Psychopharmacology (2007) 193:363–374 DOI 10.1007/s00213-007-0801-4

ORIGINAL INVESTIGATION

Contrasting effects of bromocriptine on learning of a partially baited radial arm maze task in the presence and absence of restraint stress B. N. Srikumar & T. R. Raju & B. S. Shankaranarayana Rao

Received: 1 December 2006 / Accepted: 9 April 2007 / Published online: 28 April 2007 # Springer-Verlag 2007

Abstract Rationale Severe, traumatic stress or repeated exposure to stress can result in long-term deleterious effects, including hippocampal cell atrophy and death, which, in turn, result in memory impairments and behavioural abnormalities. The dopaminergic D2 receptor agonist, bromocriptine, has been shown to modulate learning, and chronic stress is associated with dopaminergic dysfunction. Objectives In the present study, we evaluated the effects of bromocriptine in the presence or absence of restraint stress. Materials and methods Adult male Wistar rats were subjected to restraint stress for 21 days (6 h/day) followed by bromocriptine treatment, and learning was assessed in the partially baited radial arm maze task. In a separate group of animals, the effects of bromocriptine per se was evaluated. Dopamine levels were estimated by high-performance liquid chromatography with electrochemical detection. Results Stressed rats showed impairment in both acquisition and retention of the radial arm maze task, and bromocriptine treatment after stress showed a reversal of stress-induced impairment. Interestingly, in the absence of stress, bromocriptine exhibited dose-dependent differential effects on learning. While rats treated with bromocriptine 5 mg/kg, i.p., demonstrated impairment in learning, the bromocriptine 10 mg/kg B. N. Srikumar : T. R. Raju : B. S. Shankaranarayana Rao (*) Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), PB# 2900, Hosur Road, Bangalore 560 029, India e-mail: [email protected] Present address: B. N. Srikumar Department of Physiology, University of Utah School of Medicine, Salt Lake City, UT 84108, USA

and vehicle-treated groups did not differ from normal controls. To understand the neurochemical basis for the effects of bromocriptine, dopamine levels were estimated. The stressinduced decrease in dopamine levels in the hippocampus and frontal cortex were restored by bromocriptine treatment. In contrast, bromocriptine alone (5 mg/kg, i.p.) decreased dopamine levels in the frontal cortex and striatum. Conclusions Our study shows that amelioration of stressinduced learning impairment correlates with restoration of dopamine levels by bromocriptine treatment. Keywords Restraint stress . Dopamine . Radial arm maze . Spatial memory . Hippocampus . Reference memory . Bromocriptine . Dose dependency . D2 receptor . Frontal cortex

Introduction Severe and prolonged stress precipitates affective disorders and cause impairment in learning and memory. Earlier, we have demonstrated that 21 days of restraint stress impairs acquisition of T maze (Sunanda et al. 2000a) and radial arm maze tasks (Srikumar et al. 2006). Furthermore, stressinduced impairment in learning is shown in other paradigms like the Y maze (Conrad et al. 1996), Barnes maze (McLay et al. 1998) and Morris water maze (Bodnoff et al. 1995). In addition to stress, enhanced glucocorticoids (either cortisol or corticosterone), a hallmark of stress has been shown to produce learning deficits (Herbert et al. 2006). Recent and delayed declarative memories are impaired in both young and ageing humans by excess corticosteroids (Lupien et al. 2002a, b). Similarly, it has been demonstrated in animals that excessive corticosterone can impair spatial learning (de Quervain et al. 1998; McLay

