Human behavioural pharmacology.
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Behavior↗
Biomedical subjects
P Willner
Publications and source records attributed to P Willner.
Multiple variable interval schedule behaviour in humans: effects of ethanol, mood, and reinforcer size on responding maintained by monetary reinforcement.
Ethanol is an effective reinforcer but, in common with other drugs of abuse, it may derive some of its reinforcing properties from the effects it has on behaviour maintained by other reinforcers. However, any assessment of ethanol's hypothesized effect on behaviour maintained by other reinforcers must take into account the fact that ethanol may have multiple mechanisms of action. In order to address this problem the experiments reported herein used a procedure based upon Herrnstein's Matching Law which allowed joint assessment of subjects' motor capacity and reinforcer sensitivity. The effect of ethanol (0, 0.3, and 0.6 g/kg) on motor capacity and reinforcer sensitivity was assessed by studying behaviour maintained by monetary reinforcement. In the first experiment the procedure was validated by showing that the behaviour of subjects was sensitive to changes in reinforcer value and in the second experiment 0.6 g/kg ethanol reduced motor capacity but did not affect reinforcer sensitivity. As a secondary hypothesis we also studied the effect of mood on reinforcer sensitivity and motor capacity. It was found that lower mood scores (lower hedonic tone) were associated with reduced reinforcer sensitivity and that male subjects showed higher motor capacity than females. However, there was also a mood by sex interaction, which indicated that higher motor capacity in males was only found in the presence of lower mood scores. The results are discussed in relation to the mechanisms of ethanol's dopaminergic effects, interactions between ethanol and other drugs of abuse, and the changes in reinforcer sensitivity which are thought to occur in depression.
Adolescent↗
Mood, cue and gender influences on motivation, craving and liking for alcohol in recreational drinkers.
The effects of exposure to an alcohol-related cue (drinking low-alcohol beer) and a musical depression/elation mood induction procedure, on craving, motivation and liking for alcohol, were studied in male and female recreational drinkers. Alcohol craving was assessed using the multidimensional desires for alcohol questionnaire (DAQ), motivation for alcohol was assessed by performance on a progressive ratio (PR) task reinforced with small volumes (25 ml) of low-alcohol beer, and liking for the reinforcers earned in the PR task was assessed using a visual analogue scale. Consumption of a half-pint of low-alcohol beer increased alcohol craving in male subjects but had no effect or decreased craving in female subjects. Subsequent induction of a depressed mood increased craving scores, relative to elated or neutral mood groups, but these effects were confined to abstinent (non-cued) subjects, both male and female. Performance on the PR task correlated significantly with one of the four factors of the DAQ, negative reinforcement, and was increased by induction of a depressed mood in abstinent female and cued male subjects. Reinforcer liking was unchanged following mood induction in male subjects, but decreased in both groups of female subjects. To summarize, the cue of drinking low-alcohol beer increased alcohol craving in men but not in women, and induction of a depressed mood increased alcohol craving and motivation, but also decreased alcohol liking. These effects were present to different extents in different cue/gender subgroups, and were partially independent.
Adult↗
Eight-year experience in treatment of hemorrhoidal disease.
During an eight-year period 887 patients with symptoms of hemorrhoids were treated at the Department of Surgery and Outpatient Care of the Vaszary Kolos County Hospital, Esztergom. 178 patients with first degree hemorrhoids received only conservative treatment. Rubber band ligation (RBL) which can be performed on outpatients was applied in 324 patients with first, second and third degree hemorrhoids. Thrombosed external hemorrhoids were treated by excision in 215 patients. Hemorrhoidectomy (H) was mainly carried out in 91 cases for treatment of circular 3rd and 4th degree nodules involving complications. More than 80 per cent of the patients receiving rubber band ligation and hemorrhoidectomy were followed up. 65% of the RBL group and 85% of the H group were symptom free, while 76% of the RBL group and 91% of the H group showed great improvement after the treatment. Personal results, complications, and review of the literature are discussed in detail.
Adult↗
Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT1A receptor agonist and 5-HT2 receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D2/D3 receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D2/D3 receptor-mediated transmission.
Animals↗
Changes in sleep architecture following chronic mild stress.
