Transient nicotine exposure in early adolescent male mice freezes their dopamine circuits in an immature state.

How nicotine acts on developing neurocircuitry in adolescence to promote later addiction vulnerability remains largely unknown, but may hold the key for informing more effective intervention efforts. We found transient nicotine exposure in early adolescent (PND 21-28) male mice was sufficient to produce a marked vulnerability to nicotine in adulthood (PND 60 + ), associated with disrupted functional connectivity in dopaminergic circuits. These mice showed persistent adolescent-like behavioral and physiological responses to nicotine, suggesting that nicotine exposure in adolescence prolongs an immature, imbalanced state in the function of these circuits.

A non-canonical GABAergic pathway to the VTA promotes unconditioned freezing.

Freezing is a conserved defensive behaviour that constitutes a major stress-coping mechanism. Decades of research have demonstrated a role of the amygdala, periaqueductal grey and hypothalamus as core actuators of the control of fear responses, including freezing. However, the role that other modulatory sites provide to this hardwired scaffold is not known.

Nicotinic receptors promote susceptibility to social stress in female mice linked with neuroadaptations within VTA dopamine neurons.

There are about twice as many women as men who experience depression during their lifetime. Although life circumstances and especially exposure to stressful situations constitute a major risk factor to develop depression, the underlying mechanisms have yet to be unraveled. We employed the chronic social defeat procedure to elicit depressive-like symptoms in females and ketamine to validate the model.

Disrupting D1-NMDA or D2-NMDA receptor heteromerization prevents cocaine's rewarding effects but preserves natural reward processing.

Addictive drugs increase dopamine in the nucleus accumbens (NAc), where it persistently shapes excitatory glutamate transmission and hijacks natural reward processing. Here, we provide evidence, from mice to humans, that an underlying mechanism relies on drug-evoked heteromerization of glutamate -methyl-d-aspartate receptors (NMDAR) with dopamine receptor 1 (D1R) or 2 (D2R). Using temporally controlled inhibition of D1R-NMDAR heteromerization, we unraveled their selective implication in early phases of cocaine-mediated synaptic, morphological, and behavioral responses.

Dopamine and glutamate receptors control social stress-induced striatal ERK1/2 activation.

Stress has been acknowledged as one of the main risk factors for the onset of psychiatric disorders. Social stress is the most common type of stressor encountered in our daily lives. Uncovering the molecular determinants of the effect of stress on the brain would help understanding the complex maladaptations that contribute to pathological stress-related mental states.

The Amyloid Precursor Protein C-Terminal Domain Alters CA1 Neuron Firing, Modifying Hippocampus Oscillations and Impairing Spatial Memory Encoding.

There is a growing consensus that Alzheimer's disease (AD) involves failure of the homeostatic machinery, which underlies the firing stability of neural circuits. What are the culprits leading to neuron firing instability? The amyloid precursor protein (APP) is central to AD pathogenesis, and we recently showed that its intracellular domain (AICD) could modify synaptic signal integration. We now hypothesize that AICD modifies neuron firing activity, thus contributing to the disruption of memory processes.

Mesopontine cholinergic inputs to midbrain dopamine neurons drive stress-induced depressive-like behaviors.

Stressful life events are primary environmental factors that markedly contribute to depression by triggering brain cellular maladaptations. Dysregulation of ventral tegmental area (VTA) dopamine neurons has been causally linked to the appearance of social withdrawal and anhedonia, two classical manifestations of depression. However, the relevant inputs that shape these dopamine signals remain largely unknown.

Serotonin 2B Receptors in Mesoaccumbens Dopamine Pathway Regulate Cocaine Responses.

Addiction is a maladaptive pattern of behavior following repeated use of reinforcing drugs in predisposed individuals, leading to lifelong changes. Common among these changes are alterations of neurons releasing dopamine in the ventral and dorsal territories of the striatum. The serotonin 5-HT receptor has been involved in various behaviors, including impulsivity, response to antidepressants, and response to psychostimulants, pointing toward putative interactions with the dopamine system.

Constitutive and Acquired Serotonin Deficiency Alters Memory and Hippocampal Synaptic Plasticity.

Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory and underlying mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory.

Multiscale single-cell analysis reveals unique phenotypes of raphe 5-HT neurons projecting to the forebrain.

Serotonergic neurons of the raphe nuclei exhibit anatomical, neurochemical and elecrophysiological heterogeneity that likely underpins their specific role in multiple behaviors. However, the precise organization of serotonin (5-HT) neurons to orchestrate 5-HT release patterns throughout the brain is not well understood. We compared the electrophysiological and neurochemical properties of dorsal and median raphe 5-HT neurons projecting to the medial prefrontal cortex (mPFC), amygdala (BLA) and dorsal hippocampus (dHP), combining retrograde tract tracing with brain slice electrophysiology and single-cell RT-PCR in Pet1-EGFP mice.

A subpopulation of serotonergic neurons that do not express the 5-HT1A autoreceptor.

5-HT neurons are topographically organized in the hindbrain, and have been implicated in the etiology and treatment of psychiatric diseases such as depression and anxiety. Early studies suggested that the raphe 5-HT neurons were a homogeneous population showing similar electrical properties, and feedback inhibition mediated by 5-HT1A autoreceptors. We utilized histochemistry techniques in ePet1-eGFP and 5-HT1A-iCre/R26R mice to show that a subpopulation of 5-HT neurons do not express the somatodendritic 5-HT1A autoreceptor mRNA.

Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons.

Repeated traumatic events induce long-lasting behavioral changes that are key to organism adaptation and that affect cognitive, emotional, and social behaviors. Rodents subjected to repeated instances of aggression develop enduring social aversion and increased anxiety. Such repeated aggressions trigger a stress response, resulting in glucocorticoid release and activation of the ascending dopamine (DA) system.

Investigating anxiety and depressive-like phenotypes in genetic mouse models of serotonin depletion.

Emotional disorders such as depression, panic attacks, generalized anxiety, phobias and post-traumatic stress have been associated to decreased serotonin (5-HT) function, based on the positive effects of treatments that enhance 5-HT neurotransmission. However, it has been difficult to establish a primary role for 5-HT deficiency in these diseases, making preclinical models particularly useful. Over the last ten years a variety of genetic mouse models of 5-HT depletion have been produced, complementing previous pharmacologically-based models.

Flavan-3-ol esters: new agents for exploring modulatory sites on GABA(A) receptors.

Background And Purpose: Enhancement of GABAergic function is the primary mechanism of important therapeutic agents such as benzodiazepines, barbiturates, neurosteroids, general anaesthetics and some anticonvulsants. Despite their chemical diversity, many studies have postulated that these agents may bind at a common or overlapping binding site, or share an activation domain. Similarly, we found that flavan-3-ol esters act as positive modulators of GABA(A) receptors, and noted that this action resembled the in vitro profile of general anaesthetics.

A genetically defined morphologically and functionally unique subset of 5-HT neurons in the mouse raphe nuclei.

Heterogeneity of central serotonin (5-HT) raphe neurons is suggested by numerous lines of evidence, but its genetic basis remains elusive. The transcription factor Pet1 is required for the acquisition of serotonergic identity in a majority of neurons in the raphe nuclei. Nevertheless, a subset of 5-HT neurons differentiates in Pet1 knock-out mice.

Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors.

We herein describe the synthesis and positive modulatory activities of a small library of flavan-3-ol derivatives on alpha(1)beta(2)gamma(2L) GABA(A) receptors. Structure-activity relationships of various substituents on the A, B and C rings were evaluated in a functional electrophysiological assay. A trans configuration and a 3-acetoxy moiety are essential for activity.

The flavonoid glycosides, myricitrin, gossypin and naringin exert anxiolytic action in mice.

The consumption of flavonoid-rich foods, in particular fruits and vegetables, has been epidemiologically associated with a reduced risk of heart disease, neurodegenerative disease, cancer and other chronic diseases. Flavonoid glycosides, the main class of flavonoids, have been shown to exert CNS-mediated activities, particularly as sedative-hypnotics, analgesics or both, nevertheless no studies have evaluated these agents in anxiety. This study assessed the potential anxiolytic effect of three flavonoid glycosides, myrcitrin, naringin and gossypin, in the elevated plus maze test (EPM).

Hesperidin, a flavonoid glycoside with sedative effect, decreases brain pERK1/2 levels in mice.

The aim of this work was to evaluate if the intraperitoneal administration of the natural compound hesperidin, in a sedative dose, and neo-hesperidin, a hesperidin structural analog that exerts minor sedative effect, were able to induce changes in intracellular signaling cascades in different areas of the brain. The systemic administration of hesperidin produced a marked reduction in the phosphorylation state of extracellular signal-regulated kinases 1/2 (ERK 1/2), but not of Ca(+2)/calmodulin-dependent protein kinase II alpha subunit (alphaCaMKII), in the cerebral cortex, cerebellum and hippocampus. In contrast, neo-hesperidin did not markedly affect the activity of ERK 1/2 in both the cortex and the cerebellum.

Flavan-3-ol derivatives are positive modulators of GABA(A) receptors with higher efficacy for the alpha(2) subtype and anxiolytic action in mice.

Recent genetic and pharmacological studies have demonstrated that alpha(2)-containing GABA(A) receptors mediate the anxiolytic effects of benzodiazepines, setting a new strategy in developing novel, non-sedative anxiolytic agents. In this study we show that stereoisomers of 3-acetoxy-4'-methoxyflavan are positive modulators of recombinant alpha(1,2,3,5)beta(2)gamma(2L) and alpha(1)beta(2) GABA(A) receptors expressed in Xenopus laevis oocytes. GABA(C) receptors are insensitive to modulation by these compounds.

Central nervous system depressant action of flavonoid glycosides.

The pharmacological effects on the central nervous system (CNS) of a range of available flavonoid glycosides were explored and compared to those of the glycosides 2S-hesperidin and linarin, recently isolated from valeriana. The glycosides 2S-neohesperidin, 2S-naringin, diosmin, gossipyn and rutin exerted a depressant action on the CNS of mice following i.p.

Synergistic interaction between hesperidin, a natural flavonoid, and diazepam.

It has been recently reported the presence in Valeriana of the flavone 6-methylapigenin and the flavanone glycoside hesperidin. The apigenin derivative is a ligand for the benzodiazepine binding site in the gamma-aminobutyric acid receptor type A (GABA(A)) and has anxiolytic properties. Hesperidin has sedative and sleep-enhancing properties but is not a ligand for the benzodiazepine binding site.