Chronic Citalopram Administration Causes a Sustained Suppression of Serotonin Synthesis in the Mouse Forebrain

BACKGROUND:Serotonin (5-HT) is a neurotransmitter with important roles in the regulation of neurobehavioral processes, particularly those regulating affect in humans. Drugs that potentiate serotonergic neurotransmission by selectively inhibiting the reuptake of serotonin (SSRIs) are widely used for the treatment of psychiatric disorders. Although the regulation of serotonin synthesis may be an factor in SSRI efficacy, the effect of chronic SSRI administration on 5-HT synthesis is not well understood. Here, we describe effects of chronic administration of the SSRI citalopram (CIT) on 5-HT synthesis and content in the mouse forebrain. METHODOLOGY/PRINCIPAL FINDINGS:Citalopram was administered continuously to adult male C57BL/6J mice via osmotic minipump for 2 days, 14 days or 28 days. Plasma citalopram levels were found to be within the clinical range. 5-HT synthesis was assessed using the decarboxylase inhibition method. Citalopram administration caused a suppression of 5-HT synthesis at all time points. CIT treatment also caused a reduction in forebrain 5-HIAA content. Following chronic CIT treatment, forebrain 5-HT stores were more sensitive to the depleting effects of acute decarboxylase inhibition. CONCLUSIONS/SIGNIFICANCE:Taken together, these results demonstrate that chronic citalopram administration causes a sustained suppression of serotonin synthesis in the mouse forebrain. Furthermore, our results indicate that chronic 5-HT reuptake inhibition renders 5-HT brain stores more sensitive to alterations in serotonin synthesis. These results suggest that the regulation of 5-HT synthesis warrants consideration in efforts to develop novel antidepressant strategies

An Animal Model of Emotional Blunting in Schizophrenia

Schizophrenia is often associated with emotional blunting—the diminished ability to respond to emotionally salient stimuli—particularly those stimuli representative of negative emotional states, such as fear. This disturbance may stem from dysfunction of the amygdala, a brain region involved in fear processing. The present article describes a novel animal model of emotional blunting in schizophrenia. This model involves interfering with normal fear processing (classical conditioning) in rats by means of acute ketamine administration. We confirm, in a series of experiments comprised of cFos staining, behavioral analysis and neurochemical determinations, that ketamine interferes with the behavioral expression of fear and with normal fear processing in the amygdala and related brain regions. We further show that the atypical antipsychotic drug clozapine, but not the typical antipsychotic haloperidol nor an experimental glutamate receptor 2/3 agonist, inhibits ketamine's effects and retains normal fear processing in the amygdala at a neurochemical level, despite the observation that fear-related behavior is still inhibited due to ketamine administration. Our results suggest that the relative resistance of emotional blunting to drug treatment may be partially due to an inability of conventional therapies to target the multiple anatomical and functional brain systems involved in emotional processing. A conceptual model reconciling our findings in terms of neurochemistry and behavior is postulated and discussed

Major Trends in the Imaging Sciences: 2007 Eugene P. Pendergrass New Horizons Lecture

Rationale: Male 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). Objectives: We 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. Methods: 5-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. Results: In 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. Conclusions: It 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.

Medication waste in a hospital setting: concerns and considerations

The use of medication contributes significantly to the total CO2 emission caused by the public health sector. Conservative estimates reveal that the amount of medication distributed by public pharmacies but is wasted unused equalizes a total amount of 100 million euro. Data regarding medication waste in hospitals is not yet available. Besides costs, wasting unused medication also has an enormous ecological impact. We analysed the stream of medication waste in our hospital and tried to reduce this by addressing the main causes. Our medication distribution process is mainly based on financial and quality based decisions, but should impact on planetary health not also be included? To realize this, though, both ecotoxicologic data as well as information related to environmental impact of medication production should be available and easily accessible

Geneesmiddelverspilling in het ziekenhuis

The use of medication contributes significantly to the total CO2 emission caused by the public health sector. Conservative estimates reveal that the amount of medication distributed by public pharmacies but is wasted unused equalizes a total amount of 100 million euro. Data regarding medication waste in hospitals is not yet available. Besides costs, wasting unused medication also has an enormous ecological impact. We analysed the stream of medication waste in our hospital and tried to reduce this by addressing the main causes. Our medication distribution process is mainly based on financial and quality based decisions, but should impact on planetary health not also be included? To realize this, though, both ecotoxicologic data as well as information related to environmental impact of medication production should be available and easily accessible

Conceptual model.

