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Biomedical subjects

P Willner

Publications and source records attributed to P Willner.

At least 55 records · Page 3Linked to original sources
PubMed1995

Attenuation of sucrose consumption in mice by chronic mild stress and its restoration by imipramine.

Chronic exposure to mild unpredictable stressors (CMS) has previously been found to reduce the consumption of palatable, sweet solutions in rats. In the present study, the utility of this procedure was assessed in mice. Male AP mice subjected to CMS showed reduced consumption of a 2% or 4% sucrose solution. This effect was reversed by chronic (3 weeks) treatment with the tricyclic antidepressant imipramine (20 mg/kg per day). These results extend previous reports of a generalized decrease in sensitivity to reward (anhedonia) in rats caused by CMS and the efficacy of antidepressant treatment in this paradigm. Chronic unpredictable mild stress in mice appears to provide a realistic animal model of depression.

Analysis of Variance↗
PubMed1994

Effects of imipramine on serotonergic and beta-adrenergic receptor binding in a realistic animal model of depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. In the present study, in addition to confirming these behavioural observations, the binding properties of cortical beta-adrenergic and 5HT2 receptors, and hippocampal 5HT1A receptors were studied (using the ligands [3H]-dihydroalprenolol, [3H]-ketanserin and [3H]-8-OH-DPAT, respectively), following 7 weeks of CMS and 4 weeks of imipramine treatment (10 mg/kg per day). CMS increased Bmax for all three receptor systems. Imipramine decreased Bmax, reversing the effect of CMS, for beta-adrenergic and 5HT2 receptor binding, but increased Bmax for 5HT1A receptor binding. KDs were unaffected by either treatment. The beta-receptor and 5HT2 receptor binding data are consistent with accounts of antidepressant action derived from studies in normal animals, but the 5HT1A receptor binding data are more difficult to reconcile. In no case was there a good correlation between receptor binding and behavioural data.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Parallel changes in dopamine D2 receptor binding in limbic forebrain associated with chronic mild stress-induced anhedonia and its reversal by imipramine.

Chronic sequential exposure to a variety of mild stressors has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions, associated with abnormalities of dopaminergic neurotransmission in the nucleus accumbens. In the present study, 5 weeks of treatment with imipramine (10 mg/kg b.i.d.) reversed the decreased sucrose intake of rats exposed to chronic mild stress. Stress also caused a decrease in D2-receptor binding in the limbic forebrain (but not the striatum), which was completely reversed by imipramine. In nonstressed animals, imipramine decreased D1-receptor binding in both regions. However, in stressed animals, imipramine did not significantly alter D1-receptor binding in either area. Stress alone slightly increased D1-receptor binding, in striatum only. Scatchard analysis showed that all changes in receptor binding resulted from changes in receptor number (Bmax) rather than receptor affinity (KD). The results support the hypothesis that changes in D2-receptor function in the nucleus accumbens are responsible for chronic mild stress-induced anhedonia and its reversal by antidepressant drugs. They do not support the hypothesis that the sensitization of D2-receptors seen following chronic antidepressant treatment is caused by a down-regulation of D1-receptors.

Animals↗
PubMed1994

Reversal of stress-induced anhedonia by the dopamine receptor agonist, pramipexole.

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D2 agonist, were studied during 7-9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppression of sucrose intake in stressed animals, increasing sucrose intakes above the levels seen in untreated nonstressed controls. Pramipexole also increased sucrose intake in nonstressed animals; these effects were accompanied by increases in water intake and tended to correlate with weight loss. Drug-treated stressed animals also lost weight, but in this case water intake was unaffected. A second group of animals received a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipexole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two further groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice-weekly) drug treatment. Intermittent pramipexole treatments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6-8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer.

Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (+/-)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (+/-)-mianserin (2.5 mg/kg), and the other enantiomer. (-)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (+/-)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (+/-)-mianserin (2.5 mg/kg) or by (-)-mianserin. Raclopride (100 micrograms/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with (+/-)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.

