Evidence from both animal (D'Aquila et al., 2000) and human (Ebert et al., 1994, 1996; Klimke et al., 1999) studies suggests that a sensitization of dopamine-mediated behavioural responses might underlie the therapeutic effect of antidepressant drugs. Although most of the studies suggest a role for dopamine D2-like receptors in the dopamine-mediated effects considered as relevant to antidepressant action (D'Aquila et al., 2000), a more equivocal picture emerges from the evidence on the role of dopamine D1-like receptors. Dopamine D1-like receptor stimulation was suggested to be a critical event leading to the dopaminergic behavioural sensitization after repeated treatment with the antidepressant drug imipramine (Serra et al., 1990, 1991). Consistently, it was shown that acute dopamine D1-like receptor stimulation resulted in an antidepressant-like effect both in the forced swimming (Nikulina et al., 1991; D'Aquila et al., 1994) and in the learned helplessness (Gambarana et al., 1995a, b) models of depression, whereas dopamine D1-like receptor blockade prevented the effect of different antidepressant drugs and of an enkephalin catabolism inhibitor in both the models (Nikulina et al., 1991; Baamonde et al., 1992; D'Aquila et al., 1994; Gambarana et al., 1995b; Yamada et al., 2004; Shimazu et al., 2005). However, others failed to demonstrate the ability of acute dopamine D1-like receptor stimulation to induce an antidepressant-like effect (Borsini et al., 1988), whereas dopamine D2-like receptor but not D1-like receptor antagonists prevented the antidepressant-like effect of desipramine (Borsini et al., 1988), rapid eye movement (REM)-sleep deprivation (Asakura et al., 1994), N-methyl-D-aspartate (NMDA) antagonists (Maj et al., 1992) and of the indirect dopamine agonists dexamphetamine and GBR 12783 (Vaugeois et al., 1996) in the forced swimming test.
A great deal of experimental evidence suggests an involvement of neurosteroids in the pathophysiology of depression and in the mechanism of action of antidepressants (Romeo et al., 1998; Uzunova et al., 1998, 2006; Bernardi et al., 2004; Pisu and Serra, 2004; Amin et al., 2006; Pinna et al., 2006, 2009). In support of this hypothesis, it has been reported that the susceptibility of female rats to the depressive-like effect of different behavioural models of depression such as the Porsolt forced swimming test (Pare and Redei, 1993; Marvan et al., 1996, 1997; Contreras et al., 1988; Frye and Walf, 2002; Frye and Wawrzycki, 2003; Consoli et al., 2005; but see Alonso et al., 1991 for negative results), the open space forced swimming test (Sun and Alkon, 2006) and the learned helplessness paradigm (Jenkins et al., 2001; but see Setnik et al., 2004 for negative results) depends upon the phases of the estrous cycle. In all but two cases (Consoli et al., 2005; Sun and Alkon, 2006), the highest level of depressive-like behaviour corresponded to the phase (diestrus) with the lowest brain levels of the neurosteroid allopregnanolone (Frye and Walf, 2002; Zimmerberg et al., 2005). Conversely, allopregnanolone exerts an antidepressant-like effect in the forced swimming test (Khisti and Chopde, 2000; Khisti et al., 2000; Hirani et al., 2002; Molina-Hernandez et al., 2004, 2005). Moreover, different antidepressant drugs have been reported to increase allopregnanolone levels in normal animals (Jaworska-Feil et al., 2000; Nechmad et al., 2003) and to restore the reduced corticolimbic allopregnanolone levels observed in the socially isolated mouse and olfactory bulbectomized rat model of depression to the control values (Uzunova et al., 2004; Pinna et al., 2006, 2009), whereas treatment with finasteride, which inhibits allopregnanolone synthesis, abolished the difference between proestrus and diestrus in the forced swimming test (Frye and Walf, 2002). Most importantly, such a role for neurosteroids and in particular for allopregnanolone is suggested by a growing number of clinical findings, such as the reduced allopregnanolone levels in women with postpartum ‘blues’ (Nappi et al., 2001) and premenstrual syndrome (Rapkin et al., 1997), the reduced ability to increase allopregnanolone levels in response to mental stress in women with earlier episodes of depression suffering from premenstrual dysphoric disorder (Klatzkin et al., 2006), and the ability of antidepressant drugs to reverse the decreased allopregnanolone levels observed in major depression (Romeo et al., 1998) and in severe premenstrual syndrome (Freeman et al., 2002).
