CHRNA5 gene variation affects the response of VTA dopaminergic neurons during chronic nicotine exposure and withdrawal.

Nicotine is the principal psychoactive component in tobacco that drives addiction through its action on neuronal nicotinic acetylcholine receptors (nAChR). The nicotinic receptor gene CHRNA5, which encodes the α5 subunit, is associated with nicotine use and dependence. In humans, the CHRNA5 missense variant rs16969968 (G > A) is associated with increased risk for nicotine dependence and other smoking-related phenotypes.

A common SNP in Chrna5 enhances morphine reward in female mice.

The single nucleotide polymorphism (SNP) D398N (rs16969968) in CHRNA5, the gene encoding the α5 subunit of the nicotinic acetylcholine receptors (nAChR), has been associated with both nicotine and opiate dependence in human populations. Expression of this SNP on presynaptic VTA dopaminergic (DA) neurons is known to cause a reduction in calcium signaling, leading to alterations in transmitter signaling and altered responses to drugs of abuse. To examine the impact of the Chrna5 SNP on opiate reward and underlying dopaminergic mechanisms, mice harboring two copies of the risk-associated allele (Chrna5 A/A) at a location equivalent to human rs16969968 were generated via CRISPR/cas9 genome editing.

Changing Meal Sequence Affects Glucose Excursions in Gestational Diabetes Mellitus.

Studies on nutrient sequences during meals suggest that consuming carbohydrates last lowers postprandial glucose excursions more than consuming carbohydrates first. However, this phenomenon has not been studied in gestational diabetes mellitus (GDM). Ten women with GDM consumed the same caloric foods in different sequences over five successive days: (A) dish first, followed by carbohydrate and soup last; (B) carbohydrate first, followed by dish and soup last; (C) soup first, followed by dish and carbohydrate last; (D) three meals a day ad libitum; and (E) six meals a day as ad libitum.

Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories.

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus.

LINC00899 promotes osteogenic differentiation by targeting miR-374a and RUNX2 expression.

Accumulating researches indicate that long non-coding RNAs (lncRNAs) participate in human bone mesenchymal stem cells (hBMSCs) osteogenic differentiation. The present study aimed to investigate the underlying molecular mechanisms of long intergenic non-protein coding RNA 899 (LINC00899) in osteoporosis. Therefore, reverse transcription-quantitative PCR was performed to evaluate the expression levels of LINC00899, microRNA (miR)-374a and runt-related transcription factor 2 (RUNX2) in clinical tissues and hBMSCs.

LncRNA XIST Promotes Atherosclerosis by Regulating miR-599/TLR4 Axis.

Long noncoding RNAs (lncRNAs) have been reported to be implicated in various biological and pathological processes. However, the function and mechanism of XIST in vascular smooth muscle cells (VSMCs) remains unknown. The levels of XIST, miR-599, and TLR4 were tested by RT-qPCR.

Dopamine receptor activity participates in hippocampal synaptic plasticity associated with novel object recognition.

Physiological and behavioral evidence supports that dopamine (DA) receptor signaling influences hippocampal function. While several recent studies examined how DA influences CA1 plasticity and learning, there are fewer studies investigating the influence of DA signaling to the dentate gyrus. The dentate gyrus receives convergent cortical input through the perforant path fiber tracts and has been conceptualized to detect novelty in spatial memory tasks.

Dopamine Regulates Aversive Contextual Learning and Associated In Vivo Synaptic Plasticity in the Hippocampus.

Dopamine release during reward-driven behaviors influences synaptic plasticity. However, dopamine innervation and release in the hippocampus and its role during aversive behaviors are controversial. Here, we show that in vivo hippocampal synaptic plasticity in the CA3-CA1 circuit underlies contextual learning during inhibitory avoidance (IA) training.

Dopamine and norepinephrine receptors participate in methylphenidate enhancement of in vivo hippocampal synaptic plasticity.

Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g.

Dopamine D1 and D5 receptors modulate spike timing-dependent plasticity at medial perforant path to dentate granule cell synapses.

Although evidence suggests that DA modulates hippocampal function, the mechanisms underlying that dopaminergic modulation are largely unknown. Using perforated-patch electrophysiological techniques to maintain the intracellular milieu, we investigated how the activation of D1-type DA receptors regulates spike timing-dependent plasticity (STDP) of the medial perforant path (mPP) synapse onto dentate granule cells. When D1-type receptors were inhibited, a relatively mild STDP protocol induced LTP only within a very narrow timing window between presynaptic stimulation and postsynaptic response.

