Biomedical subjects
R Muscat
Publications and source records attributed to R Muscat.
An animal model of anhedonia: attenuation of sucrose consumption and place preference conditioning by chronic unpredictable mild stress.
Chronic exposure to very mild unpredictable stress has previously been found to depress the consumption of, and preference for, highly palatable sweet solutions. The present study used the place conditioning procedure to investigate whether these effects result from a decreased sensitivity to reward. Rats were subjected to chronic mild unpredictable stress for a total of 4 weeks. During weeks 3 and 4, they received four training trials, in which rewards were presented in a distinctive environment, and four further non-rewarded trials in a different environment. The rewards used in different experiments were food pellets, dilute (0.7%) and concentrated (34%) sucrose solutions, and dl-amphetamine sulphate (0.5 and 1.0 mg/kg). In all experiments, non-stressed animals showed an increase in preference for the environment associated with reward; in stressed animals, these effects were abolished or greatly attenuated. Chronic unpredictable mild stress, which may be comparable in intensity to the difficulties people encounter in their daily lives, appears to cause a generalized decrease in sensitivity to rewards.
Suppression or facilitation of operant behaviour by raclopride dependent on concentration of sucrose reward.
Rats responded under continuous reinforcement for 1%, 10% or 95% sucrose pellets, under food deprived or ad libitum access conditions. In both cases responding was highest for 10% sucrose reinforcement, and a small proportion of 95% sucrose was not consumed. Ad libitum food access reduced response rates for all sucrose concentrations. Responding for 10% and 95% sucrose pellets followed a parallel time-course; and accumulation of 95% sucrose pellets was immediate and nonprogressive. Extinction following availability of 95% sucrose pellets caused an increase in response rate, but removal of 10% sucrose led only to a decline in responding. Under both food deprived and non-deprived conditions, the dopamine D-2 antagonist raclopride dose-dependently decreased responding for 1% or 10% sucrose, but increased responding for, and consumption of, 95% sucrose reward. After eight sessions of responding under extinction conditions, the presentation of reward-associated cues increased response rate early in the session. Raclopride had no effect during this period, but decreased responding later in the session. We consider the implications of these results for theories of neuroleptic drug action.
Voltammetric evidence that subsensitivity to reward following chronic mild stress is associated with increased release of mesolimbic dopamine.
Chronic exposure to mild unpredictable stress caused a decrease in rats' consumption of a palatable weak sucrose solution, which was reversed by chronic (5 weeks) administration of imipramine (5 mg/kg/day). Dopamine (DA) release in the nucleus accumbens (NAc) and caudate putamen (CPu) was measured in vivo using fast cyclic voltammetry, following electrical stimulation of the medial forebrain bundle. Experiments were performed under chloral hydrate anaesthesia 48 h after the termination of stress and the final imipramine injection. DA release was increased in the NAc of both stressed and imipramine-treated animals; imipramine did not normalize the increased DA release in stressed animals. In a further experiment, brain slices from stressed animals tended to be subsensitive to the inhibition of DA release in the NAc by quinpirole. No changes were observed in the CPu in any experiment. We discuss the relationship of these effects to stress-induced anhedonia.
Reward-dependent suppression or facilitation of consummatory behaviour by raclopride.
Rats were presented for 1 h with 0.7%, 7% or 34% sucrose solutions, either separately with water as an alternative (two-bottle test), or with all three concentrations concurrently available (three-bottle test). In trained animals, 7% sucrose produced the highest intakes in the two-bottle test, but 34% sucrose was preferred in the three-bottle test. In both tests the dopamine D-2 antagonist raclopride (100-400 micrograms/kg) reduced intake of 0.7% sucrose solution, but increased intake of 34% sucrose; both effects were apparent during the first 5 min of testing. In the two-bottle test, intake of the intermediate 7% concentration showed both effects: an immediate decrease and a later increase. In the three-bottle test, sucrose-naive animals showed a gradual onset of preference for 34% sucrose, and enhancements of intake by raclopride were not at first immediate; immediate enhancements required three sessions of exposure. Raclopride did not alter the consumption of a 0.001% solution of quinine. We consider the implications of these results for theories of neuroleptic drug action.
