Behavioral and Neuroanatomical Consequences of Cell-Type Specific Loss of Dopamine D2 Receptors in the Mouse Cerebral Cortex

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.

522 A strange case of bradycardia in a 38-year-old woman postpartum

Methods and results A 38-year-old woman at her 4th day postpartum from a twin pregnancy, presented to the Emergency Room with general malaise, headache, and dyspnoea. Her symptoms had started to show 2 days prior to her ER admission and were worsened by bilateral pitting oedema. In particular they had started when she was administered cabergoline to suppress lactation. Her blood pressure was elevated (160/80 mmHg) and her heart rate was 40 b.p.m. On examination she was oriented in time and space. Her laboratory exams showed anaemia (Hb 8.8 g/dl), with negative D-dimer and troponin. She had no urine proteinuria, which allowed pre-eclampsia to be excluded from the diagnostic hypotheses. A 12-lead ECG was performed and showed junctional rhythm with isorhythmic dissociation at 40 b.p.m. She was admitted to the cardiology ward for diagnostic workup. Her echocardiogram showed no structural alteration and preserved ejection fraction. A cardiac magnetic resonance confirmed the absence of structural alterations or late gadolinium enhancement. During her hospital stay, sinus rhythm was spontaneously restored at 42 b.p.m.; in addition to this, restoration of sinus rhythm, although bradycardic, was associated to the resolution on both her symptoms and of her pitting oedema. She was discharged with a diagnosis of bradycardia secondary to carbegoline use. Her Holter ECG, performed 7 days after discharge, showed sinus bradycardia with occasional isorhythmic dissociation. Conclusions Cabergoline is an ergot-derived dopamine agonist usually used in the treatment of Parkinson’s disease. It acts selectively on D2 receptors. It can be associated to orthostatic hypotension, cardiac valvular fibrosis, and angina pectoris. No cases of cabergoline-induced bradycardia can be currently found in literature; however, a similar effect was seen with the use of methylergometrine in a women during her post-partum period. Furthermore, studies on mice have shown that ergot derivatives may cause reduction of heart rate. It therefore seems possible that in our case, the use of cabergoline induced the patient’s bradyarrhythmia.

Dopamine promotes aggression in mice via ventral tegmental area to lateral septum projections

Septal-hypothalamic neuronal activity centrally mediates aggressive behavior and dopamine system hyperactivity is associated with elevated aggression. However, the causal role of dopamine in aggression and its target circuit mechanisms are largely unknown. To address this knowledge gap, we studied the modulatory role of the population- and projection-specific dopamine function in a murine model of aggressive behavior. We find that terminal activity of ventral tegmental area (VTA) dopaminergic neurons selectively projecting to the lateral septum (LS) is sufficient for promoting aggression and necessary for establishing baseline aggression. Within the LS, dopamine acts on D2-receptors to inhibit GABAergic neurons, and septal D2-signaling is necessary for VTA dopaminergic activity to promote aggression. Collectively, our data reveal a powerful modulatory influence of dopaminergic synaptic input on LS function and aggression, effectively linking the clinically pertinent hyper-dopaminergic model of aggression with the classic septal-hypothalamic aggression axis.

3D-ALMOND-QSAR Models to Predict the Antidepressant Effect of Some Natural Compounds

The current treatment of depression involves antidepressant synthetic drugs that have a variety of side effects. In searching for alternatives, natural compounds could represent a solution, as many studies reported that such compounds modulate the nervous system and exhibit antidepressant effects. We used bioinformatics methods to predict the antidepressant effect of ten natural compounds with neuroleptic activity, reported in the literature. For all compounds we computed their drug-likeness, absorption, distribution, metabolism, excretion (ADME), and toxicity profiles. Their antidepressant and neuroleptic activities were predicted by 3D-ALMOND-QSAR models built by considering three important targets, namely serotonin transporter (SERT), 5-hydroxytryptamine receptor 1A (5-HT1A), and dopamine D2 receptor. For our QSAR models we have used the following molecular descriptors: hydrophobicity, electrostatic, and hydrogen bond donor/acceptor. Our results showed that all compounds present drug-likeness features as well as promising ADME features and no toxicity. Most compounds appear to modulate SERT, and fewer appear as ligands for 5-HT1A and D2 receptors. From our prediction, linalyl acetate appears as the only ligand for all three targets, neryl acetate appears as a ligand for SERT and D2 receptors, while 1,8-cineole appears as a ligand for 5-HT1A and D2 receptors.

A complementary and alternative natural antidepressant therapy with emphasis on their mechanisms of action

Medicinal plants can exert antidepressant activity by many mechanisms included neutralization of various stress mediators (regulate the activity of the hypothalamic- pituitary- adrenal axis and reduce CRF, and ACTH and corticosterone) [5], interaction with serotonergic systems (5-HT3, 5HT2A, 5-HT1A), noradrenergic (α1 and α2 receptors) and dopaminergic (D1 and D2) receptors [6],restoring monoamine transmitters and their receptors to normal limits in certain regions of the cortex, in addition to reducing of oxidative stress and amelioration of inflammatory mediators. The current review discussed the antidepressant activity of medicinal plants, with emphasis on their mechanisms of action.