Functional rundown of gamma-aminobutyric acid(A) receptors in human hypothalamic hamartomas.

Objective: Human hypothalamic hamartomas (HHs) are highly associated with treatment-resistant gelastic seizures. HHs are intrinsically epileptogenic, although the basic cellular mechanisms responsible for seizure activity are unknown. Altered gamma-aminobutyric acid (GABA) function can contribute to epileptogenesis in humans and animal models.

Functional nicotinic acetylcholine receptors containing α6 subunits are on GABAergic neuronal boutons adherent to ventral tegmental area dopamine neurons.

Diverse nicotinic acetylcholine receptor (nAChR) subtypes containing different subunit combinations can be placed on nerve terminals or soma/dendrites in the ventral tegmental area (VTA). nAChR α6 subunit message is abundant in the VTA, but α6*-nAChR cellular localization, function, pharmacology, and roles in cholinergic modulation of dopaminergic (DA) neurons within the VTA are not well understood. Here, we report evidence for α6β2*-nAChR expression on GABA neuronal boutons terminating on VTA DA neurons.

Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area.

Systemic exposure to nicotine induces glutamatergic synaptic plasticity on dopamine (DA) neurons in the ventral tegmental area (VTA), but mechanisms are largely unknown. Here, we report that single, systemic exposure in rats to nicotine (0.17 mg/kg free base) increases the ratio of DA neuronal currents mediated by AMPA relative to NMDA receptors (AMPA/NMDA ratio) assessed 24 h later, based on slice-patch recording.

Tetrahydroberberine blocks ATP-sensitive potassium channels in dopamine neurons acutely-dissociated from rat substantia nigra pars compacta.

Tetrahydroberberine (THB) exhibits neuroprotective effects but its targets and underlying mechanisms are largely unknown. Emerging evidence indicates that ATP-sensitive potassium (K(ATP)) channels in the substantia nigra pars compacta (SNc) promote Parkinson disease (PD) pathogenesis, thus blocking K(ATP) channels may protect neurons against neuronal degeneration. In the present study, we tested a hypothesis that THB blocks K(ATP) channels in dopaminergic (DA) neurons acutely dissociated from rat SNc.

Exposure of nicotine to ventral tegmental area slices induces glutamatergic synaptic plasticity on dopamine neurons.

Nicotine promotes glutamatergic synaptic plasticity in dopaminergic (DA) neurons in the ventral tegmental area (VTA), which is thought to be an important mechanism underlying nicotine reward. However, it is unclear whether exposure of nicotine alone to VTA slice is sufficient to increase glutamatergic synaptic strength on DA neurons and which nicotinic acetylcholine receptor (nAChR) subtype mediates this effect. Here, we report that the incubation of rat VTA slices with 500 nM nicotine induces glutamatergic synaptic plasticity in DA neurons.

The anticonvulsive drug lamotrigine blocks neuronal {alpha}4{beta}2 nicotinic acetylcholine receptors.

Lamotrigine (LTG), an anticonvulsive drug, is often used for the treatment of a variety of epilepsies. In addition to block of sodium channels, LTG may act on other targets to exert its antiepileptic effect. In the present study, we evaluated the effects of LTG on neuronal nicotinic acetylcholine receptors (nAChRs) using the patch-clamp technique on human α4β2-nAChRs heterologously expressed in the SH-EP1 cell line and on native α4β2-nAChRs in dopaminergic (DA) neurons in rat ventral tegmental area (VTA).

Nicotine modulates GABAergic transmission to dopaminergic neurons in substantia nigra pars compacta.

Aim: Dopaminergic neurons in the substantia nigra pars compacta (SNc) play important roles in motor control and drug addiction. As the major afferent, GABAergic innervation controls the activity of SNc dopaminergic neurons. Although it is clear that nicotine modulates SNc dopaminergic neurons by activating subtypes of somatodendritic nicotinic acetylcholine receptors (nAChRs), the detailed mechanisms of this activation remain to be addressed.

Mysterious alpha6-containing nAChRs: function, pharmacology, and pathophysiology.

Neuronal nicotinic acetylcholine receptors (nAChRs) are the superfamily of ligand-gated ion channels and widely expressed throughout the central and peripheral nervous systems. nAChRs play crucial roles in modulating a wide range of higher cognitive functions by mediating presynaptic, postsynaptic, and extrasynaptic signaling. Thus far, nine alpha (alpha2-alpha10) and three beta (beta2, beta3, and beta4) subunits have been identified in the CNS, and these subunits assemble to form a diversity of functional nAChRs.