Time-, schedule-, and reinforcer-dependent effects of pimozide and amphetamine.
Rats performed on two multiple random-interval schedules, in which sequences of ascending or descending reinforcement densities were balanced between the schedules and between the two halves of the session. Using a standard reinforcer (10% sucrose pellets), pimozide decreased response rates, while amphetamine increased responding. The effects of both drugs were schedule dependent: larger changes were evident in low response rate, reinforcement-lean components than in high response rate, reinforcement-rich components. Both effects were also time dependent, increasing over the course of the session; this casts serious doubt on the applicability of Herrnstein's matching law for studying agents acting on brain dopamine. Increasing the period of food deprivation increased response rates, while withdrawing food deprivation decreased responding. These effects were also schedule dependent, but were time dependent. Substituting 95% sucrose pellets for standard 10% sucrose pellets caused an immediate and sustained decrease in responding, and up to 10% of earned reinforcement was not consumed. Pimozide increased response rates within reinforcement-lean components and reinstated the complete consumption of earned reward typical of standard reinforcement. These apparently paradoxical effects may be consistent with a decrease in the rewarding properties of sucrose pellets. Despite low response rates, amphetamine did not affect responding maintained by 95% sucrose pellets but did further reduce the consumption of earned reward. These results call into question the generality of the rate-dependency principle in the action of psychomotor stimulants.
Reversal of antidepressant action by dopamine antagonists in an animal model of depression.
Rats subjected chronically (12 weeks) to a variety of mild, unpredictable stressors showed a reduced consumption of sucrose or a sucrose/saccharin mixture in two-bottle consumption tests (sweet solution versus water). The deficit was apparent within 2 weeks of stress; normal behaviour was restored by chronic (7 weeks) treatment with the tricyclic antidepressants desmethylimipramine (DMI) or amitriptyline (AMI). Acute administration of the dopamine D1 receptor antagonist SCH-23390 1 week after withdrawal, or the dopamine D2 receptor antagonist sulpiride 2 weeks after withdrawal, were without effect in vehicle-treated stressed animals, and in non-stressed animals. However, the DA antagonists selectively reversed the improvement of performance in DMI- or AMI-treated stressed animals. This suggests that an increase in functional activity at DA synapses is the mechanism of action of DMI and AMI in this model.
Sweetness-dependent facilitation of sucrose drinking by raclopride is unrelated to calorie content.
Previous studies have reported that dopamine receptor antagonists increase the intake of solid or liquid diets containing high concentrations of sucrose. In Experiment 1, different groups of rats were trained in two-bottle tests (sweet solution vs. water), using three concentrations of either sucrose (0.7, 7 or 34%) or saccharin (0.02, 0.2 or 0.8%). Both sweeteners showed an inverted-U-shaped concentration-intake function. Raclopride increased intake of 34% sucrose, but not of 0.8% saccharin. In Experiment 2, raclopride had similar effects in three-bottle tests (all 3 concentrations available concurrently). However, whereas 34% was the most preferred sucrose solution, 0.2% saccharin was preferred to 0.8%. Thus, 0.8% saccharin differs from 34% sucrose in two ways, being not only noncaloric, but also aversive. In Experiment 3, 34% sucrose was rendered aversive by the addition of 0.08% quinine. Intake of this cocktail was not increased by raclopride. These results suggest that the difference between sucrose and saccharin in the effects of raclopride is related to the aversive properties of a concentrated solution of saccharin, rather than to its lack of calories.
Dopaminergic mechanism of imipramine action in an animal model of depression.
Rats, subjected chronically (10-12 weeks) to a variety of mild, unpredictable stressors, showed a decrease in their consumption of weak sucrose solutions; normal behavior was restored by chronic (5-9 weeks) treatment with the tricyclic antidepressant imipramine. Acute administration of the dopamine receptor antagonist pimozide or the specific dopamine D2 receptor antagonist raclopride had no effect in nonstressed animals and in vehicle-treated stressed animals, but both drugs selectively reversed the improvement of performance in imipramine-treated stressed animals. The 5HT antagonist metergoline increased sucrose consumption in all groups. The data suggest that the mechanism of action of imipramine in this model is an increase in functional activity at dopamine (DA) synapses.
