Minke E. Jongsma

Acute and chronic effects of citalopram on postsynaptic 5-hydroxytryptamine(1A) receptor-mediated feedback: a microdialysis study in the amygdala

Microdialysis was used to assess the involvement of postsynaptic 5‐hydroxytryptamine1A (5‐HT1A) receptors in the regulation of extracellular 5‐HT in the amygdala. Local infusion of the 5‐HT1A receptor agonist flesinoxan (0.3, 1, 3 µm) for 30 min into the amygdala maximally decreased 5‐HT to 50% of basal level. Systemic administration of citalopram (10 µmol/kg) increased 5‐HT to 175% of basal level. Local infusion of 1 µm of the 5‐HT1A receptor antagonist WAY 100.635 into the amygdala augmented the effect of citalopram to more than 500% of basal 5‐HT level. 5‐HT1A receptor responsiveness after chronic citalopram treatment was determined in two ways. First, by local infusion of 1 µm flesinoxan for 30 min into the amygdala, which showed a significant 63% reduction in response (area under the concentration–time curve; AUC) for the citalopram group compared to the saline group. Second, by systemic administration of citalopram (10 µmol/kg), which increased 5‐HT to 350% of basal level. The effect was larger than in untreated animals, but more important, local infusion of 1 µm WAY 100.635 into the amygdala now failed to augment the effect of citalopram. Both the flesinoxan and WAY 100.635 data suggest an involvement of postsynaptic 5‐HT1A receptor‐mediated feedback in the amygdala, which diminishes following chronic citalopram treatment.

Differences in the effects of 5-HT1A receptor agonists on forced swimming behavior and brain 5-HT metabolism between low and high aggressive mice

RationaleMale wild house-mice genetically selected for long attack latency (LAL) and short attack latency (SAL) differ in structural and functional properties of postsynaptic serotonergic-1A (5-HT1A) receptors. These mouse lines also show divergent behavioral responses in the forced swimming test (FST, i.e., higher immobility by LAL versus SAL mice).ObjectivesWe investigated whether the line difference in 5-HT1A receptors is associated with a difference in brain 5-HT metabolism, and whether acute administration of a 5-HT1A receptor agonist could differentially affect the behavioral responses of LAL and SAL mice.Methods5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in homogenates of several brain regions using high-performance liquid chromatography. The behavioral effect of the full 5-HT1A receptor agonist, 8-OH-DPAT, and of the somatodendritic 5-HT1A autoreceptor agonist, S-15535, was examined in the FST. The effect of 8-OH-DPAT on forced swimming-induced 5-HT metabolism in brain homogenates was determined.ResultsIn most brain regions, 5-HT and 5-HIAA levels and 5-HT turnover were not significantly different between LAL and SAL mice. 8-OH-DPAT abolished the behavioral line difference in the FST by reducing immobility in LAL mice and reducing climbing in SAL mice. S-15535 induced a similar behavioral effect to 8-OH-DPAT in SAL mice, but did not alter the behavior of LAL mice. Compared with LAL, forced swimming elicited in SAL mice a higher brain 5-HT turnover, which was potently attenuated by 8-OH-DPAT.ConclusionsIt is unlikely that the difference in 5-HT1A properties between LAL and SAL mice is an adaptive compensatory reaction to changes in 5-HT metabolism. Although unspecific motor effects, at least in SAL mice, cannot be ruled out, it is suggested that the behavioral effects of 8-OH-DPAT and S-15535 may be mediated by predominant activation of postsynaptic 5-HT1A receptors in LAL mice and by presynaptic 5-HT1A receptors in SAL mice.

Increased stress vulnerability after a prefrontal cortex lesion in female rats

Neuroimaging studies in patients suffering from affective disorders have shown decreased volume and reduced regional cerebral blood flow in multiple areas of the prefrontal cortex, including the medial prefrontal cortex and the orbitofrontal cortex. This aberrant brain activity is among other things attributed to chronic stress. Affective disorders occur more often in women than in men. In the current experiment, female mPFC-lesioned and non-lesioned rats were subjected to 3 weeks of chronic unpredictable stress in order to determine the role of the mPFC in dealing with chronic stress, and the consequences of mPFC damage for coping with consecutive stressful events. mPFC damage in female rats intensified the stress-induced activation of the dorsomedial nucleus of the hypothalamus and the paraventricular nucleus of the hypothalamus as measured with Fos expression changes and markedly increased plasma catecholamine levels after 3 weeks of unpredictable stress. Additionally, an mPFC lesion significantly reduced the time of appearance of stress-induced behavioral changes in the open field. Altogether, mPFC dysfunction affects the way female rats react to chronic stress, it not only increased the activation of brain regions involved in neuroendocrine and autonomic responses to stress but it also significantly reduced the time of onset of behavioral changes.