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et al. 1998). Further, the cognitive impairment and the hippocampal degeneration associated with chronic stress are thought to be at least in part because of the elevated levels of glucocorticoids as blockade of glucocorticoid receptors or glucocorticoid synthesis prevents stress-induced dendritic atrophy and cognitive deficits (de Quervain et al. 1998; Govindarajan et al. 2006; Krugers et al. 2006; Luine et al. 1993; Magarinos and McEwen 1995). Several neurotransmitter systems like the dopaminergic (Finlay and Zigmond 1997), cholinergic (Srikumar et al. 2006), glutamatergic (Sunanda et al. 1997, 2000b), noradrenergic (Srikumar et al. 2006; Sunanda et al. 2000b) and serotonergic (McEwen et al. 1997; Sunanda et al. 2000b) systems are involved in the stress-induced deficits. Among these, alteration in the dopaminergic system is one of the main neurochemical changes after stress. Previous studies indicate that chronic restraint stress significantly decreases dopamine (DA) levels in the hippocampus (Sunanda et al. 2000b; Torres et al. 2002). It has been reported that chronic variate stress or isolated housing of rats increases the 3,4 dihydroxy phenyl acetic acid (DOPAC) levels in the frontal cortex and hippocampus (Gamaro et al. 2003; Miura et al. 2005), and in pigs, acute immobilization stress also affects the hippocampal DA turnover (Piekarzewska et al. 1999). Repeated maternal separation stress and exposure to novel environment up-regulated D1 receptor density in the stratum radiatum and moleculare of the hippocampal CA1 region (Ziabreva et al. 2003) and affected D2 receptor binding in the periaqueductal grey and ventral tegmental area (Ploj et al. 2003). Thus, there are multiple lines of evidence that DA levels, turnover and receptor status are affected in stress. DA is known to play an important role in learning and memory. For example, DA plays a central role in working memory (Goldman-Rakic 1995), and several others show that DA can modulate learning in the Morris water maze (Miyoshi et al. 2002; Da Cunha et al. 2003) and radial arm maze tasks (Packard and White 1989, 1991). Thus, DA is involved in learning and memory, and stress is associated with learning deficits and dopaminergic dysfunction. In this study, we hypothesised that stress-induced dopaminergic dysfunction produces learning deficits, and administration of a dopaminergic agonist could ameliorate the stressinduced deficits. Bromocriptine, a dopaminergic D2 receptor agonist, has been shown to affect a variety of neuronal processes. Bromocriptine demonstrated protection of the hippocampal CA1 neurons against cerebral ischaemia-induced cell death in gerbils (Liu et al. 1995; O’Neill et al. 1998). Further, bromocriptine is reported to have antidepressant activity in the chronic mild stress (CMS) model of depression (Muscat et al. 1992), wherein the CMS-induced decrease in sucrose consumption was reversed by chronic intermittent bromo-

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criptine treatment. In another study, the water immersion stress-induced gastric lesion was prevented by pre-treatment with bromocriptine (Samini et al. 2002). Furthermore, in a restraint stress model, bromocriptine attenuated the stressinduced gastric mucosal lesions and prevented the elevation of plasma corticosterone levels (Puri et al. 1994). Thus, although earlier studies have evaluated the effect of bromocriptine on stress-induced gastric lesions and depression, none of them have examined its effects on stressinduced deficits in learning and memory. Earlier studies in an animal model of brain trauma demonstrate that bromocriptine attenuates the controlled cortical impact-induced deficits in performance of the water maze task (Kline et al. 2002, 2004). Accordingly, in this study, we have evaluated the effect of bromocriptine treatment after chronic restraint stress and in the absence of stress on the radial arm maze performance. Further, the DA metabolism was assessed in the hippocampus, frontal cortex and striatum.

Materials and methods Experimental animals Adult male Wistar rats (200–250 g; 2–2.5 months old) obtained from the Central Animal Research Facility (CARF), NIMHANS, Bangalore, were used in the study. Rats were housed three per cage in polypropylene cages (22.5×35.5×15 cm) in a temperature (25±2°C), humidity (50–55%) and light-controlled (12-h light–dark cycle) environment with food and water ad libitum except during the periods of stress. An Institutional animal ethics committee approved the experimental protocols. All efforts were made to minimise both the suffering and the number of animals used. Stress and drug treatment Animals were randomly assigned to the different treatment groups. Normal control rats did not undergo stress or drug treatment. In the stress group, rats were encaged in a rodent restrainer 6 h/day for 21 days as described earlier (Shankaranarayana Rao et al. 2001; Srikumar et al. 2006). This form of restraint stress produces gastric ulcers, increases the adrenal weights (Sunanda et al. 1997, 2000b) and plasma corticosterone levels (Luine et al. 1996). Solution of bromocriptine mesylate (a gift from the Serum Institute of India, Mumbai, India) was freshly prepared in 50% DMSO-saline. After the completion of stress protocol, stress+bromocriptine group of rats received ten daily injections of bromocriptine (5 or 10 mg/kg, i.p.). The stress+ vehicle group received the vehicle alone (DMSO-saline; 2ml/kg, i.p.). In another set of experiments,

