Modelling depression in animals: at the interface of reward and stress pathways.

RATIONALE: Despite substantial research efforts the aetiology of major depressive disorder (MDD) remains poorly understood, which is due in part to the heterogeneity of the disorder and the complexity of designing appropriate animal models. However, in the last few decades, a focus on the development of novel stress-based paradigms and a focus on using hedonic/anhedonic behaviour have led to renewed optimism in the use of animal models to assess aspects of MDD. OBJECTIVES: Therefore, in this review article, dedicated to Athina Markou, we summarise the use of stress-based animal models for studying MDD in rodents and how reward-related readouts can be used to validate/assess the model and/or treatment. RESULTS: We reveal the use and limitations of chronic stress paradigms, which we split into non-social (i.e. chronic mild stress), social (i.e. chronic social defeat) and drug-withdrawal paradigms for studying MDD and detail numerous reward-related readouts that are employed in preclinical research. Finally, we finish with a section regarding important factors to consider when using animal models. CONCLUSIONS: One of the most consistent findings following chronic stress exposure in rodents is a disruption of the brain reward system, which can be easily assessed using sucrose, social interaction, food, drug of abuse or intracranial self-stimulation as a readout. Probing the underlying causes of such alterations is providing a greater understanding of the potential systems and processes that are disrupted in MDD.

Hippocampal plasticity during the peripartum period: influence of sex steroids, stress and ageing.

The peripartum period is accompanied by dramatic changes in hormones and a host of new behaviours in response to experience with offspring. Both maternal experience and maternal hormones can have a significant impact upon the brain and behaviour. This review outlines recent studies demonstrating modifications in hippocampal plasticity across the peripartum period, as well as the putative hormonal mechanisms underlying these changes and their modulation by stress. In addition, the impact of reproductive experience upon the ageing hippocampus is discussed. Finally, we consider how these changes in hippocampal structure may play a role in postpartum cognitive function and mood disorders, as well as age-related cognitive decline.

Using animal models to study post-partum psychiatric disorders.

The post-partum period represents a time during which all maternal organisms undergo substantial plasticity in a wide variety of systems in order to ensure the well-being of the offspring. Although this time is generally associated with increased calmness and decreased stress responses, for a substantial subset of mothers, this period represents a time of particular risk for the onset of psychiatric disorders. Thus, post-partum anxiety, depression and, to a lesser extent, psychosis may develop, and not only affect the well-being of the mother but also place at risk the long-term health of the infant. Although the risk factors for these disorders, as well as normal peripartum-associated adaptations, are well known, the underlying aetiology of post-partum psychiatric disorders remains poorly understood. However, there have been a number of attempts to model these disorders in basic research, which aim to reveal their underlying mechanisms. In the following review, we first discuss known peripartum adaptations and then describe post-partum mood and anxiety disorders, including their risk factors, prevalence and symptoms. Thereafter, we discuss the animal models that have been designed in order to study them and what they have revealed about their aetiology to date. Overall, these studies show that it is feasible to study such complex disorders in animal models, but that more needs to be done in order to increase our knowledge of these severe and debilitating mood and anxiety disorders.

Animal models of depression and anxiety: What do they tell us about human condition?

While modern neurobiology methods are necessary they are not sufficient to elucidate etiology and pathophysiology of affective disorders and develop new treatments. Achievement of these goals is contingent on applying cutting edge methods on appropriate disease models. In this review, the authors present four rodent models with good face-, construct-, and predictive-validity: the Flinders Sensitive rat line (FSL); the genetically "anxious" High Anxiety-like Behavior (HAB) line; the serotonin transporter knockout 5-HTT(-/-) rat and mouse lines; and the post-traumatic stress disorder (PTSD) model induced by exposure to predator scent, that they have employed to investigate the nature of depression and anxiety.

Chronic icv oxytocin attenuates the pathological high anxiety state of selectively bred Wistar rats.

Central oxytocin (OXT) has been shown to promote numerous social behaviours, to attenuate hormonal stress responsiveness of the HPA axis and to decrease anxiety. Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour, respectively, have been shown to represent a suitable animal model to study the underlying aetiology of psychopathologies like anxiety- and depression-related disorders. The goal of the present studies was to assess the effects of central OXT on anxiety- and depression-related behaviour in male and female HAB and LAB rats. Acute icv OXT (1 microg) or OXT receptor antagonist (OXT-A; 0.75 microg) administration did not affect anxiety-related behaviour in male or female HAB and LAB rats as assessed in the light-dark box. In contrast, chronic icv OXT infusion (10 ng/h; 6 d) attenuated the high level of anxiety-related behaviour in female, but not male, HAB rats, whereas chronic OXT-A infusion (7.5 ng/h; 6 d) increased anxiety-related behaviour in female, but not male, LAB rats. Neither acute nor chronic manipulation of the OXT system altered depression-related behaviour as assessed by the forced swim test. Combined, these results suggest that pharmacological manipulation of the brain OXT system is effective to attenuate extremes in trait anxiety in an animal model of psychopathological anxiety. Moreover, the data indicate that differences in the activity of the brain OXT systems between HAB and LAB rats may, at least partially, contribute to the opposing anxiety but not depression-related behaviour.