Animals↗
PubMed1994

Effects of chronic mild stress on performance in behavioural tests relevant to anxiety and depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to depress the consumption of a weak (1%) sucrose solution by rats. This effect was confirmed in each of three experiments in the present study, following which behaviour was examined in other tests relevant to either depression or anxiety. CMS did not significantly affect behaviour in the social interaction test and caused an anxiolytic-like profile in the elevated plus-maze. CMS increased submissive behaviour in the resident-intruder test, and decreased male sexual behaviour. The latter effect was more pronounced in animals reared in isolation from the time of weaning; isolation rearing did not influence sexual behaviour in nonstressed animals. Isolation rearing also potentiated the effect of CMS on sucrose drinking, in both male and female rats. These results support the relevance of the CMS procedure as a potential animal model of depression.

Aggression↗
PubMed1994

Decreased hedonic responsiveness during a brief depressive mood swing.

Female volunteers completed the Fawcett-Clark Pleasure Capacity Scale (FCPCS) and rated the pleasantness and desirability of a taste stimulus (cheese), before and during a depressive mood swing. Mood change was induced by reading negative self-referent statements, with additional 'booster' periods of mood induction to prolong the duration of the mood swing. The mood induction procedure (MIP) caused a decrease in contentment and alertness, as derived from a set of visual analogue mood scales, and also decreased hedonic capacity, as measured by responses to the taste stimulus and by the FCPCS. No changes on any measure were shown by a control group who read an equivalent set of positive self-referent statements. Prior to the MIP, there were no significant correlations between mood measures and hedonic measures, or between taste responses and the FCPCS. However, there were significant correlations between the size of the changes in these various measures following the depressive MIP. The results suggest that hedonic capacity is responsive to acute depressive mood swings.

Adult↗
PubMed1993

Subsensitivity to rewarding and locomotor stimulant effects of a dopamine agonist following chronic mild stress.

Chronic exposure to very mild unpredictable stress has previously been found to reduce or abolish the acquisition of place preference conditioning. In the present study, chronic mild stress was found to abolish the acquisition of preferences for a distinctive environment paired with systemic administration of amphetamine (0.5 mg/kg) or quinpirole (100-400 micrograms/kg) or with quinpirole (0.75 micrograms) administered bilaterally within the nucleus accumbens. The locomotor stimulant effects of quinpirole (100-400 micrograms/kg) were also attenuated in stressed animals. The result suggest that decreased sensitivity to reward following chronic mild stress results from a decreased sensitivity of dopamine D2 receptors within the nucleus accumbens.

Animals↗
PubMed1993

Behavioural sensitization to a dopamine agonist is associated with reversal of stress-induced anhedonia.

Chronic exposure to very mild unpredictable stress (CMS) has previously been found to reduce the consumption of palatable sweet solutions and to impair place preference conditioning; evidence has been presented that these effects may reflect a dysfunction of the mesolimbic dopamine system. In the present study, rats were subjected to CMS for a total of 9 weeks. CMS reduced the consumption of a 1% sucrose solution. During weeks 6 and 7, animals received quinpirole (0-400 micrograms/kg) twice weekly. Both CMS-treated animals and controls showed sensitization to the locomotor stimulant effects of quinpirole. Subsequently, a sustained recovery of sucrose drinking was observed in quinpirole-treated stressed animals. During week 8, all animals received a single pair of place preference conditioning trials, in which quinpirole (200 micrograms/kg) was administered in a distinctive environment, and vehicle in a different environment. Non-stressed animals showed an increase in preference for the environment associated with quinpirole, as did stressed animals that had been sensitized to quinpirole, this effect was absent in untreated stressed animals. Finally, in week 9, acute administration of raclopride (150 micrograms/kg) was found to reverse the recovery of sucrose drinking in quinpirole-treated stressed animals, suggesting that these effects are mediated by an increase in dopamine function.

