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Quinpirole- and amphetamine-induced hyperdipsia: influence of fluid palatability and behavioral cost

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Abstract

Daily administration of moderate doses of amphetamine or of the dopaminergic D2 agonist quinpirole is associated with the development of excessive, non-regulatory drinking. Here we compared the influence of manipulating fluid palatability and behavioral cost on the development of this drinking augmentation. Experiment 1 was based on the phenomenon of contrafreeloading (CFL): animals work for a resource even though the same resource is freely available. The effects of 15 daily injections of amphetamine (1.0 and 1.7 mg/kg i.p.) or quinpirole (0.1 and 0.56 mg/kg i.p.) were evaluated in mildly water-deprived rats. For the first 6 days the rats obtained water by lever pressing (FR3) only; over the following 9 days water was also freely available (CFL). Initially, 0.56 mg/kg quinpirole reduced lever pressing for water. A complete recover of responding was then obtained, and was followed by a progressive increment in the amount water obtained by lever pressing during the CFL phase (from 10 to 50%). Amphetamine did not affect percent CFL, but at the highest dose (1.7 mg/kg) reduced total water intake during the last 3 days of treatment. In experiment 2 the rats had free access to two bottles, one of which contained tap water, and the other contained either an ethanol (6%) or a sucrose (5%) solution. After habituation to this regimen, the rats received 10 daily i.p. injections of vehicle, amphetamine (1.0 or 3 mg/kg), or quinpirole (0.1 or 0.56 mg/kg). Quinpirole 0.56 mg/kg enhanced daily fluid intake under both sucrose and ethanol conditions, but selectively reduced ethanol preference. The higher amphetamine dose reduced fluid intake and sucrose preference. In conclusion, chronic exposure to a dopaminergic D2 agonist, but not to amphetamine, produced an increment of drinking that was resistant to manipulation of either palatability or the behavioral cost of the fluid.

Introduction

Excessive non-regulatory drinking occurs in a sizable minority of chronic psychotic patients [17], [18], [22]. Experimentally, excessive drinking can be induced by manipulating access to water, as happens in so-called schedule-induced polydipsia [12], [30], [31]. Intermittent administration of moderate doses of amphetamine has also been found to elicit excessive drinking in rats [1], [6], [7], [14], [32], [33], [34], [35], [36], [41]. Dopaminergic mechanisms probably play a major role in this effect, as suggested by two sets of evidence. First, blockade of D1 or D2 receptors by SCH-23390 and haloperidol, respectively, delays the development of amphetamine-induced hyperdipsia [34], [36]. Second, intermittent administration of the D2 agonist quinpirole also elicits excessive drinking [14]. This effect is enhanced by the dopaminergic D1 agonist SKF-38,393 and is reinstated by amphetamine. Central mechanisms are probably important for quinpirole-induced polydipsia, which in fact is only partially inhibited by the administration of the peripheral D2 antagonist domperidone [14].

The aim of the present study was to further characterize the augmented drinking behavior produced by chronic intermittent exposure to amphetamine and quinpirole. In two independent experiments we investigated the effect of modifications in the behavioral cost of drinking, as well as in fluid palatability, on the development of drinking augmentation. This goal has been achieved by adopting two different behavioral methodologies, both of which provided the animal with a choice between two different options.

The first method is based on the contrafreeloading (CFL) phenomenon: animals continue to respond for a reward in an operant setting even after the same reward becomes available at no behavioral cost [25], [26], [27], [39], [51]. CFL has been observed in a number of species, including humans, with the conspicuous exception of the domestic cat [26]. Apparently this phenomenon contradicts incentive learning theories in that it disputes the principle of selective preference for the response requiring the least effort. Recently, however, it has been suggested that CFL is adaptive as far as it allows the animal to improve and update its foraging strategies in an uncertain environment [26]. To the best of our knowledge, there have been no studies on the effects of dopaminergic drugs on CFL. However, taking into account the role of dopaminergic systems in the instrumental access to reinforcers [5], [9], [10], [42], [45], [46], it is reasonable to hypothesize that chronic intermittent dopaminergic stimulation might enhance the expression of this phenomenon. On the other hand, we have found that the hyperdipsia produced by intermittent amphetamine under conditions of free access to water disappears once the rats are tested under conditions of operant access (unpublished data from this laboratory). Thus it is possible that, inasmuch as CFL increases the cost of drinking, it might suppress drug-induced hyperdipsia.

