Effects of nicotine on microvascular responsiveness after nicotine satiety versus overnight nicotine abstinence

[no abstract available

Peripheral and central effects of smokeless tobacco on exercise endurance in men

Introduction A proliferation of nicotine use in the sport environment has been observed in recent years mainly as smokeless tobacco (Zandonai et al., 2013). Nicotine has been listed in World Anti-doping Agency’s Monitoring Program from 2012 to 2015 in order to detect potential patterns of abuse. The aim of this study was to investigate the effects of Snus (SS), an oral smokeless tobacco, on the perception of fatigue during aerobic exercise to TTE. Methods The study was a double-blind placebo controlled (SP) crossover design. Fourteen healthy male non-smokers were recruited. Subjects were studied during three sessions on cycle-ergometer: experimental session 1 (Exp1) consisted in an incremental exercise test to determine maximal aerobic power (Wmax); Exp2 and Exp3 consisted in exercise at 65% Wmax until exhaustion in SS or SP conditions. During the Exp2 and Exp3, muscle and cerebral oxygenation by means of NIRS (nearinfrared spectroscopy) and global rating of perceived exertion (RPE) were recorded. Before and after all experiments, the Profile of Mood of State questionnaire (POMS) was administered to subjects. Subjects were then tested by means of Transcranial Magnetic Stimulation (TMS) to assess changes in cortico-motor excitability due to the prolonged exercise. Results Time to exhaustion (TTE) was not significant difference (64.4 ± 41.5 min SS; 51.6 ± 17.2 min SP) (19.2%) in paired Student’s t-test. RPE in the first 30 minutes during both of the sessions showed a significant difference after 10 minutes from start exercise. POMS questionnaire values did not show any significant differences under both conditions (SS, SP). We found significant differences in the cerebral and muscular tissues oxygenation levels in the first 30 minutes of the exercise during SS and SP tests. In particular, at cerebral level, tissue oxygenation index was significantly larger in SS than in SP from the 10th to 30th min of exercise. Conclusion The study showed that the SS effect, compared to placebo condition, could not be an improvement of fatigue during an endurance exercise until exhaustion despite of an increase in tissue muscular and cerebral oxygenation. These data supported the hypothesis of a major activity induced by nicotine as a central stimulator (Mundel and Jones, 2006). References Mundel T, Jones DA. (2006). Effect of transdermal nicotine administration on exercise endurance in men. Exp Physiol, 91, 705- 713 Zandonai T, Baraldo M, Franceschi L, Zappamiglio T, Chiamulera C. (2013). Effects of smokeless tobacco (snus) administration on exercise endurance in men. SRNT Annual Meeting Boston MA (USA) p 16

Ketamine Self-Administration Reduces the Homeostasis of the Glutamate Synapse in the Rat Brain

Ketamine is a non-competitive antagonist of the NMDA glutamate receptor with psychotomimetic and reinforcing properties, although recent work has pointed out its antidepressant action following acute exposure. Our aim was to investigate the expression of crucial components of the glutamate synapse following chronic ketamine self-administration (S/A), focusing our attention on medial prefrontal cortex (mPFC) and hippocampus (Hip), two brain regions involved in compulsive drug-seeking and drug-related cognitive disorders. Rats self-administered ketamine at a sub-anesthetic dose for 5\u20136 weeks and were sacrificed 24 h after the last drug exposure. We found a general downregulation of glutamate receptor expression that was brain region-dependent. In fact, in the mPFC, we found reduced expression of NMDA receptor subunits, whereas AMPA receptor protein levels were reduced in Hip; of note, specific scaffolding proteins of NMDA and AMPA receptors were also reduced in mPFC and Hip, respectively. Moreover, the metabotropic mGluR5 receptor was similarly downregulated in these brain regions. These findings reveal a dynamic impairment of glutamate homeostasis in the mPFC and Hip that may represent a signature of long-term exposure to ketamine S/A. Further, this decrement, similarly observed in humans and animal models of schizophrenia may represent a specific feature of the human disease endophenotype

