Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration.

Converging evidence demonstrates an important role for gangliosides in brain function and neurodegenerative diseases. Exogenous GM1 is broadly neuroprotective, including in rodent, feline, and primate models of Parkinson's disease, and has shown positive effects in clinical trials. We and others have shown that inhibition of the ganglioside biosynthetic enzyme GD3 synthase (GD3S) increases endogenous levels GM1 ganglioside.

Protection genes in nucleus accumbens shell affect vulnerability to nicotine self-administration across isogenic strains of adolescent rat.

Classical genetic studies show the heritability of cigarette smoking is 0.4-0.6, and that multiple genes confer susceptibility and resistance to smoking.

Full-gestational exposure to nicotine and ethanol augments nicotine self-administration by altering ventral tegmental dopaminergic function due to NMDA receptors in adolescent rats.

In adult rats, we have shown full-gestational exposure to nicotine and ethanol (Nic + EtOH) augmented nicotine self-administration (SA) (increased nicotine intake) compared to pair-fed (PF) offspring. Therefore, we hypothesized that full-gestational exposure to Nic + EtOH disrupts control of dopaminergic (DA) circuitry by ventral tegmental area (VTA) NMDA receptors, augmenting nicotine SA and DA release in nucleus accumbens (NAcc) of adolescents. Both NAcc DA and VTA glutamate release were hyper-responsive to intra-VTA NMDA in Nic + EtOH offspring versus PF (p = 0.

Fostering itself increases nicotine self-administration in young adult male rats.

Rationale: In gestational exposure studies, a fostered group is frequently used to control for drug-induced maternal effects. However, fostering itself has varying effects depending on the parameters under investigation

Objectives: This study was designed to assess whether maternal behavior contributed to enhanced acquisition (higher number of bar presses compared to controls) of nicotine self-administration (SA) displayed by offspring with gestational nicotine and ethanol (Nic+EtOH) exposure.

Methods: Offspring were exposed to Nic+EtOH throughout full gestation, that is, gestational days (GD) GD2-20 and during postnatal days 2-12 (PN2-12), the rodent third trimester equivalent of human gestation during which rapid brain growth and synaptogenesis occur.

Genetic factors control nicotine self-administration in isogenic adolescent rat strains.

Adult cigarette smokers usually become dependent on cigarettes during adolescence. Despite recent advances in addiction genetics, little data delineates the genetic factors that account for the vulnerability of humans to smoke tobacco. We studied the operant nicotine self-administration (SA) behavior of six inbred strains of adolescent male rats (Fisher 344, Brown Norway, Dark Agouti, Spontaneous Hypertensive Rat, Wistar Kyoto and Lewis) and six selected F1 hybrids.

Genome-Wide Gene Expression Profiling of Nucleus Accumbens Neurons Projecting to Ventral Pallidum Using both Microarray and Transcriptome Sequencing.

The cellular heterogeneity of brain poses a particularly thorny issue in genome-wide gene expression studies. Because laser capture microdissection (LCM) enables the precise extraction of a small area of tissue, we combined LCM with neuronal track tracing to collect nucleus accumbens shell neurons that project to ventral pallidum, which are of particular interest in the study of reward and addiction. Four independent biological samples of accumbens projection neurons were obtained.

Social interaction promotes nicotine self-administration with olfactogustatory cues in adolescent rats.

Cigarette smoking is a social behavior. Smoking is also accompanied by distinctive gustatory and olfactory stimulation. However, none of these factors affecting nicotine intake are modeled in existing preclinical studies.

Genotype-dependent effects of adolescent nicotine exposure on dopamine functional dynamics in the nucleus accumbens shell in male and female mice: a potential mechanism underlying the gateway effect of nicotine.

Rationale: The tendency to use cocaine is determined by genetic and environmental effects across the lifespan. One critical environmental effect is early drug exposure, which is both driven by and interacts with genetic background. The mesoaccumbens dopamine system, which is critically involved in the rewarding properties of drugs of abuse, undergoes significant development during adolescence, and thus may be at particular risk to repeated nicotine exposure during this period, thereby establishing vulnerability for subsequent adult psychostimulant use.

Kv3-like potassium channels are required for sustained high-frequency firing in basal ganglia output neurons.

The GABA projection neurons in the substantial nigra pars reticulata (SNr) are key output neurons of the basal ganglia motor control circuit. These neurons fire sustained high-frequency, short-duration spikes that provide a tonic inhibition to their targets and are critical to movement control. We hypothesized that a robust voltage-activated K(+) conductance that activates quickly and resists inactivation is essential to the remarkable fast-spiking capability in these neurons.