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rats that were not subjected to stress were given ten daily injections of either vehicle alone or bromocriptine at two different doses. The number of animals in each group was 9–12 in case of behavioural experiments and was six for neurochemical experiments.

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memory error (RME), and any re-entry was considered as a WME. A re-entry into a baited arm and a re-entry into an unbaited arm were considered as WME correct and WME incorrect, respectively. Estimation of DA levels

Evaluation of behaviour in the radial arm maze Learning and memory in the radial arm maze was assessed as described earlier (Devi et al. 2003; Srikumar et al. 2004, 2006; Titus et al. 2007). The eight-arm radial maze (RAM) consisted of a computer-monitored plexiform maze (Columbus Instruments, Ohio) with equally spaced arms (42×11.4×11.4 cm) radiating from an octagonal central platform, and the maze was kept 80 cm elevated from the ground. Before the training, the animals were kept on a restricted diet, and body weight was maintained at 85% of their free feeding weight with water available ad libitum. Training To acclimatise the rats to the RAM before the acquisition, all the arms were baited, and rats were allowed to explore the maze for 10 min and were given two such sessions on consecutive days. Acquisition Rats were given two trials a day. At the beginning of each trial, the maze was thoroughly cleaned with 70% ethanol and four of the arms (2, 3, 6 and 8) were baited with food reinforcement (Kellogg’s Planets and Stars™, Kellogg India, Mumbai, India). The rat was placed in the centre of the octagon and was allowed a free choice. An arm choice was recorded when a rat ate a bait or reached the end of an arm. The arms were not rebaited, so only the first entry into the baited arm was recorded as a correct choice. The trial continued until the rat entered all the four baited arms or 5 min had elapsed. At the end of the trial, the rats were returned to the home cages and were given the second trial after an inter-trial interval of 1 h. Training was continued till the rats attained the criteria of 80% correct choice (at least four correct entries out of five). Ten days after acquisition of the task, rats were evaluated for retention of the task. Rats were given two trials, and the average of two trials was taken for analysis.

After the stress and drug treatment protocols, the hippocampus, frontal cortex and striatum were quickly dissected out and homogenised in 2 ml of 3 mM sodium acetate buffer with 20% methanol and centrifuged at 1,850 g for 30 min at 4°C. The supernatant was filtered through a 0.2-μm pore size cellulose acetate filter (Sartorius, Goettingen, Germany) and was stored at −80°C till further analysis. Stock solutions of standard DA was made at a concentration of 1 mg/ml and diluted to obtain a concentration of 10 pg/μl of injection volume. The analysis was done using isocratic ion-pair highperformance liquid chromatography (Shimadzu, Kyoto, Japan) with electrochemical detection (Biorad, California). The mobile phase consisted of sodium acetate (20 mM), heptane sulfonic acid (5 mM), ethylenediamine tetraacetic acid (0.1 mM) and dibutylamine (0.04%) mixed with methanol (5.4%). The electrochemical conditions maintained included an applied potential of 650 mV and sensitivity of 2 nA/V. DA and its metabolites were separated on a reverse phase Nucleosil C-18 analytical column (15× 0.46 cm; 3-μm particle size; Supelco, USA) with a flow rate of 0.9 ml/min and injection volume of 20 μl. Chromatography data were processed, and chromatograms were analysed with Winchrom data station (Indtech Instruments, Mumbai, India; Deepti et al. 2004). The peaks in the samples were identified by comparing their retention time with that of the standard solution and quantified by comparing its peak area with that of the standards, and the concentration of the biogenic amines was determined and expressed as ng/g tissue wet weight. Statistical analysis Data is expressed as Mean±SEM. Either two-way or oneway analysis of variance (ANOVA) followed by Tukey’s post-hoc test was used to compare the means. The correlation of behavioural data and DA levels was performed by Pearson’s correlation analysis. P<0.05 was considered statistically significant.