A matching law analysis of the effects of dopamine receptor antagonists.
Herrnstein's matching equation was used to analyze drug effects on performance in random interval reinforcement schedules. Pimozide caused effects compatible with both motor and motivational impairments, in a 5-component multiple schedule, a 3-schedule 3-day cycle (ALT-3), and a 2-schedule 2-day cycle (ALT-2). However, at low doses, both sulpiride and SCH-23390, tested in the ALT-3 and ALT-2 procedures, caused effects compatible with selective motivational impairments. In experiments using the non-multiple schedules, motivational effects increased during the course of the experimental session, under all three drugs. The interpretation of "motor" and "motivational" deficits in the ALT-2 procedure was validated by experiments in which the response-force and deprivation level were systematically varied. The results support the view that dopamine may be involved in the maintenance of rewarded behaviour, but not differentially implicate the D1 or the D2 receptor subtype.
Behavioural analysis of the anorectic effects of fluoxetine and fenfluramine.
Two sets of experiments were carried out to compare the effects of fenfluramine and fluoxetine on consummatory and operant behaviour. In food-deprived rats allowed access to a 35% sucrose solution, an initial period of sucrose consumption was followed by a short period of grooming and exploratory behaviour, later superceded by resting. This "behavioural satiety sequence" was advanced by fluoxetine, but disrupted by dl-fenfluramine, which suppressed post-prandial resting, even at sub-anorectic doses. Fluoxetine also elicited resting behaviour following water drinking. However, this did not appear to be a non-specific sedative effect, since fluoxetine increased post-prandial grooming. In rats performing on random interval schedules of food reinforcement, fluoxetine caused proportionally greater decreases in responding on a reinforcement-lean schedule (RI-300s), as compared to a reinforcement-rich schedule (RI-7.5s); this effect is similar to that of a reduction in level of food deprivation. By contrast, fenfluramine reduced responding equally on both schedules. In both paradigms, the effects of fluoxetine were compatible with an increase in postprandial satiety, but the effects of fenfluramine were not.
Pimozide does not impair sweetness discrimination.
In an initial experiment pimozide decreased preference for a weak sucrose solution but increased preference for a strong solution on the descending limb of the concentration-intake function. As these effects resemble those of dilution, we therefore investigated whether pimozide decreases the perceived intensity of sweet stimuli. Rats were trained to perform a conditional discrimination in a T-maze. A correct response was rewarded by access to a 10% sucrose solution; an incorrect response was punished by confinement in the non-rewarded arm. In the first part of this experiment the discriminative stimulus, located at the choice point of the T-maze, was either water or sucrose, initially a 10% solution, but reduced gradually to 0.0003%. In the second part of the experiment, the discriminative stimulus was either 1% sucrose or a weaker solution, which was initially 0.0001% then raised gradually to 0.5%. Performance fell below 75% accuracy at 0 versus 0.0012% and at 1% versus 0.1%. Pimozide (0.5 mg/kg) administered at these (and other) levels of difficulty decreased running speed but had no effect on discrimination accuracy. As pimozide did not affect either the threshold for sweetness perception or the discrimination of a just noticeable difference, the decreased responsiveness of neuroleptic-treated rats to sweet rewards cannot be explained by a change in the perception of sweetness.
Blockade of 8-OH-DPAT-induced feeding by dopamine antagonists.
Feeding elicited by the 5HT1A agonist 8-OH-DPAT was blocked by pretreatment with the DA antagonists SCH-23390 and sulpiride, in two experiments conducted in non-deprived rats and in three experiments conducted after 4 h food deprivation. In deprived animals, 8-OH-DPAT prolonged the initial period of feeding. However, in non-deprived animals, 8-OH-DPAT delayed the onset of eating, and suppressed post-prandial resting; both SCH-23390 and sulpiride restored the normal pattern of behaviour. All three drugs suppressed grooming. The results suggest that 8-OH-DPAT elicits feeding by a secondary disinhibition of activity postsynaptic to DA neurons. The consequences of this mechanism for the interpretation of 8-OH-DPAT-induced feeding are discussed.
