Effects of chronic citalopram treatment on 5-HT1A and 5-HT2A receptors in group- and isolation-housed mice.

Selective serotonin reuptake inhibitors (SSRI) are characterized by high clinical effectiveness and good tolerability. A 2-3 week delay in the onset of effects is caused by adaptive mechanisms, probably at the serotonergic (5-HT) receptor level. To analyze this in detail, we measured 5-HT(1A) and 5-HT(2A) receptor bindings in vitro after 3 weeks of citalopram treatment (20 mg/kg i.p. daily) in group-housed as well as isolation-housed mice, reflecting neurobiological aspects seen in psychiatric patients. Isolation housing increased somatodendritic (+52%) and postsynaptic (+30-95%) 5-HT(1A) as well as postsynaptic 5-HT(2A) receptor binding (+25-34%), which confirms previous findings. Chronic citalopram treatment did not induce alterations in raphe 5-HT(1A) autoreceptor binding, independent of housing conditions. Housing-dependent citalopram effects on postsynaptic 5-HT(1A) receptor binding were found with increases in group- (+11-42%) but decreases in isolation-housed (-11 to 35%) mice. Forebrain 5-HT(2A) receptor binding decreased between 11 and 38% after chronic citalopram administration, independent of housing conditions. Citalopram's long-term action comprises alterations at the postsynaptic 5-HT(1A) and 5-HT(2A) receptor binding levels. Housing conditions interact with citalopram effects, especially on 5-HT(1A) receptor binding, and should be more strongly considered in pharmacological studies. In general, SSRI-induced alterations were more pronounced and affected more brain regions in isolates, supporting the concept of a higher responsiveness in "stressed" animals. Isolation-induced receptor binding changes were partly normalized by chronic citalopram treatment, suggesting the isolation housing model for further analyses of SSRI effects, especially at the behavioral level.

The influence of sex and social isolation housing on pre- and postsynaptic 5-HT1A receptors.

Serotonergic (5-HT) receptors are crucial for different brain functions and play an important role in several pathological conditions. We analysed [3H]8-OH-DPAT-specific binding to 5-HT1A receptors in male and female mice after group or isolation housing by in vitro autoradiography (n = 6 per group). Females displayed higher postsynaptic 5-HT1A receptor binding compared to males, especially in the cortex. In contrast, lower [3H]8-OH-DPAT-specific binding was found in the female hippocampus. No sex difference was seen for the somatodendritic 5-HT1A autoreceptor. Sex differences in postsynaptic 5-HT1A receptor binding should be relevant to behavioural sex differences, especially in locomotor activity and hippocampus-dependent behaviours. Six weeks isolation housing caused an increase in 5-HT1A receptor binding in most of the brain regions analysed and was more pronounced in males. In isolated males, the increases were detected in the CA1 field of the hippocampus (+16.8%), in the septum (+76.8%), in the cortical amygdala (+24.6%), in the periaqueductal gray (+67.2%) and in the different cortical regions analysed (+61.8-81.4%). [3H]8-OH-DPAT-specific binding increased significantly in the dentate gyrus (+47.1%), the supramammillary nucleus (+31.2%) and in the ventromedial hypothalamus (+34.4%) of isolated females. Sex-dependent isolation-induced alterations in [3H]8-OH-DPAT-specific binding were also found in the raphe nuclei. Isolation-induced increases in 5-HT1A receptor binding could be relevant to the behavioural disinhibition with heightened arousal, impulsivity and activity often observed in isolates. The male-specific alterations in the corticolimbic system as well as in the midbrain could be crucial for isolation-induced aggression.

Serotonin 1A and 2A receptor densities, neurochemical and behavioural characteristics in two closely related mice strains after long-term isolation.