Animals↗
PubMed1992

Antidepressant-like effects of dopamine agonists in an animal model of depression.

Chronic exposure to mild unpredictable stress (CMS) has previously been found to cause an antidepressant-reversible decrease in the consumption of palatable sweet solutions. There is evidence that the effect of antidepressants in this model is mediated by an increase in transmission at dopamine (DA) synpases. The present study investigated whether another treatment known to increase the functional responsiveness of DA systems, intermittent administration of DA agonists, would have antidepressant-like effects. In three experiments in rats, CMS-induced decreases in sucrose consumption were reversed by three to four twice-weekly injections of quinpirole (100-200 micrograms/kg) or bromocriptine (2.5 mg/kg). The effects lasted for several weeks, and when they waned, could be reinstated by a single additional injection of quinpirole. As with tricyclic antidepressants, the effect of quinpirole was reversed by raclopride, administered acutely immediately prior to a sucrose consumption test; there were no changes in sucrose intake in nonstressed control animals. The results suggest that intermittent administration of DA agonists merits investigation as a novel strategy for the treatment of depression.

Animals↗
PubMed1992

Behavioural tests of the dopamine depletion hypothesis of neuroleptic-induced response decrement.

This study was carried out to test the hypothesis that neuroleptic-induced within-session response decrements reflect a fatigue process, resulting from dopamine depletion, that is present before the session begins but is masked briefly by activational cues present at the start of the session. Response decrementing effects of pimozide were examined in rats lever pressing on random interval schedules of food reinforcement. An initial experiment was carried out to rule out a pharmacokinetic explanation of the response decrement. In a second experiment, the response decrement was not exacerbated by an immediately preceding period of intense forced motor activity (wheel running). Experiments 3 and 4 tested two further predictions: that the pimozide-induced response decrement should be overcome by removing the animal to its home cage and then replacing it in the apparatus (thereby reinstating the activational cues present at the start of the session); and that response impairments should be present from the outset if the animal is confined in the apparatus prior to the start of the session (thereby allowing activational cues to dissipate). Neither prediction was confirmed. Overall, the results provide no support for the dopamine depletion hypothesis.

Animals↗
PubMed1992

Effects of chronically administered fluoxetine and fenfluramine on food intake, body weight and the behavioural satiety sequence.

Rats were administered fenfluramine (FF: 3 mg/kg) or fluoxetine (FX: 6 mg/kg) daily for 3 weeks. On acute administration, FF suppressed consumption of 35% sucrose (in a 40 min test) and overnight chow intake. Repeated administration saw the rapid development of extensive tolerance to these effects. FF had no effects on body weight, and no withdrawal effects were apparent. FX reduced chow intake and body weight throughout the treatment period, but there was evidence of some tolerance to the suppression of chow intake and sucrose drinking. Following FX withdrawal, normal body weight was restored in 4 days; food intake was normal during this period. A delayed rebound hyperphagia commenced on day 5 of withdrawal, and persisted for at least 6 days. The behavioural satiety sequence (drinking--activity--grooming--resting) was disrupted by acute FF; on chronic treatment, FF advanced the onset of postprandial resting, but also increased drinking time. FX advanced the behavioural satiety sequence on acute administration, but not after chronic treatment. We consider the implications of these results for the use of resting behaviour as an indicator of postprandial satiety.

Animals↗
PubMed1992

Reversal of stress-induced anhedonia by the atypical antidepressants, fluoxetine and maprotiline.

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions. In the present study this effect was reversed by chronic (9 weeks) treatment with the atypical antidepressants, fluoxetine and maprotiline (5 mg/kg/day); the non-antidepressant chlordiazepoxide was ineffective. Stressed animals were also subsensitive to food reward in the place conditioning procedure; however, fluoxetine and maprotiline treated animals showed normal place preference conditioning. Acute pretreatment with raclopride (100 micrograms/kg) selectively reversed the recovery of sucrose drinking in antidepressant-treated stressed animals. These results extend previous reports of the efficacy of tricyclic antidepressants in this paradigm, and support the hypothesis of a dopaminergic mechanism of antidepressant action.