Allopregnanolone interacts with dopamine transmission in several ways. For instance, it increased catecholamine synthesis and release in vitro (Charalampopoulos et al., 2005), NMDA-evoked striatal dopamine release in vitro in estrous rats (Cabrera et al., 2002), and dopamine release in the nucleus accumbens in vivo (Rouge-Pont et al., 2002). Moreover, the ability of allopregnanolone to induce lordosis when injected into the ventral tegmental area of female rats seems to involve both dopamine D1-like and D2-like receptors (Frye et al., 2004). The aim of this study, therefore, was to examine the possible involvement of dopamine neurotransmission, and in particular of dopamine D1-like and D2-like receptors, in the mechanism of the allopregnanolone-induced antidepressant-like effect in the forced swimming test in female rats. Therefore, we studied the effect of the selective antagonists of dopamine D1-like and D2-like receptors, SCH 23390 (D'Aquila et al., 1994) and raclopride (Millan et al., 2004) on the antidepressant-like effect of allopregnanolone in female Sprague–Dawley rats. Given the inconsistent evidence in relation to estrous phase-dependent vulnerability to experimentally induced depressive-like behaviour, we initially studied the behaviour of Sprague–Dawley female rats in this procedure both in estrus and in diestrus, and their response to different doses of allopregnanolone (Khisti et al., 2000). Having found no effects of estrous phase, we performed the subsequent experiments without taking into account estrous phases.
This study was carried out in accordance with Italian law (D.L. 116, 1992), and the Principles of Laboratory Animal Care (NIH publication no. 80–23, revised 1996).
Experimentally naive female Sprague–Dawley rats (Harlan, Italy), weighing between 250 and 300 g, were housed in groups of 2–3 per cage in controlled environmental conditions (temperature 22–24°C, humidity 50–60%, light on at 08.00 h, off at 20.00 h), with free access to food and water.
Determination of estrous cycle phases
The estrous cycles of 50 rats were studied for at least 15 days by checking daily vaginal cytology according to the procedure described by Marcondes et al. (2002). Eight rats were found with noncharacteristic estrous cycles. Of the remaining 42 rats, 40 were used as experimental subjects of Experiment 1 (see below).
Forced swimming test
The animals were placed individually into perspex cylinders (40 cm height, 18 cm diameter) containing 25 cm of water at 30°C for 10 min (Frye and Walf, 2002). Each session was recorded by a video camera. Experiments were performed between 10.00 and 12.30 h. The videotapes were scored by observers unaware of the treatment received by the subjects, using a time sampling procedure. Every 5 s, for a total of 120 samplings in 10 min, behaviour was categorized according to four mutually exclusive possibilities: swimming, climbing, that is, attempts to climb the cylinder wall, diving below the water surface level and immobility, that is, floating in the water making only the movements necessary to keep the nostrils above the surface level.
The subjects (n=40) were allocated to four groups (n=10) to receive different allopregnanolone doses: 0 (vehicle), 0.5, 1 and 2 mg/kg. Every subject was tested in the forced swimming test both in estrous and in diestrous phases, receiving the same allopregnanolone treatment before two sessions performed 2–4 days apart. To counter the effect of repeated exposure to the forced swimming condition, the order of testing in relation to the estrous phases was balanced across subjects.
The subjects (n=40) were allocated to two groups (n=20) receiving 0.025 mg/kg of SCH 23390 or vehicle. Every subject was tested in the forced swimming condition both after receiving 2 mg/kg of allopregnanolone and after receiving its vehicle, in two sessions performed 5 days apart, with the same SCH 23390 treatment. To counter the possible effect of repeated exposure to the forced swimming condition, the order of testing allopregnanolone treatment versus its vehicle was balanced across subjects.
The subjects (n=38) were allocated to two groups to receive allopregnanolone treatment: vehicle (n=18) and 2 mg/kg (n=20). Each of these groups was further divided into two halves one of which was treated with SCH 23390 at the dose of 0.01 mg/kg and the other one with the appropriate vehicle. Behavioural observations were performed in a single session.
