Copyright © 2004 by Institute of Pharmacology Polish Journal of Pharmacology Polish Academy of Sciences Pol. J. Pharmacol., 2004, 56, 519–526 ISSN 1230-6002

ANXIOLYTIC- AND -LIKE EFFECTS OF 7-OH-DPAT, PREFERENTIAL D3 , IN RATS

Zofia Rogó¿1,#, Gra¿yna Skuza1, Aleksandra K³odziñska2 Department of Pharmacology, Department of New Research, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Anxiolytic- and antidepressant-like effects of 7-OH-DPAT, preferential dopamine D! receptor agonist, in rats. Z. ROGÓ¯, G. SKUZA, A. K£O- DZIÑSKA, Pol. J. Pharmacol., 2004, 56, 519–526.

The aim of the present study was to examine a potential anxiolytic- and antidepressant-like action of (+)-7-hydroxy-2-(di-n-propylamino)tetralin hy- drobromide (7-OH-DPAT), a preferential dopamine D! receptor agonist, and N-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl}-2-naphthylcarboxamide (BP 897), a partial dopamine D! receptor agonist, in male Wistar rats. Diaze- pam or were used as reference compounds. The anxiolytic-like effect of those was tested in the elevated plus-maze test. The anti- depressant-like effect was estimated using the forced swimming test. The obtained results showed that 7-OH-DPAT at low doses and BP 897 (like ) induced anxiolytic-like effects in the elevated plus-maze test. 7-OH-DPAT, BP 897 and diazepam, tested at the doses effective in the model of anxiolytic-like actions, did not affect motor coordination. Moreover, 7-OH-DPAT at higher doses, like imipramine, showed antidepressant-like ef- fect, significantly reducing immobility time in the forced swimming test. Combined treatment with 7-OH-DPAT and imipramine induced a stronger effect in Porsolt’s test than administration of either drug alone, but did not increase the locomotor activity. In contrast, BP 897 was inactive in the forced swimming test when given alone but it potentiated the antidepres- sant-like effect of imipramine. These data suggest that preferential D! receptor may play a role in the therapy of anxiety and/or depression, however, further studies are necessary to elucidate the mechanism of these actions.

Key words: 7-OH-DPAT, BP 897, elevated plus-maze test, forced swim- ming test, rat