<p>A schematic drawing of our conceptual model depicting interactions between dopamine and glutamate in the amygdala nuclei. The interactions between other brain areas studied and the amygdala conceptual model are also indicated. Dashed lines symbolize inhibition, while solid lines represent stimulation. Lines between brain areas represent functional connectivity between the regions. Fear stimuli are processed first by the basolateral amygdala (BLA), activating the glutamate system in this area, but do not affect dopamine levels in either the BLA or central amygdala (CEA). Output signals inducing freezing behavior from the CEA are therefore strong via the glutamate pathway. Ketamine decreases glutamate-related fear processing in the BLA and CEA and simultaneously elevates dopamine content (storage) in the CEA, by blocking dopamine release via the dopamine D₂ autoreceptor located on the cell body (possibly the VTA). The decreased dopamine release (together with the block of glutamate transmission from the BLA to the CEA) blocks the fear-related outputs by means of increased GABA inhibition via intercalated cells projecting onto the CEA. The net effect is weak output signals from the CEA and diminished freezing behavior. Clozapine, while blocking the effects of ketamine on glutamate-related processing in the BLA and CEA, does nothing to prevent changes in dopamine levels. GABA-ergic intercalated cells therefore continue to inhibit CEA and/or BLA and normal fear-conditioned behavior cannot be retained. Can chronic clozapine treatment renormalize dopamine levels and lead to long-term remediation of negative symptoms in the animal model? <i>ACC, anterior cingulate; DA, dopamine; LC, locus coeruleus; Nacc, nucleus accumbens; PVN, paraventricular nucleus; VTA, ventral tegmental area</i></p

cFos immunocytochemical labeling.

<p>Typical examples of the brain areas stained for cFos expression, visually showing the effects of some of the treatments. Delineated areas depict areas measured. Brain slice levels were taken from the Swanson rat brain atlas <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001360#pone.0001360-Swanson2" target="_blank">[65]</a>, with appropriate co-ordinates listed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0001360#pone-0001360-t001" target="_blank">Table 1</a>. <i>CLOZ, clozapine; FC, Fear conditioning; KET, ketamine; NFC, no fear conditioning.</i></p

cFos expression.

<p>Fear conditioning (FC) increased cFos expression as compared to the NFC group in the anterior cingulate (p = 0.003; A), nucleus accumbens shell (p<0.0001; B), and paraventricular nucleus (p<0.0001; C), anterior basolateral amygdala (p = 0.002; D) and lateral amygdala (p<0.0001; E). Ketamine blocked the effect of fear conditioning (FC vs. FC+Ket) in the anterior cingulate (p<0.0001; A), nucleus accumbens shell (p = 0.002; B), paraventricular nucleus (p<0.0001; C), anterior basolateral amygdala (p = 0.001) and lateral amygdala (p = 0.004). As hypothesized, clozapine was able to counteract the blockade of ketamine on fear conditioning (FC+Ket vs. FC+Ket+Cloz) in the anterior cingulate (p<0.0001), nucleus accumbens shell (p = 0.001), paraventricular nucleus (p = 0.001), anterior basolateral amygdala (p<0.0001) and lateral amygdala (p<0.0001). A slight restoration by haloperidol was noted in the anterior cingulate (p = 0.042). <i>Cloz, clozapine; FC, fear conditioning; Halo, haloperidol; Ket, Ketamine; LY, LY 379278; NFC, no fear conditioning.</i></p

Experimental group divisions.

<p>Diagram portraying the rat group divisions. At the top of the hierarchy, we divided rats into two main groups: those receiving fear conditioning, and those not. Those animals receiving fear conditioning, were then further divided into rats receiving ketamine administration and rats receiving saline shams. The latter group would form the fear conditioning only group (FC). The rats not receiving fear conditioning were also divided into two groups depending on whether they would receive a ketamine or saline injection; the former group making up the ketamine only group (Ket), and the latter being the control group (NFC). The remaining fear conditioned rats also receiving ketamine were then further divided into those receiving either a saline injection (FC+Ket) or those receiving an additional antipsychotic injection consisting of clozapine (FC+Ket+CLOZ), haloperidol (FC+Ket+HALO), or LY 379268 (FC+Ket+LY). <i>CLOZ, clozapine; FC, Fear conditioning; HALO, haloperidol; KET, ketamine; LY, LY379268; NFC, no fear conditioning; SAL, saline.</i></p