The subjects (n=36) were allocated to three groups (n=12) receiving different raclopride doses: 0 (vehicle), 0.05 and 0.2 mg/kg. Every subject was tested in the forced swimming test both after receiving 2 mg/kg of allopregnanolone and after receiving its vehicle, in two sessions performed 5 days apart, with the same raclopride treatment. To counter the possible effect of repeated exposure to the forced swimming condition, the order of testing allopregnanolone or vehicle was balanced across subjects.
Allopregnanolone acetate (Sigma, St Louis, USA) was dissolved in a few drops of dichloromethane and the final volume was made up with corn oil and administered subcutaneously immediately before behavioural testing. SCH 23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] and raclopride [S(-)-raclopride-L-tartrate] (Sigma, St Louis, USA) were dissolved in distilled water and administered subcutaneously 15 and 30 min before behavioural testing, respectively. Volume of injections was 1 ml/kg for all treatments.
The results were analysed by analysis of variance (ANOVA), supplemented by F tests for contrasts and Newman–Keuls test. The analysis of the data from Experiment 1 involved a between-groups factor, ‘allopregnanolone’ (with four levels, corresponding to each dose) and a within-groups factor, ‘phase’ (with two levels, corresponding to estrus and diestrus). The analysis of the data from Experiments 2 and 4 involved a between-groups factor, ‘antagonist’ (with two and three levels, respectively, corresponding to each dose of SCH 23390 or raclopride) and a within-groups factor, ‘allopregnanolone’ (with two levels). The analysis of the data from Experiment 3 involved two between-group factors, antagonist (with two levels) and allopregnanolone (with two levels). The scores for diving were not subjected to statistical analysis since only very few animals displayed occasionally this behaviour.
ANOVA revealed a significant effect of the factor allopregnanolone [F(3,36)=4.30; P=0.01], but not of phase [F(1,36)=0.25; NS]. The interaction between the two factors was not significant [F(3,36)=0.12; NS]. Newman–Keuls' test showed a significant decrease of immobility scores in the animals treated with the dose of 2 mg/kg allopregnanolone, regardless of the phase of the estrous cycle (Fig. 1 top panel).
ANOVA revealed a significant effect of the factor allopregnanolone [F(3,36)=5.12, P<0.005], but not of phase [F(1,36)=0.39, NS]. The interaction between the two factors was not significant [F(3,36)=0.06, NS]. Newman–Keuls' test showed a significant increase of swimming scores in the animals treated with the dose of 2 mg/kg allopregnanolone, regardless of the phase of the estrous cycle (Fig. 1 middle panel).
ANOVA failed to show any significant effect of or interaction between the two factors [allopregnanolone: F(3,36)=0.24, NS; phase: F(1,36)=0.016, NS; allopregnanolone×phase: F(3,36)=0.62, NS] (Fig. 1 lower panel).
ANOVA revealed a significant main effect of the factor antagonist [F(1,38)=84.25, P<0.001] because of the ability of SCH 23390 0.025 mg/kg to increase immobility. The allopregnanolone×antagonist interaction was very close to statistical significance [F(1,38)=3.90, P=0.055], with no effect of the factor allopregnanolone [F(1,38)=0.52, NS] (Fig. 2 top panel).
ANOVA revealed a significant main effect of the factor antagonist [F(1,38)=26.85, P<0.001] and a significant allopregnanolone×antagonist interaction [F(1,38)=5.17, P<0.05]. The main effect of allopregnanolone was close to statistical significance [F(1,38)=3.03, P=0.089]. F tests for contrasts showed the ability of allopregnanolone to increase swimming scores and the ability of SCH 23390 0.025 mg/kg to prevent this effect. Moreover, SCH 23390 decreased swimming scores in animals treated with allopregnanolone as well as in those treated with its vehicle (Fig. 2 middle panel).
ANOVA revealed a significant effect of the factor antagonist [F(1,38)=20.23, P=0.001], because of a reduced activity in animals treated with SCH 23390 0.025 mg/kg regardless of allopregnanolone treatment. The main effect of allopregnanolone [F(1,38)=0.78, NS] and its interaction with the factor antagonist [F(1,38)=0.14, P=0.70] were not statistically significant (Fig. 2 lower panel).