Evaluation criteria

Results

Data from four trials were averaged and expressed as blocks. The data was analysed for percentage correct choice, reference and working memory errors (WME). An entry into an unbaited arm was considered a reference

Stress impairs learning in a partially baited RAM task Normal control rats reached the criterion of 80% correct choice after 24 trials (block 6). At 16 days of training, they

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11.97; p<0.001; Fig. 1c]. However, there was no significant difference between the two doses used [p>0.05].

reached a value of 89.16±1.78 percentage correct choice (Fig. 1a). Rats subjected to chronic restraint stress failed to attain the criterion of learning. The learning curve started to plateau after 20 trials. Even at 16 days of training, the percentage correct choice was 67.73±3.48 in stressed rats (Fig. 1a).

Reference memory impairment in stress and reversal by bromocriptine Entries into the arms 1, 4, 5 and 7 in the radial arm maze were considered as RMEs. Rats subjected to 21 days of restraint stress showed a significant impairment in reference memory (Fig. 2a). In block 8, the number of RMEs was 0.40±0.10 and 1.70±0.28 in control and stress groups, respectively. This increase in the number of RMEs in the stress group was significantly more than control rats [t(17)=4.48; p< 0.001; Fig 2a]. There was a significant effect of the groups on the number of RMEs [F(4,308)=18.44; p< 0.001; Fig 2b]. Bromocriptine (5 mg and 10 mg/kg, i.p.)-treated rats committed less number of errors compared to both stress- and stress+vehicle-treated rats from the sixth block

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Fig. 1 The effect of stress and bromocriptine treatment on percentage correct choice (Mean± SEM) in a partially baited radial arm maze task. a and b show the acquisition of the RAM task across trials (expressed as block of four trials; see “Materials and methods” for details). c shows performance in block 8. Stress: rats subjected to 21 days of restraint stress. Stress+Veh: rats subjected to 21 days of stress followed by 10 days of vehicle treatment. Stress+Br 5 and Stress+Br 10: stressed rats subjected to 10 days of treatment with bromocriptine 5 and 10 mg/kg, i.p., respectively. Hash sign, p<0.05; double hash sign, p<0.01; and triple hash sign, p<0.001 vs normal control. Double asterisks indicate p<0.01, and triple asterisks indicate p<0.001 vs stress; one-way ANOVA followed by Tukey’s post-hoc test (n=9–12)

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Rats subjected to stress were treated with either vehicle or bromocriptine for 10 days. Two-way ANOVA revealed a significant interaction between the treatment and the learning of the radial arm maze [F(28,305)=1.78; p< 0.05]. Bromocriptine treatment to stressed rats resulted in amelioration of the stress-induced deficits. The effect of bromocriptine treatment was statistically significant in block 7 [F(4,33)=4.41; p<0.01; Fig. 1b] and block 8 [F(4,36)=

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Fig. 2 The effect of stress and bromocriptine treatment on the number of RMEs (Mean±SEM) in a partially baited radial arm maze task. a and b show the acquisition of the RAM task across trials (expressed as block of four trials; see “Materials and methods” for details). c shows performance in block 8. Groups are as described in Fig. 1. Double hash sign, p<0.01; triple hash sign, p<0.001 vs normal control; Asterisks, p<0.05 vs stress; one-way ANOVA followed by Tukey’s post-hoc test (n=9–12)

