[Medication waste in a hospital setting: concerns and considerations]. / 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.

Dopamine physiology in the basal ganglia of male zebra finches during social stimulation.

Accumulating evidence suggests that dopamine (DA) is involved in altering neural activity and gene expression in a zebra finch cortical-basal ganglia circuit specialized for singing, upon the shift between solitary singing and singing as a part of courtship. Our objective here was to sample changes in the extracellular concentrations of DA in Area X of adult and juvenile birds, to test the hypothesis that DA levels would change similarly during presentation of a socially salient stimulus in both age groups. We used microdialysis to sample the extracellular milieu of Area X in awake, behaving adult and juvenile male zebra finches, and analysed the dialysate using high-performance liquid chromatography coupled with electrochemical detection. The extracellular levels of DA in Area X increased significantly during both female presentation to adult males and tutor presentation to juvenile males. DA levels were not correlated with the time spent singing. We also reverse-dialysed Area X with pharmacologic agents that act either on DA systems directly or on norepinephrine, and found that all of these agents significantly increased DA levels (3- to 10-fold) in Area X. These findings suggest that changes in extracellular DA levels can be stimulated similarly by very different social contexts (courtship and interaction with tutor), and influenced potently by dopaminergic and noradrenergic drugs. These results raise the possibility that the arousal level or attentional state of the subject (rather than singing behavior) is the common feature eliciting changes in extracellular DA concentration.

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.

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.

Impact of serotonin 2C receptor null mutation on physiology and behavior associated with nigrostriatal dopamine pathway function.

The impact of serotonergic neurotransmission on brain dopaminergic pathways has substantial relevance to many neuropsychiatric disorders. A particularly prominent role has been ascribed to the inhibitory effects of serotonin 2C receptor (5-HT(2C)R) activation on physiology and behavior mediated by the mesolimbic dopaminergic pathway, particularly in the terminal region of the nucleus accumbens. The influence of this receptor subtype on functions mediated by the nigrostriatal dopaminergic pathway is less clear. Here we report that a null mutation eliminating expression of 5-HT(2C)Rs produces marked alterations in the activity and functional output of this pathway. 5-HT(2C)R mutant mice displayed increased activity of substantia nigra pars compacta (SNc) dopaminergic neurons, elevated baseline extracellular dopamine concentrations in the dorsal striatum (DSt), alterations in grooming behavior, and enhanced sensitivity to the stereotypic behavioral effects of d-amphetamine and GBR 12909. These psychostimulant responses occurred in the absence of phenotypic differences in drug-induced extracellular dopamine concentration, suggesting a phenotypic alteration in behavioral responses to released dopamine. This was further suggested by enhanced behavioral responses of mutant mice to the D(1) receptor agonist SKF 81297. Differences in DSt D(1) or D(2) receptor expression were not found, nor were differences in medium spiny neuron firing patterns or intrinsic membrane properties following dopamine stimulation. We conclude that 5-HT(2C)Rs regulate nigrostriatal dopaminergic activity and function both at SNc dopaminergic neurons and at a locus downstream of the DSt.

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.

Effects of the mGluR2/3 agonist LY379268 on ketamine-evoked behaviours and neurochemical changes in the dentate gyrus of the rat.

One of the functions of group II metabotropic glutamate receptors (mGluR2/3) is to modulate glutamate release. Thus, targeting mGluR2/3s might be a novel treatment for several psychiatric disorders associated with inappropriate glutamatergic neurotransmission, such as schizophrenia. In an effort to evaluate the antipsychotic properties of LY379268, a potent and selective mGluR2/3 agonist, we examined its effect on ketamine-evoked hyperlocomotion and sensorimotor gating deficit (PPI) in rats, an animal model of schizophrenia. We also measured the ex vivo tissue level of glutamate (Glu), dopamine (DA) and serotonin (5-HT) as well as the DA metabolites DOPAC and the major 5-HT metabolite HIAA to determine the neurochemical effects of ketamine (12 mg/kg) and LY379268 (1 mg/kg) in the dentate gyrus (DG). While LY379268 (1-3 mg/kg) reduced ketamine-evoked hyperlocomotion (12 mg/kg), it could not restore ketamine-evoked PPI deficits (4-12 mg/kg). In the DG we found that ketamine decreased Glu and DA levels, as well as HIAA/5-HT turnover, and that LY379268 could prevent ketamine effects on Glu level but not on monoamine transmission. These results may indicate that the inability of LY379268 to reverse PPI deficits is attributable to its lack of effect on ketamine-induced changes in monoamine transmission, but that LY379268 can prevent ketamine-evoked changes in glutamate, which is sufficient to block hyperlocomotion. In addition to the partial effectiveness of LY379268 in the ketamine model of schizophrenia, we observed a dual effect of LY379268 on anxious states, whereby a low dose of this compound (1 mg/kg) produced anxiolytic effects, while a higher dose (3 mg/kg) appeared to be anxiogenic. Additional work is needed to address a possible role of LY379268 in schizophrenia and anxiety treatment.

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.

Differences in the effects of 5-HT(1A) receptor agonists on forced swimming behavior and brain 5-HT metabolism between low and high aggressive mice.

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-HT(1A)) 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-HT(1A) receptors is associated with a difference in brain 5-HT metabolism, and whether acute administration of a 5-HT(1A) 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-HT(1A) receptor agonist, 8-OH-DPAT, and of the somatodendritic 5-HT(1A) 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-HT(1A) 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-HT(1A) receptors in LAL mice and by presynaptic 5-HT(1A) 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.

Motor effects of a dopamine stabilizer (GMC1111) in primate models of Parkinson and hemiparkinsonism.

The effects on motor behavior of a new potential dopamine stabilizer: 2-amino-6-(N,N-di-n-propylamino)thiazolo[4,5-f]indan (GMC1111) were investigated in common marmosets with 6-hydroxydopamine lesions within the median forebrain bundle (12 unilateral, 6 bilateral). GMC1111 was administered orally or subcutaneously (s.c.) to unilaterally 6-hydroxydopamine lesioned monkeys, either alone or together with s.c. injections of apomorphine (0.2 mg/kg) and the effect on rotational behavior was examined. GMC1111 (0.03-3.0 mg/kg) alone, orally or s.c., did not induce rotational behavior. When apomorphine and GMC1111 were injected simultaneously, rotations were nearly abolished in three monkeys with a baseline apomorphine-induced rotation rate below 13/min, whereas GMC1111 did not modify the rotations in three high-rotating animals (>17/min). Oral administration of GMC1111 (1.0 and 3.0 mg/kg) abolished the apomorphine-induced rotations in another six unilaterally dopamine-denervated monkeys, indicating a good oral bioavailability. A low dose of GMC1111 (0.3 mg/kg) administered s.c. to marmosets with bilateral nigrostriatal lesions produced a reduction of Parkinson symptoms of approximately the same degree as with levodopa/benserazide (15/3.75 mg/kg), while higher doses of GMC1111 were less effective. When levodopa/benserazide was administered together with various doses of GMC1111 (0.3-3.0 mg/kg), the levodopa-induced peak-dose dyskinesias were reduced with the highest dose of GMC1111 (3 mg/kg). Taken together, GMC1111 modifies dopaminergic activity in a normalizing direction. Parkinson symptoms, as well as levodopa-induced dyskinesias are both reduced. This suggests the arrival of another member of the new dopamine stabilizer family.

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.