ANOVA revealed a significant main effect of the factor antagonist [F(1,34)=13.81, P<0.001] because of the ability of SCH 23390 0.01 mg/kg to increase immobility scores regardless of allopregnanolone administration. The main effect of allopregnanolone [F(1,34)=2.16, NS] and its interaction with antagonist [F(1,34)=0.02, NS] were not statistically significant (Fig. 3 top panel).
ANOVA revealed a significant main effect of the factors allopregnanolone [F(1,34)=6.37, P<0.02] and antagonist [F(1,34)=25.35, P<0.001] because allopregnanolone increased swimming scores regardless of SCH 23390 treatment, and SCH 23390 0.01 mg/kg decreased swimming regardless of allopregnanolone treatment. The interaction between allopregnanolone and antagonist was not significant [F(1,34)=0.18; NS] (Fig. 3 middle panel).
ANOVA failed to show any statistically significant effect [allopregnanolone: F(1,34)=0.008, NS; antagonist: F(1,34)=1.4, NS; allopregnanolone×antagonist: F(1,34)=0.01, NS] (Fig. 3 lower panel).
ANOVA revealed a significant effect of antagonist [F(2,33)=18.64; P<0.001] but not of allopregnanolone [F(1,33)=0.35, N.S.], and a significant interaction between the two factors [F(2,33)=4.66, P<0.02]. F tests for contrasts showed that allopregnanolone reduced immobility close to statistical significance in the raclopride vehicle group, failed to affect this parameter in the group treated with raclopride 0.05 mg/kg and increased immobility scores in the group treated with raclopride 0.2 mg/kg (Fig. 4, top panel).
ANOVA revealed a statistically significant effect of the factor antagonist [F(2,33)=28.86, P<0.001] but not of allopregnanolone [F(1,33)=0.011, N.S.], and a significant interaction between the two factors [F(2,33)=5.46, P<0.01]. F test for contrasts showed that allopregnanolone increased swimming scores in the vehicle treated group, failed to affect this parameter in the group treated with raclopride at 0.05 mg/kg and reduced swimming in the group treated with the dose of 0.2 mg/kg (Fig. 4, middle panel).
ANOVA revealed a statistically significant effect of allopregnanolone [F(1,33)=7.05, P<0.02] because of a reduction of climbing after allopregnanolone treatment, regardless of raclopride treatment [raclopride: F(2,33)=1,10, NS; raclopride×allopregnanolone: F(2,33)=0,88, NS] (Fig. 4, lower panel).
The results confirm the ability of allopregnanolone to exert an antidepressant-like effect in the forced swimming test, as previously observed both in mice (Khisti and Chopde, 2000; Khisti et al., 2000; Hirani et al., 2002) and rats (Molina-Hernandez et al., 2004, 2005). However, in all these studies, the antidepressant-like effect of allopregnanolone consisted in reduced immobility owing to an increase in ‘climbing’, whereas our results show that in all the experiments allopregnanolone significantly increased swimming scores, with no effect on climbing and an inconsistent effect on immobility. Indeed, in only one experiment (out of four) did allopregnanolone produce a statistically significant reduction of immobility, and its effect approached statistical significance in another one. The relevance of this issue is two-fold. On the one hand, while antidepressant drugs with a preferentially noradrenergic mechanism such as desipramine exert their effect by reducing immobility and increasing climbing, selective serotonin reuptake inhibitors (SSRI) have inconsistent effects on immobility while reliably increasing swimming (Detke et al., 1995; Detke and Lucki, 1996). In contrast, several studies have shown that SSRIs can increase neurosteroid levels both in vitro (Griffin and Mellon, 1999) and in vivo (Nechmad et al., 2003; Pinna et al., 2006), although this effect seemed to be independent of serotonin. Indeed, it was shown with doses inactive on serotonin reuptake (Pinna et al., 2006), and this led the authors to suggest renaming SSRI as selective brain steroidogenic stimulants.
The results of this study, at variance with the earlier reports (Khisti and Chopde, 2000; Khisti et al., 2000; Hirani et al., 2002; Molina-Hernandez et al., 2004, 2005), are consistent with the hypothesis that the behavioural profile of SSRIs in this depression model might depend on their brain steroidogenic stimulant effect. However, the discrepancy between our results and the earlier reports still demands an explanation. Indeed, our protocol differed in many important aspects from those employed in the other studies (e.g. time elapsed between allopregnanolone administration and behavioural tests, water temperature, length of the observation sessions, number of exposures to the forced swimming condition, to name a few), and the possible influence of each of these experimental variables should be experimentally tested. Altogether, these observations and our results show that allopregnanolone administration, similar to physiological conditions with high allopregnanolone brain levels (Frye and Walf, 2002, 2004), is consistently associated with an antidepressant-like profile in the forced swimming test, but the specific behaviours characterizing this profile may differ depending on variables which still have to be experimentally identified.