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onwards (Fig 2b). In the block 8, the number of RMEs in the bromocriptine-treated group was significantly lesser than the stress group [F(4,36)=5.63; p<0.01] and was comparable to the normal control (Fig 2b,c). On the contrary, the working memory was not affected by either stress or bromocriptine treatments. The WMEs correct were not significantly different between groups in both block 7 and Table 1 Working memory errors (correct) in rats subjected to stress and drug treatment

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8 (Table 1), and WMEs incorrect were less than 0.1 in the block 7 and was 0 for all the groups in the eighth block. Effect of stress and bromocriptine treatment on retention To assess whether the effect of bromocriptine was restricted to acquisition or if it had actions on retention of the RAM task also, rats were subjected to two trials of retention test 10 days after the acquisition of the task. In the retention test, both stressed- and stress+vehicle-treated rats sustained the impairment seen in the acquisition [F(4,34)=5.62; p< 0.01; Fig 3a]. Interestingly, stressed rats treated with bromocriptine did not show any impairment in the retention test also. The percentage correct choice was comparable to that of the normal control group (p > 0.05; Fig 3a). Similarly, the increase in the number of RMEs seen in the acquisition in the stress and stress+vehicle groups was sustained in the retention test [F(4,34)=7.25; p<0.001], and bromocriptine treatment restored this (Fig 3b). As in the

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The effect of stress and bromocriptine treatment on percentage correct choice (a), number of RMEs (b) and number of WMEs correct (c) in the retention test of the RAM task. Ten days after the last day of the acquisition of the RAM task, rats were subjected to two trials, and the results were averaged. Groups are as described in Fig. 1. Data is represented as Mean±SEM. Triple hash signs, p<0.001 vs normal control; asterisk, p<0.05; and double asterisks, p<0.01 vs stress; oneway ANOVA followed by Tukey’s post-hoc test (n=9–12)

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Because bromocriptine produced reversal of stress-induced deficits, we examined the effect of bromocriptine on the behaviour of rats that were not subjected to stress. Two-way ANOVA showed a significant interaction between the treatment and learning [F(21,317)=1.70; p<0.05]. Interestingly, at the low dose (5 mg/kg, i.p.), bromocriptine showed a significant impairment [F(3,317)=23.8; p<0.001; Fig. 4b]. Contrastingly, both the vehicle- and bromocriptine 10 mg/ kg-treated rats performed as good as the normal control (Fig. 4a). In the block 8, the percent correct choice was 65.21±3.98, a 26.86% decrease compared to the normal control (Fig. 4b). Further, there was an increase in the number of RMEs in the bromocriptine 5 mg/kg-treated group (Fig. 4c). This increase was statistically significant in the block 8 [F(3,32)=11.24; p<0.001; Fig. 4d]. However, working memory was unaffected by bromocriptine treatment, and the number of WMEs correct was similar in all the groups (Table 2), and the number of WMEs incorrect was zero for all the groups in the block 8. In the retention test also, the bromocriptine 5 mg-treated rats showed a sustained impairment, both in terms of percentage correct choice (Fig. 5a) and RMEs (Fig. 5b); whereas the bromocriptine 10 mg- and vehicle-treated rats showed performance comparable to that of normal control rats (Fig. 5a,b). Similar to the acquisition, working memory was unaffected by drug treatment (Fig. 5c). Effect of stress and bromocriptine treatment on DA levels Restraint stress decreased DA levels in the hippocampus, frontal cortex and striatum (Fig. 6). There was a 34, 52 and 43% decrease in the DA levels in the hippocampus, frontal cortex and striatum, respectively, after restraint stress. Bromocriptine treatment significantly restored the decrease in DA levels in the hippocampus [F(4,25)=48.20; p< 0.001], frontal cortex [F(4,25) = 106.4; p < 0.001] and striatum [F(4,26)=43.48; p<0.001]. The DOPAC/DA ratio did not differ significantly across groups (data not shown).