 correspondence; e-mail: [email protected] Z. Rogó¿, G. Skuza, A. K³odziñska

INTRODUCTION The present study was carried out to determine whether (+)-7-hydroxy-2-(di-n-propylamino)tetra- Behavioral and biochemical data indicate the lin hydrobromide (7-OH-DPAT), preferential D3 re- involvement of dopamine (DA) neurotransmitter ceptor agonist, which have been found to possess system in pathophysiology of anxiety and depres- 10- to 200-fold greater preference for the D3 than sion. It is well established that stress activates the for the D2 receptors [7, 15, 20], and N-{4-[4-(2- mesocorticolimbic DA system and increases extra- methoxyphenyl)-1-piperazinyl]butyl}-2-naphthylcar- cellular DA in the nucleus accumbens septi and boxamide (BP 897), a partial D3 agonist in vitro medial prefrontal cortex, inducing anxiolytic-like and either an agonist or an antagonist in vivo [31], behavioral effects [4, 9, 39]. There is also evidence whose antidepressant effects have not been studied that stress-induced increases in DA metabolism can as yet, induce anxiolytic effect in the elevated be attenuated by antianxiety drugs, such as diaze- plus-maze test and antidepressant effect in the pam and ICS 205930 (tropisetrone) [9, 11, 16]. forced swimming test in rats. However, behavioral evidences for the involvement of DA D1 receptors in anxiety are week and incon- sistent [1, 34]. On the other hand, animal studies in- MATERIALS and METHODS dicated the anxiolytic-like effects of D2 receptor antagonists, such as or [6, 30]. The experiments were carried out on male Wis- Also D2 agonists have been suggested to be in- tar rats (250–270 g). The animals had free access to volved in anxiety because low doses of apomor- food and water and were kept at a constant room phine or exhibited anxiolytic-like effects temperature (22 ± 1°C) under a 12 h light/dark cy- in animals whereas their higher doses produced cle (light on at 07.00 h). 7-OH-DPAT (sc) and BP anxiogenic-like effects [13, 40]. Biochemical stud- 897 (ip) were dissolved in saline. Both drugs were ies have indicated that haloperidol, sulpiride and injected in a volume of 2 ml/kg 30 min before the quinpirole show affinity not only for D2 but also for test. Diazepam (2.5, 5 and 10 mg/kg) and imipra- D3 receptors [42]. mine (5 and 10 mg/kg) were used as reference The D3 receptor is principally located in limbic compounds. Diazepam (suspended in a 1% aque- projection areas associated with cognitive, emo- ous solution of Tween 80) was given ip 60 min be- tional and endocrine functions [3, 42]. It has been fore the test and imipramine (dissolved in saline) demonstrated that mice without functional D3 re- was injected ip three times at 24, 5 and 0.5 h before ceptors show the reduced anxiety in the open field the test. Each experimental group consisted of 6-8 and plus-maze tests [43]. Putative D3 receptor an- naive animals/dose, and the animals were used only tagonist PNU 99194A and were re- once in each test. The experiments were performed ported to evoke behaviors in mice and rats, which by an observer blind to the treatment. All experi- may be considered as an anxiolytic action of this mental procedures were approved by the Animal compounds [14, 35, 36]. Care and Use Committee at the Institute of Phar- On the other hand, repeated administration of macology, Polish Academy of Sciences in Kraków. several classes of (, , imipramine, and tranylcy- Substances promine) and repeated electroconvulsive shock treatments significantly increased D3 receptor mRNA (+)-7-Hydroxy-2-(di-n-propylamino)tetralin hy- expression in the nucleus accumbens shell, what drobromide (7-OH-DPAT, Research Biochemicals suggests that the increased expression of the D3 re- Int., USA), N-{4-[4-(2-methoxyphenyl)-1-pipera- ceptors in that brain region results from enhanced zinyl]butyl-}2-naphthylcarboxamide (BP 897) was responsiveness in the mesolimbic D3 system [19]. synthesized by Dr. J. Boksa, Department of Medi- Also previous behavioral and biochemical studies cal Chemistry, Institute of Pharmacology, Polish demonstrated that antidepressant drugs adminis- Academy of Sciences, Kraków, Poland, diazepam tered repeatedly enhanced the reactivity of the cen- was purchased from Polfa, Poznañ (Poland) and tral mesolimbic D2 and D3 receptors in rats [8, 22, imipramine hydrochloride (IMI), from Pliva, Kra- 23, 45, 46]. ków, Poland.

520 Pol. J. Pharmacol., 2004, 56, 519–526 ANXIOLYTIC- AND ANTIDEPRESSANT-LIKE EFFECTS OF PREFERENTIAL DOPAMINE D! RECEPTOR AGONIST