The effect of chronic selective serotonin reuptake inhibitor treatment on serotonin(1B) receptor sensitivity and HPA axis activity

The authors have investigated 5-HT 1B receptor function in prefrontal cortex and dorsal hippocampus as well as the HPA axis response after subchronic (24 h) and chronic (15 days) treatment with the SSRI citalopram. All experiments were carried out in presence of citalopram to prevent rapid resensitization of the 5-HT(1B) receptors. Moreover, this more closely resembles the clinical situation. The concentration of citalopram was measured in both brain areas to ensure comparable levels in the different treatment groups. Using microdialysis, the authors found that under those conditions the effect of the 5-HT 1B receptor antagonists SB 224289 and the mixed 5-HT 1B/1D receptor antagonist GR 127935 on extracellular levels of 5-HT was unaltered by duration of treatment. Basal levels of 5-HT, however, were increased in the dorsal hippocampus following chronic treatment. In addition, plasma levels of the catecholamines adrenaline and noradrenaline and the HPA axis hormones ACTH and corticosterone were all decreased after chronic treatment.

Biochemical and behavioral effects of long-term citalopram administration and discontinuation in rats: Role of serotonin synthesis

We have investigated effects of continuous SSRI administration and abrupt discontinuation on biochemical and behavioral indices of rat brain serotonin function, and attempted to identify underlying mechanisms. Biochemistry of serotonin was assessed with brain tissue assays and microdialysis; behavior was assessed as the acoustic startle reflex. Long-term SSRI administration to rats reduced the content of 5-HT and its main metabolite shortly after inhibition of 5-HT synthesis in many brain areas with more than 50%. Turnover was not appreciably decreased, but significantly increased within 48h of drug discontinuation. The microdialysis experiments indicate that neuronal release of 5-HT depends strongly on new synthesis and emphasize the role of 5-HT(1B) receptors in the regulation of these processes. Discontinuation of the SSRI rapidly increased behavioral reactivity to the external stimulus. Additional startle experiments suggest that the increased reactivity is more likely related to the reduced extracellular 5-HT levels than to impaired synthesis. The combination of the marked reduction of serotonin content and limited synthesis may destabilize brain serotonin transmission during long-term SSRI treatment. These combined effects may compromise the efficacy of an SSRI therapy and facilitate behavioral changes following non-compliance.

Effect of 5-HT1A receptor-mediated serotonin augmentation on Fos immunoreactivity in rat brain

The consequences of pharmacologically evoked augmented serotonin (5-hydroxytryptamine, 5-HT) release on neuronal activity in the brain, as reflected by the cellular expression of the immediate early gene c-fos, were studied. Wistar rats were treated with saline, the 5-HT reuptake inhibitor citalopram (10 micromol/kg s.c.), the 5-HT(1A) receptor antagonist N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)-N-(2-pyridyl)cyclohexane carboxamine trihydrochloride (WAY 100635, 1 micromol/kg s.c.), or the combination of both drugs. At the given dosages, the combination of the drugs has previously been shown to enhance the cerebral release of 5-HT. Two hours and thirty minutes after administration, the brains were fixated, and Fos protein was histologically stained and quantified. The paraventricular nucleus of the hypothalamus, the central nucleus amygdala, the ventromedial hypothalamic nucleus, the dorsolateral striatum, and the nucleus accumbens shell were particularly responsive to increased 5-HT release. The results, illustrating the synergistic consequence of the combined drug treatments, are discussed in terms of activity of the limbic-hypothalamic-pituitary-adrenocortical system.

Augmentation strategies to improve treatment of major depression

The monoamine hypothesis has dominated almost forty years the psychopathology of depression. Yet this has not lead to antidepressants that are significantly more efficacious than the early tri- and tetracyclics from which they have evolved. Alternative hypotheses such as those involving adult neurogenesis or components of the hypothalamic-pituitaryadrenal- axis are either too premature or have not lead to drugs with improved antidepressant activity. Antidepressants may not be perfect, both in terms of efficacy and side effects, however their performance may be improved by making use of so-called augmentation strategies. Augmentation strategies that have potential to hasten and/or improve the therapeutic effect of antidepressants, in particular serotonin reuptake inhibitors, can have different forms. They can be aimed at reducing comorbid symptoms, such as anxiety, or they may be directed to processes that counteract the effect of serotonin reuptake inhibitors. Examples of the latter are those involving 5-HT1A and 5-HT1B autoreceptors, 5-HT 2C receptors and the availability of tryptophan. Another option could be exploring neuropeptide/serotonin interactions. The various augmentation strategies are reviewed in the context of literature data regarding neurobiology and pharmacotherapy of major depression.

Pharmacological Interventions That Have the Potential to Alter Neurotransmitter Levels in the Human Brain

Monitoring of neuronal activity in vivo is one of the greatest challenges in neuropsychiatry. Theoretically, levels of intra and extra synaptic neurotransmitters can be estimated through competition with suitable PET ligands at their receptors. When validating candidate receptor PET ligands for competition studies it is essential to manipulate neurotransmitter levels in vivo using interventions with drugs that have negligible affinity for the receptors aimed at and are allowed to be used in humans. Neurochemical evidence for pharmacological interventions mostly originates from microdialysis studies in animals. First we will give a brief historical and methodological overview of the microdialysis technique. We will focus on serotonin and present microdialysis data of various pharmacological interventions in rats that have the potential to alter serotonin levels in humans. Our primary aim is to broaden the arsenal of pharmacological tools for PET competition studies, in particular because the type of neuronal manipulation might be a critical factor. Microdialysis of glutamate is briefly discussed, merely to illustrate some of the shortcomings of the technique.