The metaplastic effects of NMDA receptors blockade on reactivation of instrumental memories in rats

Metaplasticity, defined as the plasticity of synaptic plasticity, could affect learning and memory at different neural levels. It was hypothesized that metaplasticity changes on glutamate receptors may affect memory destabilization, promoting or preventing reconsolidation. We investigated the metaplastic effect of NMDA channel blocker MK-801 on sucrose instrumental memory reconsolidation in a behavioural rat model associated to the assessment of molecular markers of metaplasticity, memory retrieval, destabilization and reconsolidation. Following instrumental conditioning and forced abstinence, rats were intraperitoneally treated with MK-801 or vehicle 24\u202fh before the exposure to memory retrieval or not-retrieval. Separate groups were tested for in-vivo extinction of responding (24\u202fh and 7\u202fd after reactivation) or ex-vivo assessment of transcription factor Zif268 and ribosomal protein rpS6 phosphorylation in nucleus accumbens (NAc) and amygdala (Amy). MK-801 significantly inhibited instrumental responding at extinction test, suggesting reconsolidation blockade of instrumental memory. The decrease of Zif268 and phosphorylated-rpS6 levels in NAc and Amy in MK-801/Retrieval vs. Vehicle/Retrieval group supported the behavioural findings. An increase of GluN2B, GluA1 and mGluR5 in NAc, and GluN2B in Amy, 24\u202fh after MK-801 indicated the trigger of associated metaplastic changes. Our findings show that metaplastic changes induced by NMDA receptors blockade affected sucrose instrumental memory retrieval as shown by both behavioural and molecular changes. We hypothesize that these findings however suggested a switch to extinction rather than a reconsolidation

Nicotinic acetylcholine receptors in the mesolimbic pathway: primary role of ventral tegmental area alpha6beta2 receptors in mediating systemic nicotine effects on dopamine release, locomotion, and reinforcement

\u3b16* nicotinic acetylcholine receptors (nAChRs) are highly and selectively expressed by mesostriatal dopamine (DA) neurons. These neurons are thought to mediate several behavioral effects of nicotine, including locomotion, habit learning, and reinforcement. Yet the functional role of \u3b16* nAChRs in midbrain DA neurons is mostly unknown. The aim of this study was to determine the composition and in vivo functional role of \u3b16* nAChR in mesolimbic DA neurons of male rats. Immunoprecipitation and immunopurification techniques coupled with cell-specific lesions showed that the composition of \u3b16* nAChR in the mesostriatal system is heterogeneous, with (non-\u3b14)\u3b16\u3b22* being predominant in the mesolimbic pathway and \u3b14\u3b16\u3b22* in the nigrostriatal pathway. We verified whether \u3b16* receptors mediate the systemic effects of nicotine on the mesolimbic DA pathway by perfusing the selective antagonists \u3b1-conotoxin MII (CntxMII) (\u3b13/\u3b16\u3b22* selective) or \u3b1-conotoxin PIA (CntxPIA) (\u3b16\u3b22* selective) into ventral tegmental area (VTA). The intra-VTA perfusion of CntxMII or CntxPIA markedly decreased systemic nicotine-elicited DA release in the nucleus accumbens and habituated locomotion; the intra-VTA perfusion of CntxMII also decreased the rate of nicotine infusion in the maintenance phase of nicotine, but not of food, self-administration. Overall, the results of these experiments show that the \u3b16\u3b22* nAChRs expressed in the VTA are necessary for the effects of systemic nicotine on DA neuron activity and DA-dependent behaviors such as locomotion and reinforcement, and suggest that \u3b16\u3b22*-selective compounds capable of crossing the blood\u2013brain barrier may affect the addictive properties of nicotine and therefore be useful in the treatment of tobacco dependence

Novel stem/progenitor cells with neuronal differentiation potential reside in the leptomeningeal niche