Data analysis for 2 min (approximately 95% of animals) were placed again on the same rotating rod after drug ad- The data were evaluated by a one-way analysis ministration and were observed for 2 min. The of variance (ANOVA), followed, when appropriate, number of animals falling from the rota-rod within by individual comparisons with the control using 2 min was recorded [17]. 7-OH-DPAT (0.05 mg/kg) Dunnett’s test. and BP 897 (0.5 mg/kg) were injected 30 min be- Elevated plus-maze test fore the test. There were 8 rats in each group. The construction of the elevated plus-maze and Forced swimming (Porsolt’s) test the testing procedure of the elevated plus-maze were based on a method described by Pellow and The animals were subjected to two trials during File [29]. Each rats was placed in the center of the which they were forced to swim in a cylinder plus-maze, facing one of the closed arms imme- (40 cm high, 18 cm in diameter) filled with water diately after a 5 min adaptation in a wooden box (23–25°C) to a height of 15 cm. There was a 24-h (60 × 60 × 35 cm). During a 5 min test period, two interval between the first and second trial; the first experimenters, who were sitting in the same room trial lasted 15 min, the second 5 min. The total du- approximately 1 m from the end of the open arms, ration (s) of immobility was measured throughout recorded the number of entries into the closed or the second trial (Porsolt et al. [32]). 7-OH-DPAT the open arm, as well as the time spent in each type (0.1, 0.3 and 1 mg/kg), BP 897 (0.1, 0.25 and of arms. The entry with all four feet put into one 0.5 mg/kg) and IMI (5 and 10 mg/kg) were given arm was defined as an arm entry. At the end of each three times at 24, 5 and 0.5 h before the test. Also trial, the maze was wiped clean. 7-OH-DPAT (0.05, 7-OH-DPAT (0.1 or 0.3 mg/kg) and BP 897 0.1 mg/kg) and BP 897 (0.25, 0.5 mg/kg) were in- (0.25 and 0.5 mg/kg) were given in combination jected 30 min before the test. Diazepam (1.25, 2.5 with IMI (5 mg/kg) at 24, 5 and 0.5 h before the and 5 mg/kg) was given at 60 min before the test. test. Each group consisted of 8 rats. Each experimental group consisted of 6-8 rats. Locomotor activity Rota-rod test 7-OH-DPAT (0.1, 0.3 and 1 mg/kg), BP 897 Rats were preselected 1 h before the test on the (0.1, 0.25 and 0.5 mg/kg) and IMI (5 and 10 mg/kg) rotating rod (BD-10, COTM Bia³ystok; 8 cm in di- were given three times at 24, 5 and 0.5 h before the ameter, 6 r.p.m.). Those staying on the rotating rod test (like in the forced swimming test). Also 7-OH-DPAT (0.1 or 0.3 mg/kg) and BP 897 (0.25 Table 1. Effect of 7-OH-DPAT, BP 897 and diazepam in the and 0.5 mg/kg) were given in combination with elevated plus-maze test in rats IMI (5 mg/kg) at 24, 5 and 0.5 h before the test. The locomotor activity was studied in photoresistor Compounds (mg/kg) % of time spent % of open in open arms arm entries actometers (two light beams, two photoresistors; (mean ± SEM) (mean ± SEM) L×W×H=40×40×25cm)[24, 25], in which the animals were placed individually. The activity Vehicle 13.5 ± 5.4 35.7 ± 9.9 counts were recorded for 5 min. Each group con- 7-OH-DPAT 0.05 65.7 ± 14.9** 67.1 ± 9.7* sisted of 8 rats. 7-OH-DPAT 0.1 16.2 ± 3.8 36.7 ± 6.1 BP 897 0.25 31.5 ± 6.4 41.6 ± 5.2 BP 897 0.5 57.7 ± 12.4** 65.6 ± 8.4* RESULTS Vehicle 10.9 ± 1.1 38.5 ± 3.1 Elevated plus-maze test Diazepam 1.25 20.3 ± 5.5 45.2 ± 8.9 Diazepam 2.5 47.2 ± 5.3* 73.8 ± 4.2* The total number of entries (open + closed arm Diazepam 5 70.4 ± 10.9** 76.2 ± 8.8** entries) observed in control rats during the 5 min test session was about six in the present set of ex- 7-OH-DPAT (sc), BP 897 (ip) were given 30 min, diazepam periments and was taken as 100%. In control rats, (ip) 60 min before the test. The animals were observed for 5 min. The results represent the means ± SEM; n = 6–8, 35.7 and 38.5% of the entries were made into the * p < 0.05, ** p < 0.001 (ANOVA followed by Dunnett’s test) open arms (Tab. 1), and 13.5 and 10.9% of the total vs. vehicle-treated group time (244 s) spent in the arms (either type) was