Invited review: the evolution of antidepressant mechanisms.

Present antidepressants are all descendents of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identification of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; first, with noradrenaline then 5-hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identified a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.

Testing the validity of c-fos expression profiling to aid the therapeutic classification of psychoactive drugs.

RATIONALE: Different stimuli, including pharmacological stimuli, induce different neuroanatomical profiles of c-fos expression. Can these profiles be used in classifying psychoactive drugs and predicting therapeutic utility? OBJECTIVE: To test the validity of c-fos expression profiling to aid therapeutic classification. METHODS: Anxiolytics, antidepressants, antipsychotics and psychostimulants were compared. (i) A meta-analysis was performed and profiles compiled from literature reports of changes in c-fos expression in rat brain regions, measured by in situ hybridisation histochemistry or immunohistochemistry, after acute injection of psychoactive drugs. (ii) Male rat brains were profiled for changes in c-fos mRNA expression induced by acute injection of psychoactive drugs. RESULTS: (i) The meta-analysis showed that anxiolytics activate few (mostly stress-related) brain regions; antidepressants activate more regions, including the central amygdaloid nucleus; antipsychotics activate more regions still, including the nucleus accumbens and striatal areas; and psychostimulants activate the greatest number of all, including the most cortical regions (especially the piriform cortex). Profiles also varied within drug classes. (ii) Our experimental profiles confirmed and extended meta-analysis profiles, showing more downregulation. (iii) Sites activated by mirtazapine (an antidepressant not previously profiled) matched those of the antidepressant imipramine. CONCLUSIONS: (i) Differences between drug classes support their classification by means of c-fos profiling. Differences within classes may reflect mechanistic variations. (ii) Greater downregulation in our experiments might be because of inclusion of low, clinically relevant, drug doses and fuller coverage of brain regions. (iii) The agreement between mirtazapine and imipramine increases our confidence in the validity of c-fos expression profiling to aid drug classification and predict therapeutic utility.

Orthodontics--the North American way.

The Orthologic award for clinical excellence is granted annually by the Scholarship Committee at the British Orthodontic Conference. It is judged on the presentation of detailed clinical records of three patients treated with an edgewise fixed appliance system. This scholarship is open to practitioners who have gained their initial orthodontic qualification within the last 12 years and provides funds of up to 2000 pounds towards visiting orthodontic centres overseas. With such a generous travel award one could indeed go far!

The treatment of severe 'gummy' Class II division 1 malocclusion using the maxillary intrusion splint.

This paper describes a modified Maxillary Intrusion Splint (M.I.S.) system which incorporates a near vertical pull headgear, and its use in the management of severe 'gummy' Class II division 1 malocclusion. The appliance was designed to reduce the visibility and vulnerability of the maxillary incisors in this difficult clinical situation by achieving the intrusion of maxillary teeth, restraining maxillary growth, and encouraging an element of subsequent forward mandibular rotation. The authors' initial experience using this system is presented in a retrospective cephalometric analysis of the lateral skull films of 26 treated patients contrasted with a similar number of comparable controls. The results showed that the principal effects of the M.I.S. were on the maxillary teeth giving decisive overjet control and incisor retraction with actual maxillary incisor intrusion. There was a similar effect on the maxillary molar and the M.I.S. provided effective en masse vertical control of the maxillary dentition. There was some degree of maxillary restraint in the M.I.S. group, but no noticeable difference in the change of mandibular position between the groups at the end of treatment. The possible reasons for this are discussed and suggestions made to improve this aspect of treatment in these patients.

Occupational medicine as a specialty.

Occupational medicine is one of the more recently accepted specialties and is best defined by the social context in which it is practiced. The current structure of the specialty is more easily understood in the light of its historical background. Occupational medicine brings together knowledge from a wide spectrum of disciplines which is reflected in its academic and research bases. A great variety of activities and environments are covered and this has posed problems in defining and organizing higher specialist training. Occupational considerations impact on almost every aspect of medical practice and there is a need for wider understanding of occupational medicine principles in the profession as a whole both in this country and abroad.

Bimaxillary proclination in patients of Afro-Caribbean origin.

The facial morphology of the Afro-Caribbean Negro is reviewed and the aims of treatment for bimaxillary proclination and its subsequent stability are discussed. Treatment approaches to various clinical situations are described, together with their known limitations.

A comparative analysis of the Class III malocclusion with and without an anterior mandibular displacement on closure.

A retrospective cephalometric study investigated the differences in the skeletal pattern of the Class III malocclusion. Thirty Caucasian adolescents with an anterior mandibular displacement on closure were compared to an equal number without such a displacement before treatment, at the end of treatment and at least 1 year out of retention.