Subventricular zone neural progenitors from rapid brain autopsies of elderly subjects with and without neurodegenerative disease.

In mice and in young adult humans, the subventricular zone (SVZ) contains multipotent, dividing astrocytes, some of which, when cultured, produce neurospheres that differentiate into neurons and glia. It is unknown whether the SVZ of very old humans has this capacity. Here, we report that neural stem/progenitor cells can also be cultured from rapid autopsy samples of SVZ from elderly human subjects, including patients with age-related neurologic disorders.

Distinctive nicotinic acetylcholine receptor functional phenotypes of rat ventral tegmental area dopaminergic neurons.

Dopaminergic (DAergic) neuronal activity in the ventral tegmental area (VTA) is thought to contribute generally to pleasure, reward, and drug reinforcement and has been implicated in nicotine dependence. nAChRs expressed in the VTA exhibit diverse subunit compositions, but the functional and pharmacological properties are largely unknown. Here, using patch-clamp recordings in single DAergic neurons freshly dissociated from rat VTA, we clarified three functional subtypes of nAChRs (termed ID, IID and IIID receptors) based on whole-cell current kinetics and pharmacology.

GABA(A) receptor-mediated excitation in dissociated neurons from human hypothalamic hamartomas.

The cellular mechanisms underlying intrinsic epileptogenesis in human hypothalamic hamartoma (HH) are unknown. We previously reported that HH tissue is composed predominantly of GABAergic neurons, but how GABAergic-neuron-rich HH tissue is intrinsically epileptogenic is unclear. Here, we tested the hypotheses that some HH neurons exhibit immature features and that GABA excites these neurons via activation of GABA(A) receptors (GABA(A)Rs).

alpha-Chloralose diminishes gamma oscillations in rat hippocampal slices.

alpha-Chloralose is an anesthetic characterized by its ability to maintain animals in physiological conditions though immobilized and anesthetized. In addition, alpha-chloralose induces a loss of consciousness with little influence on either pain response or cardiovascular reflexes. The pharmacological mechanisms of alpha-chloralose's actions are poorly understood.

The neuropharmacology of (-)-stepholidine and its potential applications.

(-)-Stepholidine (SPD), a natural product isolated from the Chinese herb Stephania, possesses dopamine (DA) D1 partial agonistic and D2 antagonistic properties in the nigrostriatal and mesocorticolimbic DAergic pathways. These unique dual effects have suggested that SPD can effectively restore previously imbalanced functional linkage between D1 and D2 receptors under schizophrenic conditions, in which, SPD improves both the negative and positive symptoms of schizophrenia. SPD also relieves the motor symptoms of Parkinson's disease (PD) when co-administered with Levodopa.

Electrophysiological properties and subunit composition of GABAA receptors in patients with gelastic seizures and hypothalamic hamartoma.

Abnormalities in GABA(A) receptor structure and/or function have been associated with various forms of epilepsy in both humans and animals. Whether this is true for patients with gelastic seizures and hypothalamic hamartoma (HH) is unknown. In this study, we characterized the pharmacological properties and native subunit composition of GABA(A) receptors on acutely dissociated single neurons from surgically resected HH tissues using patch-clamp, immunocytochemical, and RT-PCR techniques.

Iptakalim modulates ATP-sensitive K(+) channels in dopamine neurons from rat substantia nigra pars compacta.

Iptakalim, a novel cardiovascular ATP-sensitive K(+) (K(ATP)) channel opener, exerts neuroprotective effects on dopaminergic (DA) neurons against metabolic stress-induced neurotoxicity, but the mechanisms are largely unknown. Here, we examined the effects of iptakalim on functional K(ATP) channels in the plasma membrane (pm) and mitochondrial membrane using patch-clamp and fluorescence-imaging techniques. In identified DA neurons acutely dissociated from rat substantia nigra pars compacta (SNc), both the mitochondrial metabolic inhibitor rotenone and the sulfonylurea receptor subtype (SUR) 1-selective K(ATP) channel opener (KCO) diazoxide induced neuronal hyperpolarization and abolished action potential firing, but the SUR2B-selective KCO cromakalim exerted little effect, suggesting that functional K(ATP) channels in rat SNc DA neurons are mainly composed of SUR1.