ISSN 1230-6002 521 Z. Rogó¿, G. Skuza, A. K³odziñska

Table 2. Effect of 7-OH-DPAT, BP 897 and imipramine (IMI) Rota-rod test on the immobility time in the forced swimming test and on the locomotor activity in rats 7-OH-DPAT (0.05 mg/kg) and BP 897 (0.5 mg/kg) at doses effective in the elevated plus-maze test did Compounds Immobility time (s) Activity counts not disturb motor coordination tested in the rota- (mg/kg) (mean ± SEM) (mean ± SEM) rod test in rats (data not shown). Vehicle 234.0 ± 7.3 121.0 ± 11.9 Forced swimming (Porsolt’s) test 7-OH-DPAT 0.1 253.1 ± 7.4 100.2 ± 7.7 7-OH-DPAT 0.3 179.1 ± 13.4** 129.3 ± 7.1 7-OH-DPAT at doses of 0.3 and 1 mg/kg re- 7-OH-DPAT 1 149.1 ± 8.9** 256.0 ± 28.1** duced the immobility time of rats [F (5,42 = 21.05; IMI 5 238.1 ± 5.4 114.3 ± 9.5 p < 0.001] (Tab. 2). The dose of 0.1 mg/kg was in- IMI 10 194.5 ± 8.7* 90.0 ± 8.8 active in that test. IMI, used as a reference drug, at a dose of 10 mg/kg (but not 5 mg/kg) significantly Vehicle 251.3 ± 5.9 109.6 ± 14.3 shortened the immobility time of rats (Tab. 2). Joint BP 897 0.1 249.9 ± 7.3 128.5 ± 5.3 administration of 7-OH-DPAT (0.3 mg/kg but not BP 897 0.25 251.4 ± 6.1 99.3 ± 12.2 0.1 mg/kg) and IMI (5 mg/kg) induced a stronger BP 897 0.5 259.6 ± 6.4 96.6 ± 11.6 effect in Porsolt’s test [F (5,42) = 25.41; p < 0.001] than administration of either drug alone (Tab. 3). In 7-OH-DPAT (sc), BP (ip) and IMI (ip) were given three times, at 24, 5 and 0.5 h before the test. The animals were observed for contrast, BP 897 used at doses of 0.1, 0.25 and 5 min. The results represent the means ± SEM from 8 rats. * p < 0.5 mg/kg was ineffective in the forced swimming 0.05, ** p < 0.001 (ANOVA followed by Dunnett’s test) vs. test [F (3,28) = 0.48; ns] (Tab. 2), but a dose of 0.25 vehicle-treated group mg/kg (but not 0.5 mg/kg) showed synergistic in- spent in the open arms. Administration of the lower teraction with IMI (5 mg/kg), significantly short- dose of 7-OH-DPAT was required to induce signifi- ening the immobility time of rats [F (5,42) = 12.08; cant behavioral changes. 7-OH-DPAT at the dose of p < 0.001] (Tab. 3). 