of these effects were similar to those of apomorphine. Pargyline, a B type MAO-inhibitor, (Johnston, 1968; Neff and Yang, 1974) caused a marked reduction of the conditioned emotional response in a dose-related manner, and decreased the motor activity of the non-shocked animals with the larger doses. These
289
effects may be related to the finding that acute administration of MAO inhibitors elevated levels of NA, dopamine and serotonin in the brain (Finberg and Youdim, 1983). However, the condition under which lethal doses of tranylcypromine, a nonselective MAO-inhibitor, has no effect on the conditioned emotional response, remains uncertain. The decrease of motor activity in the non-shocked animals may be less under the administration of an MAO-inhibitor than under tricyclic or tetracyclic antidepressants, probably due to the fact that an MAO-inhibitor has a limited blocking effect on E-adrenaline in the postsynaptic receptor sites. Tricyclic and tetracyclic antidepressants show, in general, anti-depressant effects in the clinical treatment of depression. In the present study, two weeks of chronic, but not acute, administration of imipramine (1, 5 mg/kg) caused a reduction of the conditioned emotional response at 24 hr, but not 30min, after the termination of this treatment. Administration of imipramine did not cause a decrease in the motility of the non-shocked mice. In most cases, the concentration of imipramine in plasma and brain falls to negligible values 24 hr after single or chronic administration (Daniel, Adamus and Melzacka, 1981; Dingell, Sulser and Gillette, 1964). Thus, the effect of imipramine at 30min after administration may have shown that the chronic action of the drug is overshadowed by the acute action. In addition, the effects of amitriptyline and desipramine produced similar effects to those imipramine in both the shocked and the non-shocked animals. Moreover, chronic, but not acute, administration of dimetacrine caused the reduction of the conditioned emotional response and maprotiline also tended to cause such an effect. On the other hand, the chronic administration of diphenhydramine did not cause a reduction of the conditioned emotional response, although acute administration did show a dose-dependent reduction. These results can be interpreted as follows: the effects of tricyclic and tetracyclic antidepressants on the conditioned emotional response are mediated by some neuronal mechanisms or some changes‘in the neuronal systems that developed during the repeated administration of the drugs, even after the effects of acute administration of tricyclic and tetracyclic antidepressants had disappeared. The chronic administration of antidepressants to reduce the conditioned emotional response in the present experiments is consistent with clinical treatment using these drugs, in that several weeks of administration are usually required for the treatment of depression. However, the chronic administration of mianserin, which was found to be effective in reducing emotional responses in a swimming test as described by Porsolt (Kitada et al., 1981) did not cause a reduction of the conditioned emotional response in the present study. This discrepancy may be related to methodological differences between the forced swimming and conditioned suppression. It may be that there is a certain similarity
290
T.
KAMEYAMA cf ul.
between the effects of tricyclic antidepressants, alleviating the depression or enhancing the motivation for everyday living in clinical cases, and those attenuating the conditioned emotional response or enhancing exploratory behavior in animals. Thus, the present finding that the conditioned emotional resDonse could be attenuated by the chronic administration of antidepressant drugs suggest that the conditioned ~rtXdXKd response paradigm is a USefUI means Of screening antidepressants. In conclusion, the common mechanism of action of tricyclic and tetracyclic antidepressants and inhibitors of MAO in reducing the
conditioned
emotional
response
in the
acute
administration paradigm remains uncertain. The chronic administration of antidepressants did produce the attenuation of the conditioned emotional response. REFERENCES
Kameyama T. and Nagasaka M. (1982a) Effects of apomorphine and diazepam on a quickly learned conditioned suppression in rats. Phormac. B&hem. Behav. 17: 59-63. Kameyama T. and Nagasaka M. (1982b) The effects of analgesics on a quickly learned conditioned suppression in mice. ~europharmac~l~g~~ 21: 1283-1289. Kameyama T. and Nagasaka M. (1983) Effects of apomorphine and methamphetamine on a quickly-learned condjtioned-suppression response in rats. Nelrropharmacology 22: 8 13-S 17. Kita& y.. Mivauchi T., Satoh A. and Satoh S. (1981) Effects antidepressants in the rat forced swimming test.
of
Eur. J. Pharmai. 72: 145-152.
Kuhn R. (1958) The treatment of depressive states with G-22355 (imipramine hydrochloride). Am. J. Ps_whiat. 115: 4S9-464.
Langer S. Z. and Raisman R. (f983) Binding of ()H)imipramine and (3H)desipramine as biochemical tools for studies in depression. Neuropharmacology 20:
407-413. Loomer H. P., Saunders J. C. and Kline N. S. (1957) A clinical and pharmacodynamic evaluation of iproniazid as a osvchic energizer. Psychiatric Research Reports (No. 8), ~0s;1;:;41, American Psychiatric Association, WashingI
Bunnev W. E. and Daris J. M. (1965) Norepinephrine in depressive reactions. Archs gen. Psychiut. l% 483494. Calsson A.. Corrodi H.. Fuxe K. and Hukfelt T. (1969) Effect of ‘antidepressant drugs on the depletion of ‘intra: neuronal brain 5-hydroxytryptamine stores caused by 4-methyl-a-ethyl-meta-tyramine. Eur. J. Pharmac. 5: 357-366.