Animals↗
PubMed1992

Effects of the 5-HT uptake inhibitors, femoxetine and paroxetine, and a 5-HT1A/B agonist, eltoprazine, on the behavioural satiety sequence.

In rats allowed access to a 35% sucrose solution, following a 4-h period of food and water deprivation, an initial period of sucrose consumption was followed by a short period of grooming and exploratory behaviour, later superseded by resting. This "behavioural satiety sequence" was advanced in time by the 5-HT uptake inhibitors femoxetine and paroxetine and by the 5-HT1A/B agonist eltoprazine at anorectic and subanorectic doses. These effects, which are similar to those previously observed with another 5-HT uptake inhibitor, fluoxetine, are compatible with an increase in postprandial satiety.

Animals↗
PubMed1992

Additive effects of chronic treatment with antidepressant drugs and intermittent treatment with a dopamine agonist.

Locomotor activity in response to the D2/D3 agonist quinpirole was studied in male rats treated chronically (25-40 days) with imipramine, amitriptyline or mianserin (5 mg/kg/day). All three antidepressants potentiated the response to quinpirole. Repeated administration of quinpirole at 3-day intervals also caused a marked increase in the locomotor response to quinpirole. Imipramine-treated animals were more active than vehicle-treated animals on all quinpirole trials. Animals tested in the locomotor activity apparatus for the first time following their fifth quinpirole injection showed sensitization, but to a lesser extent than animals tested repeatedly under quinpirole. This context-independent sensitization was potentiated by all three antidepressants. We discuss the potential clinical relevance of these results.

Animals↗
PubMed1992

Suppression of sucrose drinking by chronic mild unpredictable stress: a methodological analysis.

Previous studies have demonstrated that chronic exposure of rats to a melange of ultra-mild stressors causes an antidepressant-reversible decrease in the intake of palatable weak sucrose solutions, as well as other evidence of insensitivity to rewards. In the present study, we analyzed some of the behavioral requirements for the suppression of consummatory behaviour by chronic mild stress. Rats exposed to our standard chronic mild stress protocol and tested following 20 h food and water deprivation showed a decrease in intake of 1% sucrose, but not of water or chow. The effect on sucrose intake was also present, but smaller, in non-deprived animals, and wa seen in both singly- and pair-housed animals. Experiments designed to identify the crucial elements of the stress procedure showed that one element, paired housing (in animals normally housed singly) was particularly potent. However, no one element was either necessary to cause the decrease in sucrose intake, or sufficient to maintain the impairment for longer than 4 weeks: Variety and frequency of microstressors appeared to be the essential features of procedures causing a prolonged anhedonia.

Adrenal Glands↗
PubMed1992

Decreased reactivity to sweetness following chronic exposure to mild unpredictable stress or acute administration of pimozide.

Consumption of a palatable wet mash was examined in rats subjected chronically (4-10 weeks) to unpredictable mild stress. Intake of mash containing 0, 10%, or 20% additional sucrose was normal in stressed animals. In control animals, the addition of 30% or 40% sucrose caused a decrease in the quantity of mash consumed, but increased the rate of eating. Both the increase in eating rate and the decrease in intake, at high sucrose concentration, were markedly attenuated in stressed animals (which therefore had higher intakes of very sweet mash and lower rates of eating, relative to control animals). Like chronic mild stress, the dopamine receptor antagonist pimozide (0.2 mg/kg) also increased the intake of a wet mash with 30% added sucrose, while decreasing the rate of consumption. Stressed animals were relatively insensitive to pimozide, though there were significant additive effects on duration of eating (increased) and on postprandial resting (suppressed). The failure of stressed animals to adapt their intake to increases in sweetness, and the similarities between the effects of chronic mild stress and acute pimozide, are compatible with the hypothesis that animals exposed to chronic mild stress are anhedonic.

Animals↗