0.05 mg/kg (but not at 0.1 mg/kg) significantly (up to 65.7%, [F (2,15) = 9.7; p < 0.05]) increased the Table 3. Effect of 7-OH-DPAT and BP 897 given alone or in combination with imipramine (IMI) on the immobility time in percentage of the time spent in the open arms and the forced swimming test and on the locomotor activity in rats the percentage of entries into the open arms (up to 67.1%, [F (2,15) = 3.85; p < 0.01]. BP 897 adminis- Compounds (mg/kg) Immobility time Activity counts tered at a dose of 0.25 mg/kg, did not change the (s) (mean ± SEM) number of open arms entries or time spent in the (mean ± SEM) open arms. When given at a dose of 0.5 mg/kg, it significantly [F (2,18) = 5.57; p < 0.05] increased Vehicle 259.3 ± 3.8 78.5 ± 4.2 the time spent in the open arms (up to 57.7%), and 7-OH-DPAT 0.1 259.8 ± 3.2 59.3 ± 10.6 the percentage of entries into the open arms (up to 7-OH-DPAT 0.3 226.3 ± 4.9* 79.8 ± 10.6 65.6%), [F (2,18) = 4.18; p < 0.05] (Tab. 1). 7-OH- IMI 5 243.9 ± 7.6 71.8 ± 6.8 DPAT and BP 897 (at both used doses) did not 7-OH-DPAT 0.1 + IMI 5 256.8 ± 3.6 74.6 ± 6.9  change the total number of entries nor the total time 7-OH-DPAT 0.3 + IMI 5 182.1 ± 9.8 63.0 ± 3.2 spent in the arms (either type) (data not shown). Vehicle 245.4 ± 5.2 88.5 ± 5.3 Diazepam, i.e. the positive standard, administered BP 897 0.25 266.3 ± 4.3 75.0 ± 8.1 at a dose of 1.25 mg/kg was ineffective in that test, BP 897 0.5 252.1 ± 5.2 88.0 ± 8.9 however, when given at doses of 2.5 and 5 mg/kg, it significantly [F (3,22) = 14.52; p < 0.001] in- IMI 5 246.0 ± 3.2 79.5 ± 10.4 BP 897 0.25 + IMI 5 204.0 ± 6.8 69.1 ± 5.3 creased the percentage of the time spent in the open  arms (up to 47.2 and 70.4 %, respectively), as well BP 897 0.5 + IMI 5 234.4 ± 9.5 44.8 ± 3.2 as the percentage of entries into the open arms (up 7-OH-DPAT (sc)orBP(ip) and IMI (ip) were co-administered to 73.8 and 76.2%, respectively [F (3,22) = 5.87; three times, at 24, 5 and 0.5 h before the test. The animals were p < 0.001] (Tab. 1). Diazepam at a dose of 5 mg/kg observed for 5 min. The results represent the means ± SEM  (but not lower) significantly reduced (by 52%) the from 8 rats. * p < 0.001 vs. vehicle-treated group, p < 0.001 vs. total number of entries (data not shown). 7-OH-DPAT-, BP 897- or IMI- treated group

