Profiling of behavioral changes and hippocampal gene expression in mice chronically treated with the SSRI paroxetine.

INTRODUCTION: Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve--indicating the involvement of effects distant from reuptake inhibition. OBJECTIVE: To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression. MATERIALS AND METHODS: The behavioral response to long-term paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology. RESULTS AND DISCUSSION: Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice. CONCLUSION: Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.

Alcohol self-administration in two rat lines selectively bred for extremes in anxiety-related behavior.

According to the tension reduction hypothesis, individuals with an elevated anxiety level may be more sensitive to the anxiolytic effects of alcohol and may, therefore, have a higher predisposition to consume alcohol. To examine this hypothesis, we studied the drinking behavior as well as the sensitivity to the anxiolytic effect of alcohol in two rat lines that were bred and selected for differences in anxiety-related behavior on the elevated plus-maze: the extremely anxious HAB (high anxiety-related behavior) and the non-anxious LAB (low anxiety-related behavior) lines. Alcohol self-administration and the occurrence of an alcohol deprivation effect were studied in female and male HAB and LAB rats in a free-choice, 4-bottle home cage paradigm. The sensitivity of HAB and LAB rats to the anxiolytic effect of alcohol was assessed by testing their behavior on the elevated plus-maze after an acute application of ethanol. During the first days of voluntary ethanol drinking, the ethanol intake and preference of female LABs was significantly higher than that of female HABs. Although not statistically significant, the same trend could be seen in male LABs. Moreover, male as well as female LAB but not HAB rats showed a significant alcohol deprivation effect after abstinence. There were no differences when saccharin was presented to naive animals, indicating that the different ethanol drinking behavior of HAB and LAB rats does not represent a general difference in the consumption of new liquids. Application of ethanol resulted in an anxiolytic effect in HAB but not in LAB rats on the elevated plus-maze. In summary, increased inborn anxiety and voluntary ethanol consumption of HAB and LAB rats were correlated to some extent; however, this relationship was a negative one. It is concluded that, although such a relationship might exist in some individuals, increased levels of inborn anxiety and alcohol consumption are not necessarily related.

Long-term voluntary ethanol drinking increases expression of NMDA receptor 2B subunits in rat frontal cortex.

Forced ethanol drinking for several days and application of ethanol to cell cultures changes expression levels of various NMDA receptor subunits in rodents. Therefore, we investigated the influence of long-term voluntary ethanol consumption on the expression of NMDA receptor 2B (NR2B) subunits in several forebrain regions of rats [corrected]. This result is in accordance with and extends findings from studies using high doses of ethanol for a short period and suggests that the NR2B might be a potential target for an effective treatment of alcoholic patients.

Chronic mild stress (CMS) in mice: of anhedonia, 'anomalous anxiolysis' and activity.

BACKGROUND: In a substantial proportion of depressed patients, stressful life events play a role in triggering the evolution of the illness. Exposure to stress has effects on different levels in laboratory animals as well and for the rat it has been shown that chronic mild stress (CMS) can cause antidepressant-reversible depressive-like effects. The adoption of the model to the mouse seems to be problematic, depending on the strain used and behavioural endpoint defined. Our aim was to evaluate the applicability of CMS to mice in order to induce behavioural alterations suggested to reflect depression-like symptoms. METHODOLOGY/PRINCIPAL FINDINGS: A weekly CMS protocol was applied to male mice of different mouse strains (D2Ola, BL/6J and BL/6N) and its impact on stress-sensitive behavioural measures (anhedonia-, anxiety- and depression-related parameters) and body weight was assessed. Overnight illumination as commonly used stressor in CMS protocols was particularly investigated in terms of its effect on general activity and subsequently derived saccharin intake. CMS application yielded strain-dependent behavioural and physiological responses including 'paradox' anxiolytic-like effects. Overnight illumination was found to be sufficient to mimic anhedonic-like behaviour in BL/6J mice when being applied as sole stressor. CONCLUSIONS/SIGNIFICANCE: The CMS procedure induced some behavioural changes that are compatible with the common expectations, i.e. 'anhedonic' behaviour, but in parallel behavioural alterations were observed which would be described as 'anomalous' (e.g. decreased anxiety). The results suggest that a shift in the pattern of circadian activity has a particular high impact on the anhedonic profile. Changes in activity in response to novelty seem to drive the 'anomalous' behavioural alterations as well.

Stress and alcohol drinking.

The concept of stress-relief by alcohol has led to many investigations in order to elucidate the mechanisms of interactions of stress and alcohol, and the stress-reducing effect of alcohol as a motivation for alcohol consumption. The hypothalamo-pituitary-adrenocortical (HPA) system is one of the biological systems affected by both stress and alcohol. However, there is a high individual variation in the response of the HPA axis to either stress or alcohol. Factors like quality, severity and duration of stress, dose of alcohol and frequency of stress or alcohol exposure add to the individual response to stress or alcohol. The individual response is determined by interactions of genetic, environmental and experiential factors. Facing that complexity, with even more factors to be named, the often reported inconsistencies in both human and animal studies are not only attributable to methodological differences. Nevertheless, there are studies showing an influence of stress on alcohol consumption which most likely depends on the sample of probands examined. To our view, the concept of stress-relief by alcohol as a basic motivation for developing alcohol drinking habits is only applicable to subgroups of drinkers. Individuals with a dysfunctional HPA axis, inherited and/or acquired, might represent such a subgroup of stress-motivated drinkers.