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Effect of bromocriptine treatment in the absence of stress on DA levels Ten days of bromocriptine (5 mg/kg) treatment to unstressed rats decreased the DA levels in the frontal cortex [F(3,20)=97.99; p<0.001; Fig. 7b] and striatum [F(3,20)= 62.14; p<0.001; Fig. 7c] but did not affect the hippocampal DA levels (Fig. 7a). In the bromocriptine (10 mg)treated group, the DA level was comparable to the normal control in all the three regions (Fig. 7). There was a marginal increase in the frontal cortex DOPAC/DA ratio in the bromocriptine 5 mg group (0.13±0.01) compared to the normal control (0.09±0.01) [F(3,20)=6.51; p<0.01]. In the vehicle-treated group and the bromocriptine (10 mg)-treated group, the DOPAC/DA ratio was 0.10± 0.01 and was comparable to normal control. In the striatum Table 2 Working memory errors (correct) in rats subjected to bromocriptine treatment Normal Vehicle Bromocriptine Bromocriptine control 5 mg 10 mg 0.07± 0.07

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Fig. 4 The effect of bromocriptine treatment in the absence of stress on percentage correct choice (a and b) and the number of RMEs (c and d) in a partially baited radial arm maze task. a and c show the acquisition of the RAM task across trials (expressed as block of four trials; see “Materials and methods” for details). b and d shows the performance in block 8. Vehicle: rats subjected to 10 days of vehicle treatment. Br 5 and Br 10: rats subjected to 10 days of treatment with bromocriptine 5 and 10 mg/kg, i.p., respectively. Data is expressed as Mean±SEM (n=9–12). Hash sign, p<0.05; triple hash signs, p<0.001 vs normal control; oneway ANOVA followed by Tukey’s post-hoc test

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also, a similar trend was observed, while in the hippocampus, the DOPAC/DA ratio was unaffected (data not shown).

Discussion The salient findings in the current study are that chronic restraint stress impairs learning of the eight-arm radial maze task that is reversed by 10 days of bromocriptine treatment. The learning impairment after stress was associated with a decrease in DA levels that was restored by the bromocriptine treatment. The modulation of the dopaminergic system has been shown to produce effects on spatial learning. For instance, the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine lesion of the substantia nigra produced behavioural deficits in the Morris water maze task (Miyoshi et al. 2002; Da Cunha et al. 2003) and was associated with decreased DA levels in the striatum and frontal cortex (Miyoshi et al. 2002). Particularly, the dopaminergic D2 receptor has been implicated in the early memory consolidation processes (Packard and White 1989). In the present study, bromocriptine treatment to rats subjected to 21 days of restraint stress reversed the deficit in performance of a partially baited task. Our present results are in agreement with earlier reports that demonstrate the use of bromocriptine or other

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The effect of bromocriptine treatment in the absence of stress on percentage correct choice (a), number of RMEs (b) and number of correct WMEs (c) in the retention test of the RAM task. Ten days after the last day of the acquisition of the RAM task, rats were subjected to two trials, and the results were averaged. Groups are as described in Fig. 4. Data is represented as Mean±SEM. Hash sign, p<0.05 vs normal control; one-way ANOVA followed by Tukey’s post-hoc test (n=9–12)