Chronic exposure to mild unpredictable stress causes subsensitivity to rewards (anhedonia). These effects are reversible by chronic treatment with antidepressant drugs, and have been proposed as an animal model of depression. In the present study, sleep architecture, particularly the rapid eye movement (REM) component, was mapped in rats following exposure to chronic mild stress. The study used a unique large scale automated sleep system to record and analyze the sleep signals from 32 rats simultaneously. The effects of stress on sleep were maximal following 21 days of stress, at which time the stressed animals demonstrated decreases in active waking and deep sleep, and disruptions of REM sleep. The changes in REM sleep included increases in the duration of and transitions into REM sleep over the sleep part of the sleep-wake cycle, and most importantly, a reduced latency to the onset of the first REM period. These sleep abnormalities, and in particular the decrease in REM latency, are consistent with those reported in endogenous depression. The results provide further support for the validity of the chronic mild stress paradigm as an animal model to study the mechanisms underlying endogenous depression.
Animals↗
Validity, reliability and utility of the chronic mild stress model of depression: a 10-year review and evaluation.
This paper evaluates the validity, reliability and utility of the chronic mild stress (CMS) model of depression. In the CMS model, rats or mice are exposed sequentially, over a period of weeks, to a variety of mild stressors, and the measure most commonly used to track the effects is a decrease in consumption of a palatable sweet solution. The model has good predictive validity (behavioural changes are reversed by chronic treatment with a wide variety of antidepressants), face validity (almost all demonstrable symptoms of depression have been demonstrated), and construct validity (CMS causes a generalized decrease in responsiveness to rewards, comparable to anhedonia, the core symptom of the melancholic subtype of major depressive disorder). Overall, the CMS procedure appears to be at least as valid as any other animal model of depression. The procedure does, however, have two major drawbacks. One is the practical difficulty of carrying out CMS experiments, which are labour intensive, demanding of space, and of long duration. The other is that, while the procedure operates reliably in many laboratories, it can be difficult to establish, for reasons which remain unclear. However, once established, the CMS model can be used to study problems that are extremely difficult to address by other means.
Animals↗
Diurnal variation in the effect of chronic mild stress on sucrose intake and preference.
Diurnal variation (depression worse in the morning) is one of the diagnostic criteria for the melancholic subtype of major depression. This study examined diurnal variation in the effects of chronic mild stress (CMS), an animal model of depression, by testing Wistar rats at different phases of the light-dark cycle. CMS decreased sucrose intake and sucrose preference in animals tested at the start of the dark phase (the most active period in this nocturnal species), but not in animals tested during the light phase. CMS also decreased body weight in both groups; however, the effects of CMS on sucrose intake in the dark phase were not secondary to body weight changes. On the contrary, loss of body weight led to underestimates in the magnitude of the effects of CMS on sucrose intake. The results support the validity of the CMS procedure as a model of melancholia. The discussion addresses criticisms of this position that have been raised in two recent publications.
Animals↗
The mesolimbic dopamine system as a target for rapid antidepressant action.
Chronic treatment with antidepressant drugs produces a variety of changes in dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at dopamine D2/D3 receptors within the nucleus accumbens. Evidence from animal models of depression (the forced swim test and the chronic mild stress procedure) indicates that these effects are crucial for the therapeutic effect of antidepressants in these models. Antidepressant-like effects in animal models are also seen with drugs that act directly on the dopaminergic system. Because of its prolonged time-course, the chronic mild stress procedure can be used to examine onset latencies. Some dopamine-active drugs (e.g. the catechol-O-methyltransferase inhibitor tolcapone; D2/D3 agonists administered intermittently) are active in this procedure but have a time-course comparable to that of conventional antidepressants. Other dopamine-active drugs may have a more rapid onset; the evidence to date suggests this possibility for the D2/D3 agonist pramipexole and the preferential presynaptic antagonist amisulpride. In clinical studies, rapid-onset latencies have been claimed for the D2/D3 agonist roxindole, the preferential presynaptic antagonist sulpiride and the relatively selective dopamine-uptake inhibitor amineptine. The mechanisms that might give rise to a rapid onset of dopamine-mediated antidepressant effects are discussed.
Animals↗
The dopamine hypothesis of schizophrenia: current status, future prospects.
The dopamine hypothesis of schizophrenia is reviewed in the context of recent advances in dopamine research. These include the following: the discovery that there are several subtypes of dopamine receptor, the recognition that the activity of dopamine neurons is controlled by negative feedback systems; insights into the functions of different subsystems of dopamine neurons; the discovery that different subsystems of dopamine neurons interact with one another; and a growing understanding of the functions and mode of operation of the forebrain regions that the dopamine projections innervate. The paper reviews some of the complexities that the dopamine hypothesis has encountered, and continues to encounter, with a particular focus on three issues: the adequacy of our understanding of neuroleptic drug action, the heterogeneity of schizophrenic symptoms and the paucity of direct evidence to support the hypothesis. It is concluded that schizophrenia does not reflect primary abnormalities of dopamine transmission, but probably does reflect abnormalities in systems that have an intimate interaction with the dopamine system. The primary substrates for schizophrenia will probably be found within the major targets of the ascending dopamine projections: the fronto-striato-pallido-thalamic loops, and the limbic structures, such as amygdala and hippocampus, with which the fronto-striatal system interacts.