522 Pol. J. Pharmacol., 2004, 56, 519–526 ANXIOLYTIC- AND ANTIDEPRESSANT-LIKE EFFECTS OF PREFERENTIAL DOPAMINE D! RECEPTOR AGONIST

Locomotor activity in the elevated plus-maze paradigm in mice [33] and in the ultrasonic vocalization test in rats [1]. In In the locomotor activity test, 7-OH-DPAT, the latter test, only D3 receptor agonists (quinpi- given three times (as in Porsolt’s test) and meas- role, , roxindole, , (±)-7- ured for 5 min, only at a dose of 1 mg/kg statisti- OH-DPAT, PD 128907) at low doses inhibited ul- cally significantly [F (5,42) = 18.86; p < 0.001] en- trasonic vocalization [1]. The D2 (haloperidol, ra- hanced the activity in rats, the lower doses of this clopride) and D3 (U99194A, S(-)DS121) receptor drug (0.1 and 0.3 mg/kg) did not affect locomotor antagonists, D1 receptor agonists (R(+)-SKF 38393) activity (Tab. 2). IMI (5 and 10 mg/kg) did not or antagonists (SCH 23390) and DA uptake inhibi- change the locomotor activity. Also combined tors (GBR 12909, GBR 12935) lacked significant treatment with IMI (5 mg/kg) and 7-OH-DPAT (0.1 inhibitory effects on ultrasonic vocalization [1]. or 0.3 mg/kg) did not affect locomotor activity This fact, together with other data presented in [F (5,42) = 1.21; ns] (Tab. 3). BP 897 (0.1, 0.25 and the above-cited paper, suggest that D2 and D3 auto- 0.5 mg/kg) did not change the locomotor activity receptors may be a new target(s) for the develop- [F (3,28) = 1.63; ns] (Tab. 2). Only, joint admini- ment of an autoreceptor-selective agonist for the stration of the higher dose of BP 897 (0.5 mg/kg) treatment of anxiety disorders. There are a number and IMI (5 mg/kg) decreased the locomotor activity of advantageous characteristics of D3 autoreceptor [F (5,42) = 4.96; p < 0.01] (Tab. 3). which make it the most interesting candidate for such development, namely: (a) the heterogeneity in DISCUSSION localization of D2 and D3 receptors [3], their nearly complete confinement to the mesolimbic structures An anxiolytic-like effect of preferential D3 re- and relatively high abundance of D3 receptors in ceptor agonist 7-OH-DPAT and BP the areas, which are associated with emotional 897, was evaluated in the elevated plus-maze test. function [20, 42], (b) distinct modes of regulation In this test, the total number of entries (open + [12, 21], (c) good correlation between inhibition of closed arm entries/test session) is regarded as an in- DA cell firing and D3 but not D2 receptors binding dex of drug effect on the locomotor activity, but affinity [18], and (d) relatively strong affinity of all this is a relatively insensitive measure [29]. The agonists active in ultrasonic vocalization test for present study indicated that 7-OH-DPAT and BP the D3 receptor subtypes and the relative selectivity 897 did not change the total number of entries or of at least some of them for the D3 receptor sub- the total time spent in the arms (either type). 7- types. On the basis of these data, it may be con- OH-DPAT (0.05 mg/kg) and BP 897 (0.5 mg/kg) cluded that preferential D3 receptor agonists, like demonstrated significant anxiolytic-like activity in 7-OH-DPAT at low doses, produce an anxiolytic- the elevated plus-maze test in rats, as they in- like effect, what suggests the involvement of D3 creased the % of time spent in open arms and % of autoreceptors in pathomechanism of anxiety. open arm entries. The effect of 7-OH-DPAT and BP The antidepressant-like effects of 7-OH-DPAT 897 in this test was similar to that produced by di- and BP 897 were evaluated in the forced swimming azepam at doses of 2.5 or 5 mg/kg. Also our previ- test in rats. Antidepressant-like effect of 7-OH-DPAT ous studies indicated that 7-OH-DPAT at doses of was previously observed in the tail-suspension test in 0.05 and 0.1 mg/kg exhibited an anxiolytic-like ac- mice (at doses of 1 and 2 mg/kg) [10], but not in the tivity in the conflict drinking test, significantly in- rat learned helplessness test (at a dose of 10 mg/kg) creasing the number of shocks accepted during the [44]. The present studies demonstrated that 7-OH- experimental session in the Vogel test. Similarly, DPAT at a dose of 0.3 mg/kg (six times higher than BP 897 was active in the Vogel test at a dose of 0.5 in the conflict drinking test or in the elevated plus- mg/kg. The effect of 7-OH-DPAT or BP 897 was maze paradigm, i.e. in anxiolytic tests), like IMI (10 comparable to that evoked by diazepam at a dose of mg/kg), showed antidepressant-like effect, induced 5 mg/kg [38]. significant reduction of immobility time in the An involvement of preferential D3 receptor ago- forced swimming test, but did not enhance the lo- nists in psychiatric disorders, such as anxiety, has comotor activity. Additionally, the combined treat- been suggested by other authors [1, 34]. Anxio- ment with 7-OH-DPAT (0.3 mg/kg) and ineffective lytic-like effects of (±)-7-OH-DPAT were observed dose of IMI (5 mg/kg) demonstrated the signifi-