Stem cells capable of generating neural differentiated cells are recognized by the expression of nestin and reside in specific regions of the brain, namely, hippocampus, subventricular zone and olfactory bulb. For other brain structures, such as leptomeninges, which contribute to the correct cortex development and functions, there is no evidence so far that they may contain stem/precursor cells. In this work, we show for the first time that nestin-positive cells are present in rat leptomeninges during development up to adulthood. The newly identified nestin-positive cells can be extracted and expanded in vitro both as neurospheres, displaying high similarity with subventricular zone-derived neural stem cells, and as homogeneous cell population with stem cell features. In vitro expanded stem cell population can differentiate with high efficiency into excitable cells with neuronal phenotype and morphology. Once injected into the adult brain, these cells survive and differentiate into neurons, thus showing that their neuronal differentiation potential is operational also in vivo. In conclusion, our data provide evidence that a specific population of immature cells endowed of neuronal differentiation potential is resident in the leptomeninges throughout the life. As leptomeninges cover the entire central nervous system, these findings could have relevant implications for studies on cortical development and for regenerative medicine applied to neurological disorders. \ua9 2009 The Authors Journal compilatio

Novel stem/progenitor cells with neuronal differentiation potential reside in the leptomeningeal niche

Abstract Stem cells capable of generating neural differentiated cells are recognized by the expression of nestin and reside in specific regions of the brain, namely hippocampus, subventricular zone (SVZ), and olfactory bulb. For other brain structures, such as leptomeninges, which contribute to the correct cortex development and functions, there is no evidence so far that they may contain stem/precursor cells. In this work, we show for the first time that nestin-positive cells are present in rat leptomeninges during development up to adulthood. The newly identified nestin-positive cells can be extracted and expanded in vitro both as neurospheres, displaying high similarity with SVZ-derived neural stem cells, and as homogeneous cell population with stem cell features. In vitro expanded stem cell population can differentiate with high efficiency into excitable cells with neuronal phenotype and morphology. Once injected into adult brain, these cells survive and differentiate into neurons, thus showing that their neuronal differentiation potential is operational also in vivo. In conclusion, our data provide evidence that a specific population of immature cells endowed of neuronal differentiation potential is resident in the leptomeninges throughout the life. As leptomemniges cover the entire central nervous system, these findings could have relevant implications for studies on cortical development and for regenerative medicine applied to neurological disorders

Memantine reduces consumption of highly palatable food in a rat model of binge eating

Excessive consumption of highly palatable food has been linked to the development of eating disorders and obesity, and can be modeled in non-food-deprived rats by offering them a limited (2-h daily) access to an optional dietary fat. Since the glutamatergic system has recently emerged as a viable target for binge-eating medication development, we compared the effects of subchronic treatment with glutamatergic receptor antagonists to the effects of a reference appetite-suppressing agent sibutramine on highly palatable food (lard) and normal chow intake. In three separate experiments, the consumption of a standard laboratory chow and lard were measured during 12 days of medication treatment and for 6 days afterwards. Generalized estimating equations analysis demonstrated that sibutramine (7.5 mg/kg, PO) significantly decreased lard consumption, with a concurrent increase in chow consumption. Sibutramine effects disappeared after treatment discontinuation. The NMDA receptor antagonist memantine (5 mg/kg, IP) significantly decreased lard consumption and increased chow consumption, comparable to effects of sibutramine; however, memantine’s effects persisted after treatment discontinuation. The effects of the mGluR5 antagonist MTEP (7.5 mg/kg, IP) on food consumption were in the same direction as seen with memantine, but the observed differences were not significant. In an additional control experiment, sibutramine and memantine reduced unlimited (24 h) chow intake during the treatment phase. Present results provide evidence that glutamatergic neurotransmission might be involved in the regulation of excessive consumption of highly palatable foods, and suggest that NMDA receptor may be an attractive target for developing obesity and disordered eating pharmacotherapies