Nicotine self-administration differentially modulates glutamate and GABA transmission in hypothalamic paraventricular nucleus to enhance the hypothalamic-pituitary-adrenal response to stress.

The mechanisms by which chronic nicotine self-administration augments hypothalamo-pituitary-adrenal (HPA) responses to stress are only partially understood. Nicotine self-administration alters neuropeptide expression in corticotropin-releasing factor (CRF) neurons within paraventricular nucleus (PVN) and increases PVN responsiveness to norepinephrine during mild footshock stress. Glutamate and GABA also modulate CRF neurons, but their roles in enhanced HPA responsiveness to footshock during chronic self-administration are unknown.

An ultra-short dopamine pathway regulates basal ganglia output.

Substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus critical for movement control. Its GABA-containing projection neurons intermingle with nigral dopamine (DA) neuron dendrites. Here we show that SNr GABA neurons coexpress dopamine D(1) and D(5) receptor mRNAs and also mRNA for TRPC3 channels.

Nicotine self-administration differentially regulates hypothalamic corticotropin-releasing factor and arginine vasopressin mRNAs and facilitates stress-induced neuronal activation.

Acute nicotine is a potent stimulus for activation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, while chronic nicotine self-administration (SA) desensitizes the ACTH response to self-administered nicotine but cross-sensitizes to mild footshock stress (mFSS). To identify underlying mechanisms, we investigated (1) the effects of chronic nicotine SA on the coexpression of corticotropin-releasing factor (CRF) and arginine vasopressin (AVP) mRNAs, the primary hypothalamic neuropeptides regulating ACTH release, in the parvocellular division of paraventricular nucleus (pcPVN), and (2) mFSS-induced activation of these neurons during nicotine SA. Adult male Sprague Dawley rats were given 23 h/d unlimited access to self-administer nicotine (0.

Constitutively active TRPC3 channels regulate basal ganglia output neurons.

A hallmark of the GABA projection neurons of the substantia nigra pars reticulata (SNr), a key basal ganglia output nucleus, is its depolarized membrane potential and rapid spontaneous spikes that encode the basal ganglia output. Parkinsonian movement disorders are often associated with abnormalities in SNr GABA neuron firing intensity and/or pattern. A fundamental question remains regarding the molecular identity of the ion channels that drive these neurons to a depolarized membrane potential.

Combined exposure to nicotine and ethanol throughout full gestation results in enhanced acquisition of nicotine self-administration in young adult rat offspring.

Rationale: Epidemiological evidence shows positive correlation between either maternal cigarette smoking or alcohol consumption on subsequent drug-taking behavior in offspring. However, the consequences of full gestational exposure to both drugs have not been studied experimentally despite concurrent use frequently reported among women of childbearing age. Such comorbid gestational drug exposure may increase susceptibility to acquiring cigarette smoking (i.

Guidelines on nicotine dose selection for in vivo research.

Rationale: This review provides insight for the judicious selection of nicotine dose ranges and routes of administration for in vivo studies. The literature is replete with reports in which a dosaging regimen chosen for a specific nicotine-mediated response was suboptimal for the species used. In many cases, such discrepancies could be attributed to the complex variables comprising species-specific in vivo responses to acute or chronic nicotine exposure.

Acquisition of nicotine self-administration in adolescent rats given prolonged access to the drug.

As most human tobacco use begins during adolescence and ongoing development of the adolescent central nervous system could affect acquisition of nicotine self-administration (SA), our established rat SA procedure was modified to study adolescent acquisition of SA with prolonged access to nicotine (23 h/day). Postnatal age 43-45 female Lewis rats, without prior shaping, conditioning, or food deprivation, were housed in operant chambers equipped with two levers; pressing the active lever triggered an i.v.

Prenatal alcohol exposure delays the development of the cortical barrel field in neonatal rats.

In-utero alcohol exposure produces sensorimotor developmental abnormalities that often persist into adulthood. The rodent cortical barrel field associated with the representation of the body surface was used as our model system to examine the effect of prenatal alcohol exposure (PAE) on early somatosensory cortical development. In this study, pregnant female rats were intragastrically gavaged daily with high doses of alcohol (6 gm/kg body weight) throughout the first 20 days of pregnancy.

