Role OF 5-HT2C receptors in dyskinesia

By integrating knowledge gained by pharmacogenetic, neuroanatomical and pharmacological studies, a model can be constructed how serotonin (5-HT) affects the vulnerability to induce tardive dyskinesia. From neuroanatomical studies, it can be concluded that 5-HT inhibits the release of dopamine (DA) within the dorsal striatum by affecting 5-HT2C receptors and also within the ventral striatum and prefrontal cortex by affecting 5-HT2A receptors. However, considering the low affinity of DA for its receptors, it is unlikely that the so released DA is able to displace atypical antipsychotics from DA D2 and D3 receptors. 5-HT2C receptors and, to a lesser extent, 5-HT2A receptors, have constitutive activity and therefore, atypical antipsychotics can have inverse agonistic effects. It is hypothesized that decreasing the activity of 5-HT2 receptor carrying medium spiny neurons (MSNs) within the dorsal striatum represents the mechanism showing how atypical antipsychotics have limited ability to cause tardive dyskinesia

ROLE OF 5-HT2C RECEPTORS IN DYSKINESIA

By integrating knowledge gained by pharmacogenetic, neuroanatomical and pharmacological studies, a model can be constructed how serotonin (5-HT) affects the vulnerability to induce tardive dyskinesia. From neuroanatomical studies, it can be concluded that 5-HT inhibits the release of dopamine (DA) within the dorsal striatum by affecting 5-HT2C receptors and also within the ventral striatum and prefrontal cortex by affecting 5-HT2A receptors. However, considering the low affinity of DA for its receptors, it is unlikely that the so released DA is able to displace atypical antipsychotics from DA D2 and D3 receptors. 5-HT2C receptors and, to a lesser extent, 5-HT2A receptors, have constitutive activity and therefore, atypical antipsychotics can have inverse agonistic effects. It is hypothesized that decreasing the activity of 5-HT2 receptor carrying medium spiny neurons (MSNs) within the dorsal striatum represents the mechanism showing how atypical antipsychotics have limited ability to cause tardive dyskinesia.Â

Circuits regulating pleasure and happiness in bipolar disorder

According to our model, the motivation for appetitive-searching vs. distress-avoiding behaviors is regulated by two parallel cortico-striato-thalamo-cortical (CSTC) re-entry circuits that include the core and the shell parts of the nucleus accumbens, respectively. An entire series of basal ganglia, running from the caudate nucleus on one side to the centromedial amygdala on the other side, control the intensity of these reward-seeking and misery-fleeing behaviors by stimulating the activity of the (pre)frontal and limbic cortices. Hyperactive motivation to display behavior that potentially results in reward induces feelings of hankering (relief leads to pleasure); while, hyperactive motivation to exhibit behavior related to avoidance of aversive states results in dysphoria (relief leads to happiness). These two systems collaborate in a reciprocal fashion. We hypothesized that the mechanism inducing the switch from bipolar depression to mania is the most essential characteristic of bipolar disorder. This switch is attributed to a dysfunction of the lateral habenula, which regulates the activity of midbrain centers, including the dopaminergic ventral tegmental area (VTA). Froman evolutionary perspective, the activity of the lateral habenula should be regulated by the human homolog of the habenula-projecting globus pallidus, which in turn might be directed by the amygdaloid complex and the phylogenetically old part of the limbic cortex. In bipolar disorder, it is possible that the system regulating the activity of this reward-driven behavior is damaged or the interaction between the medial and lateral habenula may be dysfunctional. This may lead to an adverse coupling between the activities of the misery-fleeing and reward-seeking circuits, which results in independently varying activities

An evaluation of three processing methods and the effect of reduced culture times for faster direct identification of pathogens from BacT/ALERT blood cultures by MALDI-TOF MS

Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) is a fast and reliable method for the identification of bacteria from agar media. Direct identification from positive blood cultures should decrease the time to obtaining the result. In this study, three different processing methods for the rapid direct identification of bacteria from positive blood culture bottles were compared. In total, 101 positive aerobe BacT/ALERT bottles were included in this study. Aliquots from all bottles were used for three bacterial processing methods, i.e. the commercially available Bruker’s MALDI Sepsityper kit, the commercially available Molzym’s MolYsis Basic5 kit and a centrifugation/washing method. In addition, the best method was used to evaluate the possibility of MALDI application after a reduced incubation time of 7 h of Staphylococcus aureus- and Escherichia coli-spiked (1,000, 100 and 10 colony-forming units [CFU]) aerobe BacT/ALERT blood cultures. Sixty-six (65%), 51 (50.5%) and 79 (78%) bottles were identified correctly at the species level when the centrifugation/washing method, MolYsis Basic 5 and Sepsityper were used, respectively. Incorrect identification was obtained in 35 (35%), 50 (49.5%) and 22 (22%) bottles, respectively. Gram-positive cocci were correctly identified in 33/52 (64%) of the cases. However, Gram-negative rods showed a correct identification in 45/47 (96%) of all bottles when the Sepsityper kit was used. Seven hours of pre-incubation of S. aureus- and E. coli-spiked aerobe BacT/ALERT blood cultures never resulted in reliable identification with MALDI-TOF MS. Sepsityper is superior for the direct identification of microorganisms from aerobe BacT/ALERT bottles. Gram-negative pathogens show better results compared to Gram-positive bacteria. Reduced incubation followed by MALDI-TOF MS did not result in faster reliable identification

Evolution of circuits regulating pleasure and happiness with the habenula in control

The habenula, which in humans is a small nuclear complex within the epithalamus, plays an essential role in regulating the intensity of reward-seeking and adversity-avoiding behavior in all vertebrate ancestors by regulating the activity of ascending midbrain monoaminergic tracts. In lampreys, considered to possess a brain comparable to humans’ earliest evolutionary vertebrate ancestor, the activity of the lateral habenula is controlled by a subset of glutamatergic neurons of the animal’s pallidum (habenula-projecting globus pallidus) that inhibit reward-seeking behavior when this conduct is not successful enough. The pathophysiological roles of the habenula and habenula-projecting globus pallidus in humans have hardly been studied, which is probably due to insufficient resolution of common neuroimaging techniques. Their dysregulation may, however, play an essential role in the pathogenesis of mood and stress disorders and addiction

The evolutionary old forebrain as site of action to develop new psychotropic drugs

Background: Previously, the authors have developed a model of how reward-seeking and distress- avoiding behaviour is regulated by the human brain. The forebrain's evolution in vertebrates was taken as a starting point. Aims: The authors want to inspire colleagues to study in particular the pharmacological effects on the described ancient forebrain structures in order to modify specific symptoms of mental disorders. Methods: Compilation of data and ideas of previous articles, with examples to illustrate. Results: A primary (lamprey-like), secondary (frog-like) and tertiary (mammal-like) forebrain can be distinguished, organized according to a Russian doll model. The first constituent is primarily involved in producing the emotional response, while the last is principally concerned with constructing conscious cognitive behaviour (including verbal and written communication). Mental disorders comprise (partly related and partly unrelated) biological and rational phenomena. The secondary system regulates the intensity of reward-seeking and distress-avoiding behaviour. An essential component of the primary forebrain evaluates the results of behavioural actions: the lateral habenula-projecting pallidum. These neurons regulate the activity of ascending dopaminergic pathways. The authors suggest that these habenula-projecting pallidum neurons are targeted by subanaesthetic dosages of ketamine. The medial habenula is enriched with nicotinergic acetylcholine receptors and regulates the activity of ascending adrenergic and serotonergic neurons. This may link varenicline-induced hostility to selective serotonin reuptake inhibitor-induced aggression. Conclusions: Studying the effects of new compounds on the primary and secondary brains in lampreys and frogs may yield interesting new treatments of mental disorders