Antipsychotic Agents↗
The behavioural pharmacology of anxiety and depression.
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Anti-Anxiety Agents↗
Social influences on morphine conditioned place preference.
Social defeat in dominant male rats has previously been shown to result in a loss of rank, together with decreased consumption of a palatable sucrose solution, suggestive of a decrease in hedonic tone. The present study further investigated the effect of defeat on hedonic capacity using the conditioned place preference paradigm. Stable dominance hierarchies were determined in pairs of male PVG rats by repeated observation of agonistic behaviour at the onset of the dark phase of the dark-light cycle. Dominant animals and singly housed animals were then subjected to defeat by a male of the aggressive Tryon Maze Dull (TMD) strain, either 1 (singly housed animals only) 3 or 7 days prior to the first conditioning session. Each animal was tested for place conditioning with morphine (1 mg/kg i.p.) using one rewarded and one non-rewarded conditioning trial. In this paradigm, dominant animals as well as singly housed animals showed an increase in time spent in the drug-associated side but their submissive partners did not. Three days following the defeat of a dominant animal by a TMD, place conditioning to morphine was absent in the defeated animals, but was now present in their submissive partners. Seven days following defeat, conditioning was absent in defeated animals that were now submissive, but present in defeated animals that had maintained their dominant status. In isolated animals, place conditioning was absent 1 day following defeat, but was present 3 and 7 days post-defeat. These findings suggest that morphine-induced place conditioning is influenced by both the experience of defeat and the effects of defeat on social status.
Agonistic Behavior↗
Changes in dopamine receptor mRNA expression following chronic mild stress and chronic antidepressant treatment.
This study used in-situ hybridization to examine D1 and D2 receptor mRNA expression in the brains of rats subjected to chronic mild stress and/or chronic treatment (5 weeks) with the antidepressant drugs imipramine and fluoxetine. As in previous studies using the chronic mild stress procedure, stress decreased the consumption of a palatable sucrose solution, and both antidepressants reversed this effect. In-situ hybridization to D1 and D2 receptor probes was studied in midbrain and forebrain sections. In the midbrain sections, stress decreased the D2 receptor message in the substantia nigra and in the lateral part of the ventral tegmental area (VTA), but not in the medial part of the VTA. Imipramine, but not fluoxetine, increased the D2 receptor message in the VTA, but only in the non-stressed group. In the basal ganglia, stress decreased the D2 receptor message in the nucleus accumbens (core and shell) and in the lateral, but not the medial, part of the caudate nucleus, in both control and stressed groups. Both imipramine and fluoxetine increased the D2 receptor message in the lateral, but not the medial, part of the caudate nucleus and in the shell, but not the core, of the nucleus accumbens. There were no significant changes in D1 receptor message. The results, which are consistent in some respects, and inconsistent in others, with predictions from earlier work, support the hypothesis that forebrain dopamine systems are involved in mediating the behavioural effects of chronic mild stress and their reversal by antidepressants.
Animals↗
Palatable food induces an appetitive behaviour in satiated rats which can be inhibited by chronic stress.
An experimental model for the study of antidepressant treatments was devised by exploiting the response maintained by vanilla pellets in rats freely fed on a standard diet. The apparatus used was a Y-maze and the rats were trained, during 10-12 consecutive sessions, to earn a vanilla pellet placed at the end of the one of the two divergent arms. Animals exposed to repeated unavoidable stressors during the training phase did not develop the appetitive behaviour. Rats previously trained on the Y-maze, however, did not modify their performance under the effect of repeated stressors. Long-term treatment with imipramine and fluoxetine, given for 2 weeks before training and during the whole of the training phase, was able to antagonize the disrupting effect of chronic stress on the acquisition of the Y-maze. Finally, vanilla pellet consumption in trained animals induced a consistent increase in extraneuronal dopamine in the nucleus accumbens, as measured by microdialysis.
Acute Disease↗
Pharmacological validation of the chronic mild stress model of depression.
Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions, and this effect was reversed by chronic treatment with a variety of antidepressant drugs. The present study reports three experiments examining the effects in this model of further antidepressant agents, a number of non-antidepressants, and some compounds of indeterminate clinical status. Male Wistar rats were exposed sequentially to a variety of mild stressors, which continued throught the experiments. Drug treatments commenced after 3 weeks of stress, by which time intake of a 1% sucrose solution (measured in a 1-h weekly test) was significantly depressed. No drug effects were seen after 1 week of treatment. Normal levels of sucrose drinking were seen following chronic (3-5 weeks) of treatment with the antidepressants imipramine (10 mg/kg per day), brofaromine (20 mg/kg per day), and buspirone (5 mg/kg per day). Positive effects were also seen following chronic treatment with atropine (1 mg/kg per day) and mepyramine (5 mg/kg per day). d-Amphetamine (1 and 3 mg/kg per day), the neuroleptics haloperidol and chlorprothixene (1 mg/kg per day), and morphine (administered at doses rising to 110 mg/kg per day) were ineffective; amphetamine (3 mg/kg) and morphine decreased sucrose intake in control animals. No inferences can be drawn from the effects of atropine and mepyramine, which are of indeterminate clinical status; data from the other seven agents tested support the hypothesis that the chronic mild stress model responds appropriately to antidepressant and non-antidepressant agents.
Animals↗
Decreased hedonic responsiveness following chronic mild stress is not secondary to loss of body weight.
Chronic exposure to mild unpredictable stress (CMS) has previously been found to decrease hedonic responsiveness, as measured by the consumption of palatable sweet solutions or sensitivity to brain stimulation reward. These effects are reversed by chronic treatment with antidepressant drugs, and the CMS procedure has been proposed as a relatively valid animal model of depression. It has recently been suggested that the behavioural effects of CMS may be secondary to loss of body weight. This article collates data from five laboratories using the CMS procedure. Data are presented from seven studies using five different rat strains, as well as CD1 mice. Three-week exposure to CMS significantly decreased sucrose consumption by Lister hooded, PVG hooded, Wistar, and Wistar WU rats, and by CD1 mice, and sensitivity to brain stimulation reward in Ibm:Ro Ro rats. Weight loss in different experiments varied between 0 and 10%. Hedonic sensitivity relative to body weight (e.g., mg sucrose/g body weight) decreased significantly in all experiments. Animals maintained on a restricted feeding regime lost weight but did not show decreases in sucrose intake. It is concluded that decreased hedonic sensitivity following chronic mild stress cannot be attributed to loss of body weight.
Animals↗
Parametric analysis of the effects of cocaine and cocaine pretreatment on dopamine release in the nucleus accumbens measured by fast cyclic voltammetry.
Fast cyclic voltammetry was used to measure dopamine (DA) release in the nucleus accumbens of anaesthetized rats, in response to electrical sine-wave stimulation of the ventral tegmental area. Voltammetric signals followed increases in either frequency (50-100 Hz), intensity (50-100 microA) or duration (0.5-5.0 s) of the stimulus. Cocaine administration (10 mg/kg) preferentially increased DA release by weak electrical stimuli. Cocaine pretreatment (3 x 10 mg/kg, two weeks earlier) preferentially increased DA release by stronger stimuli, and the effects of acute cocaine were potentiated in these animals. The effects of increasing stimulus duration conformed to first order kinetics. Cocaine pretreatment selectively increased the kinetic parameter representing maximal release, while acute cocaine administration preferentially decreased the parameter representing the stimulus duration eliciting half maximal release. The lack of statistical interaction between these two effects suggests that sensitization of the response to acute cocaine by cocaine pretreatment may simply reflect an increase in the size of the releasable pool of DA.
Animals↗
Subjective and behavioural evaluation of cigarette cravings.
Cigarette cravings were evaluated in a sample of moderately heavy smokers, using the Questionnaire on Smoking Urges (QSU: Tiffany and Drobes 1991), which produces scores on two factors, related to the positive (factor I) and negative (factor II)-reinforcing properties of smoking, respectively. Smoking motivation was also assessed behaviourally using a progressive-ratio operant procedure, in which responding on a computer keyboard was reinforced by puffs on a cigarette, under a progressively increasing work requirement. Abstinence (4-14 h) increased scores on both subjective and behavioural measures. In non-deprived subjects, behavioural measures and cigarette liking correlated more strongly with factor I of the QSU than with factor II, while in abstinent subjects, correlations with factor II were stronger than with factor I. The significant relationships between the QSU and cigarette-reinforced progressive-ratio operant performance support the validity of both of these procedures as measures of cigarette craving.
Adult↗