Prenatal alcohol exposure (PAE) reduces the size of the forepaw representation in forepaw barrel subfield (FBS) cortex in neonatal rats: relationship between periphery and central representation.

Prenatal alcohol exposure (PAE) alters limb development that may lead to structural and functional abnormalities of the limb reported in children diagnosed with Fetal Alcohol Spectrum Disorder. To determine whether PAE alters the central representation of the forelimb we used the rodent barrel cortex as our model system where it was possible to visualize and quantitatively measure the size of the forepaw representation in the forepaw barrel subfield (FBS) in first somatosensory cortex. In the present study, we examined the effects of PAE on pattern and size of the forepaw and forepaw representation in FBS in neonatal rats at gestational day 32 that corresponds to postnatal day 9.

Gestational nicotine exposure reduces nicotinic cholinergic receptor (nAChR) expression in dopaminergic brain regions of adolescent rats.

Children of women who smoked during pregnancy are at increased risk of dependence when smoking is initiated during adolescence. We previously reported that gestational nicotine exposure attenuated dopamine release induced by nicotine delivered during adolescence. In this study, we determined the effects of gestational nicotine exposure on nicotinic cholinergic receptor (nAChR) expression.

Prenatal alcohol exposure alters the size, but not the pattern, of the whisker representation in neonatal rat barrel cortex.

Maternal alcohol exposure results in a variety of neurodevelopmental abnormalities that include cognitive and sensorimotor dysfunctions that often persist into adulthood. Many reports of central nervous system disturbances associated within a clinical diagnosis of fetal alcohol syndrome point toward disturbances in central information processing. In this study, we used the rat barrel field cortex as a model system to examine the effects of prenatal alcohol exposure (PAE) on the organization and size of the large whisker representation in layer IV of the posteromedial barrel subfield (PMBSF) in somatosensory cortex.

Expression of three carnitine palmitoyltransferase-I isoforms in 10 regions of the rat brain during feeding, fasting, and diabetes.

Inhibition of carnitine palmitoyltransferase-I (CPT-I) activity in the brain has been shown to decrease food intake in rats. We examined the expression of mRNA encoding all three known CPT-I isoforms (alpha, beta, and gamma in 10 different major regions of the rat brain in normal, chow-fed rats, in fasting rats, and in insulin-dependent diabetic rats. Compared with the effects of fasting and diabetes on CPT-I mRNA in the liver and heart, there was either less effect or no effect depending on the particular brain region examined.

Role of the cyclic AMP-dependent protein kinase in homologous resensitization of the beta1-adrenergic receptor.

A fundamental question in biology is how the various motifs in G protein-coupled receptors participate in the divergent functions orchestrated by these molecules. Here we describe a fundamental role for a serine residue at position 312 in the third intracellular loop of the human beta(1)-adrenergic receptor (beta(1)-AR) in endocytic recycling of the agonist-internalized receptor. In receptor recycling experiments that were monitored by confocal microscopy, the agonist-internalized wild-type (WT) beta(1)-AR recycled with a t(0.

Gestational nicotine exposure attenuates nicotine-stimulated dopamine release in the nucleus accumbens shell of adolescent Lewis rats.

The effects of chronic gestational exposure to nicotine on the nucleus accumbens dopamine response to acute nicotine were determined during adolescence (postnatal day 29-36) in cross-fostered and noncross-fostered Lewis rats. In both males and females, gestational nicotine exposure diminished the adolescent nucleus accumbens dopamine response to 0.07 mg/kg nicotine i.

Norepinephrine release in amygdala of rats during chronic nicotine self-administration: an in vivo microdialysis study.

The essential role of the amygdala in learning and memory, including cue-associated learning, is influenced by local release of norepinephrine (NE). The current study investigated changes in amygdaloid NE secretion in rats learning to self-administer nicotine in an unlimited access model (23 h/day). In vivo microdialysis of NE was performed for 9 h intervals during three phases of nicotine self-administration: acquisition (day 1); early maintenance, when self-administration rates first stabilized (day 8.

Chronic self-administration of nicotine in rats impairs T cell responsiveness.

Chronic exposure of rodents to nicotine via subcutaneously or intracerebroventricularly implanted miniosmotic pumps affects T cell function. However, this method of continuous nicotine administration does not replicate the self-motivated administration of nicotine in human smokers. To determine whether nicotine impairs the immune system under conditions pertinent to human smokers, we investigated the T cell responsiveness of male Lewis rats self-administering (SA) nicotine (0.