Knowledge about individual differences in behavioural traits and their neurostructural and neurochemical correlates should improve therapeutic approaches of corresponding psychopathology. The presented investigations are aimed to reveal interrelationships between central nervous serotonergic [5-HT] receptor densities and neurochemical as well as behavioural traits in two mice strains. Male AB-Halle [ABH] and AB-Gatersleben [ABG] mice differing in aggression were investigated after 6 weeks of isolation housing. 5-HT1A and 5-HT2A receptors were analysed in different brain regions by in vitro autoradiography. HPLC determinations of aminergic transmission in the cortex, hippocampus, striatum as well as in the raphe-region and radioimmunoassay determination of serum corticosterone were done before (basal condition) and after behavioural tests (challenge condition). Receptor autoradiography revealed higher 5-HT1A receptor densities, especially in limbic regions, and lower 5-HT2A receptor densities in the basal ganglia of ABH mice. Furthermore, ABH mice characterized as behaviourally more active in the open field and plus maze as well as more reactive and aggressive during the social interaction test showed lower basal 5-hydroxyindolacetic acid [5-HIAA] concentrations in the hippocampus, cortex and raphe-region as well as a different activation pattern in serotonergic, dopaminergic and noradrenergic brain systems after challenge in comparison to ABG mice. Additionally lower corticosterone concentrations were found in ABH mice. Lower basal serotonergic and striatal dopaminergic, but higher basal cortical dopaminergic metabolism in contrast to enhanced challenge-induced central nervous serotonergic and cortical dopaminergic reactivities are discussed to be crucial for an enhanced reactive behavioural trait, which could secondarily result in aggression-related behaviours, where higher 5-HT1A receptor and lower 5-HT2A receptor densities may be essential.

A multicenter study about Neurobiology of Suicidal Behavior: design, development, and preliminary results.

The subproject 1.5 "Neurobiology of Suicidal Behavior" is a multicenter study assessing peripheral parameters of the serotonergic, noradrenergic, and dopaminergic transmitter systems. Additionally, stress hormones and the lipid system as well as inhibitory and excitatory amino acids will be investigated. The different parameters are collected in cerebral spinal fluid (CSF), blood, and saliva. Patients with a depressive spectrum disorder with and without a suicide attempt (during the last three weeks) and being medication free for two weeks are included in the study. So far, 103 patients and controls have been recruited. The design and development of this project as well as interconnections with the others subprojects are described. Preliminary results about the stress hormone system and suicidality are presented.

High correlation between salivary MHPG and CSF MHPG.

RATIONALE: Determination of 3-methoxy-4-hydroxy-phenylglycol (MHPG) as a major metabolite of noradrenaline may reflect changes in noradrenergic activity dependent on psychiatric illness and drug therapy. OBJECTIVE: This study was designed to investigate the relationship between CSF and salivary MHPG, and thus the utility of saliva MHPG as a marker for CSF MHPG. METHOD: Twenty-one paired samples of saliva and CSF were assayed for MHPG by solid-phase extraction and HPLC-ED. RESULT: Salivary MHPG was highly positively correlated with CSF MHPG ( P<0.001). CONCLUSION: This finding supports the use of salivary MHPG as an index for CSF MHPG, and enhances the usefulness of salivary MHPG measurements as a non-invasive approach for clinical studies investigating noradrenergic systems.

Autoradiographic analyses of 5-HT1A and 5-HT2A receptors after social isolation in mice.

