Biomedical subjects

R Muscat

Publications and source records attributed to R Muscat.

At least 19 recordsLinked to original sources

PubMed2006

Dopamine manipulations limited to preexposure are sufficient to modulate latent inhibition.

Four experiments are reported that demonstrated that dopamine (DA) transmission is involved in the acquisition of latent inhibition (LI) of a conditioned taste aversion. LI refers to weaker conditioning as a consequence of nonreinforced preexposure (PE) of the future conditioned stimulus. Although it is known to depend on DA transmission during the conditioning phase, it is usually thought that the cognitive processes involved in the establishment of LI (during the PE phase) are DA independent. Either amphetamine (AMPH; 0.5 or 1.0 mg/kg) or haloperidol (HAL; 0.1 mg/kg) were injected before 1 or all of the 3 PE sessions. AMPH blocked the acquisition of LI if it was injected before each or before only the last PE session and HAL potentiated LI.

Amphetamine↗

PubMed2001

Acute interferon-alpha administration modulates sucrose consumption in the rat.

One of the two core symptoms of depression as defined by the Diagnostic and statistical manual of mental disorders (DSM-IV) (American Psychiatric Association) is anhedonia, or a loss of interest or pleasure. Sucrose consumption has been described as a valid measure of sensitivity to reward. In the present set of studies, changes in sucrose consumption (three-bottle test using 1, 8 and 32% sucrose) were taken as a measure of the anhedonic effect of interferon-alpha (IFN-alpha). Sucrose tests were carried out following the i.p. administration (20 min pre-treatment time) of Recombinant Human Interferon-alphaA (rHIFN-alpha), 10(1), 10(2), 10(4) units(U) and Rat Interferon alpha (rRIFN-alpha), 1,10 and 100 IRU. Both types of IFN-alpha produced a decrease in sucrose consumption and drinking rate (DR) at the highest doses, with the greatest inhibition being at the lowest sucrose concentration (1%). Longer pre-treatment times with rHIFN-alpha (40 and 80 min prior to commencement of 1 h drinking test) resulted in insignificant effects. Significant hypothermia relative to vehicle-injected rats was observed following interferon administration in the 20 min pre-treatment condition, but showed no significant difference when compared to vehicle at 40 or 80 min. Overall these results confirm a depression-like behavioural syndrome (anhedonia) following administration of IFN-alpha.

Animals↗

PubMed1999

MK-801 interaction with the 5-HT transporter: a real-time study in brain slices using fast cyclic voltammetry.

The effects of a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine ((+)-MK-801) and a competitive NMDA antagonist, (+/-)-3-2-carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP) were compared in electrically evoked 5-HT release in the brain slices incorporating the substantia nigra pars reticulata (SNr) or the dorsal raphé nucleus (DRN) using fast cyclic voltammetry (FCV). Electrical stimulation of either the SNr or the DRN with 50 pulses at frequencies greater than 10 Hz generated signals that were indistinguishable from 5-HT. In the SNr, 0.6-60 microM MK-801 concentration dependently potentiated stimulated 5-HT release. CPP 20 microM or NMDA 100 microM had no effect on 5-HT release evoked by electrical stimulation. In the SNr, 1 microM fluvoxamine or 0.6-60 microM MK-801 potentiated electrically evoked release of 5-HT. Pre-exposure to 20 microM MK-801 inhibited the enhancing effects of 1 microM fluvoxamine on electrically evoked 5-HT release in the SNr. In the DRN, the presence of 1 microM fluvoxamine or 20 microM MK-801 weakly potentiated 5-HT release. In the presence of 1 microM methiothepin (a nonselective 5-HT1-2 antagonist), 1 microM fluvoxamine or 20 microM MK-801 were equipotent in potentiating the concentration of 5-HT released in response to electrical stimulation. The T1/2 values for 5-HT release following MK-801 or fluvoxamine administration were significantly increased. Potentiation of 5-HT release by MK-801 in the SNr and the DRN and lack of effect of either CPP or NMDA on 5-HT release or uptake argues against a role for NMDA receptors in modulation of 5-HT release. Inhibition of fluvoxamine induced potentiation of 5-HT signal in the presence of MK-801 suggests that MK-801 and fluvoxamine may interact at the level of the 5-HT transporter.