dopaminergic D2 receptor agonists to ameliorate cognitive dysfunctions. In traumatic brain injury, bromocriptine showed improvement in a working memory paradigm of the water maze task (Kline et al. 2002). Intra-cerebro ventricular quinpirole injection in freely moving animals inhibited depotentiation (Manahan-Vaughan and Kulla 2003) and reversed the impairment in radial-arm maze learning after medial cholinergic pathway lesion (McGurk et al. 1992). It has been shown that the non-selective DA agonist apomorphine or selective agonist quinpirole prevents the scopolamine-induced impaired consolidation of passive avoidance behaviour (Sigala et al. 1997) or facilitate learning in an aversively motivated Stone maze (Umegaki et al. 2001). An earlier study found that 4 weeks of restraint and water immersion stress impaired memory in a T-maze task associated with dopaminergic dysfunction in the prefrontal cortex, and administration of the dopaminergic D1 receptor agonist, SKF 81297, reversed this deficit (Mizoguchi et al. 2000). Unlike this study, our present results indicate that there were no working memory deficits (Table 1) after chronic restraint stress. It is likely that the effects of stress manifests in different forms in different learning paradigms. However, the effects of a D1 receptor agonist administration on stress-induced deficits in performance of the radial arm maze task remain to be established. Nevertheless, both the earlier report by Mizoguchi et al (2000) and our present results suggest the role of both dopaminergic D1 and D2 receptors in stress-induced cognitive deficits. In the study by Kline et al (2002), bromocriptine produced recovery in the acquisition of the spatial memory task, and it restored the hippocampal CA3 cell loss analogous to the partial restoration of the spatial memory task. In restraint stress, our earlier studies document hippocampal CA3 neuronal dendritic atrophy (Shankaranarayana Rao et al. 2001; Sunanda et al. 1995) and impaired learning in a T-maze task (Sunanda et al. 2000a). It remains to be investigated whether the reversal of RAM performance by bromocriptine in our present study involves the reversal of dendritic atrophy. In the present study, the DA level in the frontal cortex, hippocampus and striatum was decreased after 21 days of restraint stress, reiterating our earlier findings (Sunanda et al. 2000b). The decreased DA concentration was reversed in a dose-dependent manner in the hippocampus and frontal cortex with the higher dose (10 mg/kg) being more

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Fig. 6 The effect of stress and bromocriptine treatment on dopamine levels in the hippocampus (a), frontal cortex (b) and striatum (c). Groups are as described in Fig. 1. Data is represented as Mean±SEM (n=6). Double hash sign, p<0.01 and triple hash sign, p<0.001 vs normal control. Double asterisks, p<0.01; triple asterisks, p<0.001 vs stress; one-way ANOVA followed by Tukey’s post-hoc test

effective. There was a significant correlation between the performance of the radial arm maze in the eighth block of the acquisition and the DA levels in the hippocampus (r= 0.93; p<0.05), frontal cortex (r=0.93; p<0.05) and striatum (r=0.88; p<0.05). Thus, it is likely that bromocriptine is reversing the stress-induced impairment in behaviour by enhancing DA levels. Berger et al. (2002) have shown that the dopaminergic D2 receptors are up-regulated in the CA1 region of the hippocampus after exposure to pre-natal stress. It can be reasoned that the hypodopaminergic state after stress could produce an up-regulation of the dopaminergic receptors as a compensatory phenomenon. In this context, administration of dopaminergic agonists could produce the behavioural recovery by acting on these receptors in addition to enhancing endogenous DA levels. However, the effects of bromocriptine on stress-induced changes in the dopaminergic receptor status that might accompany the behavioural recovery brought about by this agonist need further evaluation. Other possible mechanisms like antioxidant and neurotrophic support may also play a role as bromocriptine decreases lipid peroxidation (Kline

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et al. 2004), scavenges free radicals (Yoshikawa et al. 1994) and transactivates the phosphoinositide 3-kinase signalling pathway (Nair and Sealfon 2003). Bromocriptine, in the absence of stress had contrasting dose-dependent effects on the acquisition of the RAM task. None of the studies in our knowledge thus far have examined the effect of chronic bromocriptine treatment on performance of a partially baited RAM task. Local infusion of quinpirole (also called as LY171555) into the ventral hippocampus caused an improvement in choice accuracy (Wilkerson and Levin 1999), and post-training intrahippocampal infusions of LY171555 improved win-shift retention without affecting the performance in the win-stay task (Packard and White 1991). However, systemic quinpirole administration produced a dose-dependent increase in the latency of choices in a delayed non-match to sample task of the RAM (Chrobak and Napier 1992). In an early study, LY171555 over a broad range of doses increased the latency to finish the maze without significantly affecting the number of choices needed to finish the task (Levin and Bowman 1986). Thus, it appears that the effect of dopa-