In contrast to several earlier reports (Pare and Redei, 1993; Marvan et al., 1996, 1997; Contreras et al., 1988; Jenkins et al., 2001; Frye and Walf, 2002; Frye and Wawrzycki, 2003; Consoli et al., 2005; Sun and Alkon, 2006), we failed to observe differences in depressive-like behaviour between estrous phases. This discrepancy might depend on the strains employed in the experiments; positive results in the FST were observed in Long–Evans and Wistar rats (Marvan et al., 1996, 1997; Frye and Walf, 2002), whereas a study on Sprague–Dawley rats, that is, the strain used in the present experiments, failed to show any difference (Alonso et al., 1991). However, no differences in the antidepressant-like effect of allopregnanolone between estrus and diestrus were observed.
SCH 23390 administration abolished the effect of allopregnanolone on swimming only at the higher dose, whereas the lower dose reduced the basal level of activity without affecting the effect of allopregnanolone, thus suggesting that the interaction between the high dose of the dopamine D1-like receptor antagonist and allopregnanolone is likely the result of a nonspecific depressant effect. Raclopride reduced the basal level of swimming both at the high and at the low dose. Moreover, the lower dose abolished the effect of allopregnanolone on swimming, whereas the higher dose turned the antidepressant-like effect of allopregnanolone into a potentiation of the depressive-like effect of forced swimming. Thus, while dopamine D1-like receptor blockade resulted in a relatively selective effect on basal activity, dopamine D2-like receptor blockade resulted in a relatively selective effect on the response to allopregnanolone.
The results in the literature suggest that both dopamine D1-like and D2-like receptors are involved in the behavioural response to forced swimming. Indeed, both dopamine D1-like (Nikulina et al., 1991; D'Aquila et al., 1994; but see Borsini et al., 1988) and dopamine D2-like receptor agonists (Borsini et al., 1988) have been shown to exert an antidepressant-like effect in the forced swimming test. However, the dopamine D1-like and D2-like receptor families seem to be differently involved in the antidepressant-like effect of the different treatments, with the dopamine D1-like receptors playing a major role in the effects of the MAO-B inhibitor drug selegiline (Shimazu et al., 2005) and of the enkephalin catabolism inhibitor RB 101 (Baamonde et al., 1992), and with the dopamine D2-like receptors playing a major role in the effect of REM-sleep deprivation (Asakura et al., 1994), NMDA antagonists (Maj et al., 1992), and of the indirect dopamine agonists dexamphetamine and GBR 12783 (Vaugeois et al., 1996). Moreover, they seem equally important in the antidepressant-like effect of the nonselective dopamine reuptake inhibitors, nomifensine and bupropion (Yamada et al., 2004). As for tricyclic antidepressants, the observation that dopamine-D2 receptor blockade prevents desipramine effects stands unchallenged (Borsini et al., 1988), while inconsistent results have been reported on the effect of the dopamine D1-like receptor antagonist SCH 23390, which was shown to antagonize the effect of imipramine at a dose devoid of motor effects (D'Aquila et al., 1994), but failed to antagonize the effect of desipramine (Borsini et al., 1988).
The current results suggest an involvement of dopamine transmission in the antidepressant-like effect of allopregnanolone in the forced swimming test, and indicate that this effect depends mainly on stimulation of dopamine D2-like receptors. Moreover, they provide support for the view that dopamine transmission is involved in the antidepressant effect of treatments with different pharmacological mechanisms of action (D'Aquila et al., 2000). However, the meaning and the relevance of the involvement of the different dopamine receptor subtypes in the antidepressant-like effect of drugs in the forced swimming test, let alone in their therapeutic effect, remain to be fully understood.
The authors thank Dr Vittorio Mazzarello for his advice in setting up the procedure for the diagnosis of estrous phase. This study was funded by the Ente Fondazione Cassa di Risparmio Pistoia e Pescia.
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