Animals↗

PubMed1998

Real time measurement of stimulated dopamine release in the conscious rat using fast cyclic voltammetry: dopamine release is not observed during intracranial self stimulation.

Fast cyclic voltammetry (FCV) was used to measure real time release of electrically stimulated endogenous dopamine in the nucleus accumbens (NAc) of conscious freely moving rats for up to 17 days. The method of electrode construction, implantation, electrical stimulation and recording of changes of extracellular dopamine concentration in the conscious rat are described. Rats trained on a continuous reinforcement schedule to perform intracranial self stimulation (ICSS) were implanted with electrodes for FCV. During ICSS, no faradaic signal was observed at an electrode implanted in the NAc. Decreasing the intensity of the stimulating current abolished ICSS, increasing the stimulating current disrupted ICSS. Operator delivered electrical stimulations using currents greater than those needed for ICSS yielded dopamine signals. It is concluded that during ICSS, sufficient dopamine does not reach the extracellular fluid space to yield a faradaic signal detectable by FCV.

Animals↗

PubMed1996

Comparison of somatodendritic and axon terminal dopamine release in the ventral tegmental area and the nucleus accumbens.

Fast cyclic voltammetry at a carbon fibre microelectrode was used to measure dopamine release following electrical or chemical stimulation in rat brain slices incorporating either the ventral tegmental area or the core region of the nucleus accumbens. Electrical or chemical stimulation gave clear voltammetric signals which corresponded to dopamine; less dopamine was released in the ventral tegmental area than in the nucleus accumbens. In contrast to the nucleus accumbens, electrically stimulated dopamine release in the ventral tegmental area was not sensitive to tetrodotoxin, was not modified by the presence of dopamine uptake inhibitors, or agonist or blockers acting at dopamine D2 autoreceptors.

Amphetamine↗

PubMed1996

The role of ventral tegmental dopamine neurons in locomotor sensitization following quinpirole or (+)-amphetamine: ex vivo voltammetric evidence.

Behavioural sensitization to the locomotor stimulating effects of (+)-amphetamine or quinpirole was induced in rats by intermittent drug administration. Following expression of sensitization, locomotor activity scores on day 9 were: vehicle 87 +/- 9, (+)-amphetamine 1441 +/- 227 and quinpirole 2078 +/- 214. Electrically stimulated dopamine release was measured on day 12 in ventral tegmental slices using fast cyclic voltammetry. Dopamine release was significantly elevated in the (+)-amphetamine- and quinpirole-treated groups when compared to vehicle-treated controls over a wide range of stimulation frequencies (5-200 Hz) and pulses (1-200). Quinpirole (1 microM) in the perfusion fluid attenuated dopamine release following 40-pulse, 200-Hz electrical stimulation, by 31.6 +/- 2.8% in the ventral tegmental area of the vehicle-treated group, by 14.8 +/- 5.6% in the (+)-amphetamine-treated group and 8 +/- 7.3% in the quinpirole-treated group. This study shows that dopamine release is increased in the ventral tegmental area following sensitization with either a direct or indirectly acting dopamine agonist. The findings that dopamine release was elevated at all stimulation frequencies in sensitized animals, and that quinpirole only attenuated this release at the highest stimulation frequency, would suggest that in addition to D2 autoreceptor subsensitivity, other mechanisms contribute to the enhanced release of dopamine in these animals.

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↗

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↗

PubMed1992

Chronic mild stress-induced anhedonia: a realistic animal model of depression.

Chronic sequential administration of a variety of mild stressors causes a decrease in responsiveness to rewards in rats, which is reversed by chronic administration of antidepressant drugs. This paper reviews the validity of chronic mild stress-induced anhedonia as an animal model of depression, and the evidence that changes in hedonic responsiveness in this model are mediated by changes in the sensitivity of dopamine D2 receptors in the nucleus accumbens. The review opens with an analysis of the design features of animal models of depression, and ends with a brief account of other animal models of anhedonia.

Animals↗