Social isolation of rodents is used to model human psychopathological processes. In the present study, the effects of intermediate and long term isolation housing on postsynaptic 5-HT(1A) and 5-HT(2A) receptors were analyzed in male mice housed in groups or isolation for 4 and 12 weeks. [3H]8-OH-DPAT and [3H]ketanserin were used to label 5-HT(1A) and 5-HT(2A) receptors. Four representative sagittal sections (planes 1-4) were scored by in vitro autoradiography. Whereas after 4 weeks of housing both receptor densities were lowered significantly in isolated mice, after 12 weeks of housing only marginal isolation effects were seen. Intermediate isolation reduced 5-HT(1A) receptors especially in the lateral frontal, parietal and entorhinal cortex (-63%), in the lateral CA1-3 and dentate gyrus region of the hippocampus (-68%), in the basolateral, basomedial, central and medial amygdaloid nuclei (between -38 and -66%), and in the hypothalamus (-28%). 5-HT(2A) receptors were strongly reduced in the frontal cortex (between -47 and -74%), in the hippocampus (between -47 and -95%), in the striatum (between -66 and -76%), and in the accumbens nucleus (between -59 and -73%) in comparison to group housed control mice. After 12 weeks of isolation in the hippocampus continuously decreased 5-HT(1A) receptor densities were demonstrated (between -24 and -61%). But increased 5-HT(2A) receptor densities were seen in the lateral striatum (+86%) compared to control mice. Age-dependent effects were also found. After 12 weeks of group housing the 5-HT(1A) and 5-HT(2A) receptor densities were decreased (between -28 and -54%) in all analyzed brain regions in comparison to 4 weeks of group housing. Isolated animals showed diminished 5-HT(1A) receptor densities in the cortex (-14%) and hippocampus (-15%), but increased 5-HT(1A) receptor densities in the amygdala (+33%) after 12 weeks. The 5-HT(2A) receptor densities were increased in all analyzed regions (between +31 and +96%) after 12 weeks of isolation compared to 4 weeks. To explain these dynamic, time-dependent pattern of isolation-induced changes different regulation processes are supposed regarding 5-HT(1A) and 5-HT(2A) receptors. Besides metabolism-related adaptation processes also neurotransmitter and hormonal (e.g., glucocorticoid) interactions especially in limbic regions have to be considered.

A diverse development of 5-HT1A receptor binding is relevant to behavioral differences observed in adult mice of two genetically closely related inbred strains.

Only few genetic loci were supposed to be crucial for strong behavioral differences, especially in locomotion and aggression, in two closely related mice inbred strains: AB/Halle (ABH) and AB/Gatersleben (ABG). Previously we reported remarkable strain differences in 5-HT1A receptor binding in adult mice. In the present study, we were interested if the strain-specific 5-HT1A receptor binding pattern is already present very early in ontogeny which could indirectly hint at a gene that is differentially regulated in these 2 mouse strains. Since the 5-HT1A receptor is involved in the regulation of locomotion and aggression, one genetic determinate for the behavioral differences in ABH and ABG mice would have been found. Therefore, we measured [³H]8-OH-DPAT specific binding at postnatal day (PND) 1 and 21 (weanlings) using in vitro autoradiography. 5-HT1A receptor binding was not significantly different at PND 1 between strains. However, in weanlings the same 5-HT1A receptor binding pattern was observed as in adults, i.e. ABH mice display a higher forebrain 5-HT1A receptor binding compared to ABG mice. So the strain-specific forebrain 5-HT1A receptor binding pattern develops during the first 3 postnatal weeks and genetically driven mechanisms seem to be crucial. However, early environmental influences, e.g. differences in maternal care, can't be excluded.

Higher BDNF concentrations in the hippocampus and cortex of an aggressive mouse strain.

Although genetically closely related AB-Halle (ABH) and AB-Gatersleben (ABG) mice inbred strains differ in activity and aggressive behaviour. These behavioural traits have been observed especially in response to social challenges, where ABH mice develop a highly aggressive and active behaviour, which cannot be observed in their ABG counterparts. In contrast to ABG mice, basal brain serotonin, dopamine and noradrenaline concentrations in ABH mice are low but highly stimulated by social challenges. Since brain-derived neurotrophic factor (BDNF) modulates central neurotransmitter systems and has been involved in aggressive and activity behaviour, we studied specific concentrations of BDNF and NGF protein in several brain regions of ABG and ABH mice. A significant higher concentration of BDNF protein was found in the hippocampus of 5 weeks and 5 months old ABH mice, when compared to ABG mice. BDNF was also higher in the cortex of 5 weeks and 5 months old ABH mice. Moreover BDNF concentrations were higher in the striatum of 5 months old ABH mice when compared to ABG mice. NGF concentrations in ABH mice were not changed in all measured brain regions but higher in older age in the hippocampus of ABG mice as compared to ABH mice. We hypothesize, that BDNF might be involved in the behavioural and neurochemical mechanisms of aggressive behaviour.