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Fig. 7 The effect of bromocriptine treatment in the absence of stress on dopamine levels in the hippocampus (a), frontal cortex (b) and striatum (c). Groups are as described in Fig. 4. Data is represented as Mean±SEM (n=6). Triple hash signs, p<0.001 vs normal control; one-way ANOVA followed by Tukey’s post-hoc test

372

minergic modulation on learning is governed by multiple factors such as the route of drug administration, the dose of the drug used and the kind of the behavioural task itself. It is not entirely clear why bromocriptine in the present study exhibits a dose-dependent effect on RAM performance. Our results demonstrate that bromocriptine at a 5-mg dose decreases the DA levels in the frontal cortex and striatum; while the DA concentration in rats administered with 10 mg of bromocriptine was comparable to normal control. This possibly explains the dose-dependent dichotomy in radial arm maze behaviour. An earlier report shows a dose-dependent dimorphism on bromocriptine-induced striatal extracellular DA level with a 5-mg/kg dose increasing DA levels, while at 10 mg/kg, it was decreased (Brannan et al. 1993). Such inverted U-shaped or U-shaped dose-dependent effects on behaviour have been observed with other psychoactive drugs like the cholinesterase inhibitor heptylphysostigmine (Braida et al. 1996) or the D3-preferring agonist 7-OH-DPAT (Khroyan et al. 1995). The frontal cortex and striatum express the dopaminergic D1 and D2 receptors (Bergson et al. 1995; Hersch et al. 1995). The other subtypes have also been expressed albeit in lesser quantities (Bouthenet et al. 1991; MeadorWoodruff et al. 1992). The D2 receptors are present both post-synaptically and pre-synaptically, and the predominant pre-synaptic receptors are important in the regulation of DA release (Carter and Muller 1991; Lahti et al. 1992). The D2 receptor agonists at lower concentrations are believed to act primarily on these sites to decrease the DA release (Fusa et al. 2002). Most of the studies, particularly in Parkinson’s disease, are limited to behavioural evaluations, and none of them examine the effect of chronic dopaminergic agonist administration on DA levels. Acute administration of D2 agonists has been shown to decrease firing of the dopaminergic neurons (Yarbrough et al. 1984). It is likely that bromocriptine at low doses, such as 5 mg, produces effects predominantly on the pre-synaptic sites; whereas at higher doses could bring about its effects through actions on the post-synaptic D2 receptors. This could explain the dose-dependent effects of bromocriptine on learning of the radial arm maze. Similar effects of dopaminergic agonists have been reported elsewhere. D2 receptor agonists show biphasic effects on sleep–wake cycle, with low doses increasing and high doses decreasing sleep (Monti et al. 1988). Although bromocriptine is a strong agonist of the D2like receptors, it is not possible to rule out the role of other dopaminergic receptors or other neurotransmitter systems in these effects as bromocriptine is a partial antagonist of the D1-like receptors and has shown affinity to non-dopaminergic receptors, particularly 5-HT1, 5-HT2 and α2-adrenoceptors (Closse et al. 1984; Gibson and Samini 1979; McPherson and Beart 1983; Fukuzaki et al. 2000).

Psychopharmacology (2007) 193:363–374

To summarise, we demonstrate the ameliorative effects of bromocriptine administration on radial arm maze learning in restraint stressed rats. Further, we show that bromocriptine produces a differential dose-dependent effect on learning after administration to stress-naïve rats. Furthermore, these alterations in behaviour were attributable at least in part to the changes in the DA levels. Earlier studies show that D2 receptor agonists like bromocriptine or quinpirole have antidepressant (Muscat et al. 1992; Borsini et al. 1988) or anxiolytic activity (Bruhwyler et al. 1991). In this context, our present study underscores the role of dopaminergic system in stress and reversal of stress disorders. Acknowledgement Bromocriptine was a generous gift from the Serum Institute of India, Mumbai, India. The authors thank Titus, Bindu and Harsha for their technical assistance in the neurochemistry experiments; Bhagya and Veena for their help in data entry.

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