ISSN 1230-6002 523 Z. Rogó¿, G. Skuza, A. K³odziñska cantly increased antidepressant-like effect, but line differences were observed between knockout without enhancement of the locomotor activity. (C57BL/6J and B6129SF2/J) and wide-type mice The higher dose of 7-OH-DPAT (1 mg/kg) also re- from either background strain in locomotor activity duced the immobility time, but this effect was not or in performance in the forced swimming test. specific, since at this dose, the locomotor activity Furthermore, pramipexole showed similar efficacy was elevated. In contrast, BP 897 (partial ago- in the forced swimming test in both wide-type and nist/antagonist of D3 receptors) was ineffective in knockout mice. These results suggest that the D2 the forced swimming test, but given at a dose of receptor rather than the D3 receptor is important to 0.25 mg/kg (but not at 0.5 mg/kg) jointly with ineffec- the antidepressant-like activity observed with pra- tive dose of IMI (5 mg/kg) produced “antidepressant- mipexole in the mouse forced swimming test. like” effect, significant reduction of immobility Moreover, Willner et al. [47] reported that in ani- time, but no increase in locomotor activity. A lack mal model of anhedonia regarded as having some of antidepressant-like effect after co-administration functional equivalence to human depression, the of higher dose of BP 897 (0.5 mg/kg) and IMI may anhedonic response was reversed by pramipexole. reflect a decrease in general activity, since com- There is also evidence from clinical studies that bined administration of BP 897 and IMI failed to pramipexole has clear antidepressant potential in decrease the locomotor activity of rats, measured in humans [2]. photoresistor actometers. Moreover, our prelimi- In conclusion, 7-OH-DPAT, a preferential D3 nary studies indicate that S33084 (a selective D3 re- agonist at low doses, and BP 897, a partial D3 ago- ceptor antagonist [28]) at a dose inactive in the Por- nist, produced anxiolytic-like effects in the animal solt’s test (0.2 mg/kg) only partly inhibited an models, what suggests the involvement of D3 auto- antidepressant-like effect induced by 7-OH-DPAT receptors in pathomechanism of anxiety. Addition- given alone or jointly with IMI. In contrast, sul- ally, it was shown that 7-OH-DPAT at higher doses piride (a dopamine D2/3 ) at also exerted antidepressant-like effect and that both a dose inactive in the forced swimming test (10 types of postsynaptic D2 and D3 receptor might play mg/kg) completely abolished the effect of 7-OH- a role in the action of 7-OH-DPAT in the forced DPAT given alone or jointly with IMI. Also the swimming test in rats. Further studies are necessary antidepressant-like effect of BP 897 (given with to elucidate the mechanism of these effects using IMI) was completely blocked by sulpiride (but not the most selective D3 receptor agonists and antago- by S33084). The above results together with other nists. data presented in the paper by Rogó¿ and Skuza [37] suggest that postsynaptic D2 and D3 receptors REFERENCES may contribute to the mechanism of action of 1. 7-OH-DPAT and BP 897 (given jointly with IMI) in Bartoszyk GD: effects of dopamine recep- tor ligands: I. Involvement of dopamine autoreceptors. the forced swimming test in rats. In addition, our Life Sci, 1998, 62, 649–663. previous study showed that another preferential D3 2. Becker PM, Corrigan MH, Kasper S, Lin S-C, Mont- receptor agonist, pramipexole [5, 26, 27] at a dose plaisir J, Szegedi A, Willner P: Clinical efficacy of of 0.3 mg/kg (three times higher than in the ultra- pramipexole in the treatment of conditions other than sonic vocalization test, i.e. anxiolytic test), evoked Parkinson’s disease. Rev Contemp Pharmacother, 2001, antidepressant-like effect in the forced swimming 12, 87–104. 3. test in rats, and in this test, it enhanced the effects Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz J-C: Localization of dopamine D! recep- of a number of antidepressant drugs, including IMI, tor mRNA in the rat brain using in situ hybridization amitriptyline, , fluoxetine and histochemistry: comparison with dopamine D recep- [24, 25]. Moreover, Siuciak and Fujiwara [41] tor mRNA. Brain Res, 1991, 564, 203–219. showed that pramipexole also reduced the immo- 4. Cabib S, Puglissi-Allerga S: Opposite responses of bility time in the forced swimming test in mice and mesolimbic dopamine system to controllable and un- controllable aversive experiences. J Neurosci, 1994, LU-201640, a selective D3 receptor antagonist, 14, 3333–3340. failed to block the antidepressant-like effect of 5. Carter AJ, Müller RE: Pramipexole, a dopamine D! pramipexole. In contrast, the efficacy of pramipex- autoreceptor agonist, decreases the extracellular con- ole in the forced swimming test was completely centration of dopamine in vivo. Eur J Pharmacol, blocked by the D2 antagonist, haloperidol. No base- 1991, 200, 65–72.

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