Chen G. and Bohner B. (1961) The anti-reserpine effects of certain centrally-acting agents. f. Pharma~. exp. Ther. 131: 179-184.
Chessin M., Kramer E. R. and Scott C. C. (1957) Modifications of the pharmacology of reserpine and serotonin by iproniazid. J. Phormac. exp. Ther. 11% 453-46t’.
Coppen A. (1967) The biochemistry of affective disorders. Br. J. Psychiut. 113: 1237-1264. Costa E., Garattini S. and Valzelli L. (1960) Interactions between reserpine, chlorpromazine, and imipramine. Experientia 16: 461-463.
Daniel W., Adamus A. and Meizacka M. (1981) Cerebral pharmaco-kinetics of imipramine in rats after single and multiple dosages. Nauqn -Schmiedeberg,r Arch. Pharmac. 317: 209-213.
Dingell J. V., Sulser F. and Gillette J. R. (1964) Species differences in the metabolism of imipramine and desmethylimipramine (DMI). J. Pharmac. exp. Ther. 143: 14-22. Finberg J. P. L. and Youdim M. B. H. (1983) Selective MAO A and B inhibitors: their mechanism of action and pharmacology. Neuropharmacology 22: 441-446. Garzon J. and Rio J. D. (1981) Hyperactivity induced in rats by long term isolation: Further studies in a new animal model for the detection of antidepressants. Eur. J. Pharmat. 74: 287-294.
Glowinski J. and Axelrod J. (1964) inhibition of uptake of tritiated noradrenaline in the intact rat brain by imipramine and structurally related compounds. Nature 204: 1318-1319. Goodlet S. E., Mireylees S. E. and Sugrue M. F. (1977) Effects of mianserin, a new antidepressant, on the in uivo and in vitro uptake of monoamines. Br. J. Pharmac. 61: 307-313. Grimson T. A. (1977) Reactions to cimetidine. Lancer 1: 858. Hatotani N., Nomura J., Inoue K. and Kitayama I. (1979) Psychoendocrine of depression. Psychonertroendocrirlology 4: 155-172.
Johnston J. P. (1968) Some observations upon a new inhibitor of monoamine oxidase in brain tissue. Biochem. Pharmac. 17: 1285-I 297.
,
1
,
Maitre L., Waldmeier P. C., Baumann P. A. and Stachelin M. (1974) Serotonin-new vistas. In: Histochemistry and Pharmacology, Vol. 10, p. 297. Raven Press, New York. Nagasaka M. and Kameyama T. (1981) Involvement of dopamine on the quickly learned conditioned suppression (OLCS) in rats. Jup. J. Pharmac. 31: Swol. 163 P. Nagisaka M. and Kameyama T. (1983) Effe% of diazepam, meprobamate, chlorpromazine and apomorphine on a quickly learned conditioned suppression in mice. 1. Pharmat. Dyn. 6: 523-526. Nefl’ N. H. and Yang H.-Y. T. (1974) Another look at the
monoamine oxidases and the monoamine oxidase inhibitor drugs. Life Sri. 14: 2061-2074. Oswald I., Brezinova V. and Dunleavy D. L. (1972) On the slowness of action of tricyclic antidepressant drugs. Br. J. Psych&.
120: 673-677.
Porsolt R. D., Pichon M. L. E. and Jalfre M. (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266: 730-732. Post R. M., Kotin J. and Goodwin F. K. (1974) The effect of cocaine on depressed patients. A!n. J. Psyrhint. 131: 51 I-517. Ross S. B. and Renyi A. L. (1967) Inhibition of the uptake of tritiated catecholamines by antidepressant and related agents. Eur. J. Pharmac. 2: 181.-186. Schildkraut J. J. (1965) The catecholamine hypothesis of affective disorders: A review of supporting evidence. An?. J. Psychiat. 122: 509-522.
Segawa T., Mizuta T. and Nomura Y. (1979) Modifications of central S-hydroxytryptamine binding sites in synaptic membranes from rat brain after long-term administration of tricyclic antidepressants. Eur. J. Pharmuc. 58: 75-83. Seligman M. E. P. and Maier S. F. (1967) Failure to escape traumatic shock. J. exp. Psychol. 74: l-9. Sherman A. D., Sacquitne J. L. and Petty F. (1982) Specificity of the learned helplessness model of depression. Pharmnc. Biochern. Behau. 16: 449-454. Telner J. I. and Singhai R. L. (1981) Effects of nortriptyline treatment on learned helplessness in the rat. Pharmac. Biochem. Behav. 14: 823-826. U’Prichard D. C., Greenberg D. A., Sheehan P. P. and Snvder S. H. (1978) Tricvclic antidepressants: therapeuric properties ani affinity fdr a-noradrenergic recepto; binding sites in the brain. Science 199: 1977198. Yoshizaki T. and Tonda K. (1981) Effects of tricyclic antidepressants on tetrabenazine-induced depletion of brain monoamines in rats. 2. Dopamine. Jap. J. Ph~rmac. 31: 433-449.