The second experiment utilized the two bottles paradigm in which rats chose between water and either an ethanol (a relatively unpalatable and low caloric fluid) or a sucrose (a highly palatable, highly caloric fluid) solution. Studies with 6-hydroxydopamine-induced lesions and with dopaminergic D2 antagonists have provided evidence that the functional integrity of the dopaminergic mesotelencephalic system is essential for the ingestion of ethanol or sucrose solutions [20], [23], [24], [49], [52]. However, the effects of systemically administered dopaminergic agonists on these behaviors depend on the dose and on the schedule of administration. Thus, acute administration of low doses of quinpirole has been found to inhibit ethanol intake and preference [8], [11], [16], whereas the opposite effect is produced by high doses [29]. Low-level continuous exposure to amphetamine increases ethanol intake and preference, which, in contrast, are either non-affected, or even reduced, by the intermittent administration of the drug [13], [28], [29], [38], [53]. Microinjection studies have shown that at low doses quinpirole inhibits sucrose and ethanol-reinforced responding when microinjected into the ventral tegmental area [21], whereas it exhibits a biphasic effect when injected into the nucleus accumbens [19]. These findings can be explained by the fact that at low doses, D2 agonists preferentially stimulated presynaptic D2 receptors, which inhibit dopaminergic transmission and blunt reward processes, whereas at high doses they activate postsynaptic dopaminergic receptors, thereby facilitating reward processes [8], [37]. We do not know how the complex effects of quinpirole and amphetamine on ethanol and sucrose ingestion might interact with hyperdipsia produced by chronic exposure to these drugs. Nevertheless, if the hyperdipsic effects of quinpirole and amphetamine are due to a change of hydrosaline balance, we predict that the development of hyperdipsia would not covary with changes in the preference for ethanol or sucrose.

Section snippets

Animals

The study was performed using 120 Sprague–Dawley male rats (Harlan Nossan, Correzzana, MI, Italy) weighing approximately 200 g at the start of the experiments. The rats were individually housed at 23°C with a light–dark cycle of 12 h (07:00–19:00 h). During the first week the animals had free access to water and food (Standard Diet 4RF21, Mucedola s.r.l.).

Experiment 1: CFL

Sixty rats were used in this experiment. The CFL experiment was performed by using four custom made operant chambers for rats equipped with a

Experiment 1 (CFL)

For the first 6 days the animals had access to water by lever pressing only. The amount of water gained by rats under basal conditions was roughly 5 ml per session and was significantly affected by drug treatment (Fig. 1). Accordingly, ANOVA indicated significant differences for both treatment (F4,40=5.216, P=0.002) and days of treatment (F20,200=2.342, P=0.002). Post-hoc analysis attributes these differences to the almost complete suppression of responding in groups receiving quinpirole 0.56

Discussion

The present study investigated the effect of repeated administrations of quinpirole and amphetamine on the intake of fluids under different experimental conditions. There were four major findings. First, under a free access two bottle paradigm, quinpirole increased the intake of both water and 5% sucrose solution, without modifying the preference ratio between the two fluids (Fig. 3). Second, under a free access two bottle paradigm, quinpirole increased total fluid intake by increasing the

Acknowledgements

We thank Aldo Badiani MD for his constructive comments on the paper. This work has been supported by a grant ‘Finanziamento progetti di ricerca Ateneo e attrezzature scientifiche’.

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