Effects of dopamine receptor antagonists on sucrose consumption and preference.
Effects of the dopamine D2 receptor antagonist sulpiride and the D1 antagonist SCH-23390 were examined, in rats, in two-bottle preference tests (sucrose versus water) and in single-bottle tests, at different sucrose concentrations. Both drugs decreased sucrose intake in single bottle tests, at low sucrose concentrations, but had no effect at high concentrations; reducing drive level had exactly the opposite pattern of effects. In two-bottle tests, both drugs reduced preference for the weakest sucrose concentration (0.7%) but increased preference for the strongest concentration (34%). The effects of antagonizing either subtype of DA receptor appear to be similar to those of reducing the concentration of sucrose.
Noradrenergic receptor interactions in feeding elicited by stimulation of the para-ventricular hypothalamus.
Food intake and feeding behaviour were examined after the administration of noradrenaline (NA) or clonidine to the para-ventricular nucleus of the hypothalamus, or after systemic administration of clonidine. In 20-hr deprived animals all treatments dose-dependently reduced pellet consumption; however, at a low dose (2-5 micrograms) central clonidine increased eating time and bout length. In 4-hr deprived animals all treatments increased sucrose consumption. Clonidine (peripheral and central) increased feeding time but did not alter feeding rate; NA did not alter feeding time, but did increase feeding rate; NA also increased activity and decreased resting. The effects of NA on feeding rate, activity and resting were blocked by propranolol; however, the propranolol-NA combination increased feeding time. Thus, NA and clonidine increased feeding by different mechanisms, but after propranolol pretreatment the effects of NA were similar to those of clonidine. It is concluded that clonidine enhances feeding by inhibiting satiety and that the feeding stimulant effect of NA is mediated by a complex interaction of alpha- and beta-receptors.
Tests of functional equivalence between pimozide pretreatment, extinction and free feeding.
Both pimozide pretreatment and free feeding caused within-session and between-session decrements in variable interval operant performance; response decrements generated under pimozide were maintained on transfer to free feeding, and vice versa. On subsequently testing under extinction conditions (after food deprivation and drug free) large initial increases in responding were seen in all groups, and subsequent response decrements in extinction were steeper than in either pimozide or free feeding conditions. The effects of pimozide pretreatment do not resemble those of extinction, but may in some circumstances be functionally equivalent to a decrease in drive level.
Changes in dopamine autoreceptor sensitivity in an animal model of depression.
Rats exposed for 6 weeks to a variety of mild unpredictable stressors showed reduced consumption of a preferred sucrose solution. The deficit was apparent after 1 week of stress and was maintained for at least 2 weeks after termination of the stress regime. Sucrose preference was unaffected by 2 weeks of treatment with the tricyclic antidepressant DMI but returned to normal after 3 weeks of DMI treatment. Subsensitivity to the anorexic effect of a low dose of apomorphine was seen in vehicle-treated stressed animals, and in unstressed animals following withdrawal from DMI. In both cases, the changes resulted from a failure of apomorphine to reduce eating time (rather than from changes in eating rate); this effect is assumed to represent a subsensitive response to stimulation of dopamine cell body autoreceptors. As the same effect is seen in anhedonic stressed animals and in animals withdrawn from DMI, it is concluded that dopamine autoreceptor desensitization probably does not contribute to clinical improvement following chronic antidepressant treatment.
Behavioural specificity of 8-OH-DPAT-induced feeding.
8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) has been reported to increase food intake. This effect was confirmed in rats consuming plain or sweetened wet mash. However, the consumption of a 35% sucrose solution or of a range of other flavoured liquids was enhanced marginally if at all by a single low dose of 8-OH-DPAT, and the drug actually decreased the consumption of a high protein liquid diet. 8-OH-DPAT did, however, increase gnawing on a wooden block. These results suggest that 8-OH-DPAT-induced "hyperphagia" may to some extent be secondary to the elicitation of chewing behaviour. 8-OH-DPAT also caused certain other behavioural changes, including a suppression of grooming.