Nicotine Administration Research Articles

Adolescent nicotine administration impacts working memory and reversal learning but not cognitive flexibility.

There has been increased interest in early exposure to nicotine through tobacco products and vaping specifically as it relates to addiction, yet fewer studies have focused on whether behavioral effects resulting from early nicotine exposure may persist into adulthood. Our experiments tested the hypothesis that exposure to nicotine during adolescence would impair selective aspects of behavioral cognition in rodents in adulthood. Male and female adolescent rats received either nicotine (0.4mg/kg) or vehicle injections (intraperitoneal) once daily for 10 days (PND 29-38) followed by a washout period before behavioral testing. Animals were followed in a longitudinal design and evaluated on a battery of both behavioral and cognitive tasks during adulthood (PND 90+) that included locomotor activity, working memory (novel object recognition), cognitive flexibility (attentional set-shifting task, ASST), and anxiety-like behaviors. Data suggested that subchronic exposure to nicotine during adolescence produced significant changes in working memory, in two reversal problems in the ASST, and in anxiety-related behaviors. Taken together these data may suggest that limited early exposure to nicotine may produce selective longer term impairments in cognitive and behavioral processes related to working memory and reversal learning.

Deconvolution of Systemic Pharmacokinetics Predicts Inhaled Aerosol Dosimetry of Nicotine

Absorption of inhaled compounds can occur from multiple sites based on upper and lower respiratory tract deposition, and clearance mechanisms leading to differential local and systemic pharmacokinetics. Deriving inhaled aerosol dosimetry and local tissue concentrations for nose-only exposure in rodents and inhaled products in humans is challenging. In this study we use inhaled nicotine as an example to identify regional respiratory tract deposition, absorption fractions, and their contribution toward systemic pharmacokinetics in rodents and humans. A physiologically based pharmacokinetic (PBPK) model was constructed to describe the disposition of nicotine and its major metabolite, cotinine. The model description for the lungs was simplified to include an upper respiratory tract region with active mucociliary clearance and a lower respiratory tract region. The PBPK model parameters such as rate of oral absorption, metabolism and clearance were fitted to the published nicotine and cotinine plasma concentrations post systemic administration and oral dosing. The fractional deposition of inhaled aerosol in the upper and lower respiratory tract regions was estimated by fitting the plasma concentrations. The model predicted upper respiratory tract deposition was 63.9% for nose-only exposure to nicotine containing nebulized aqueous aerosol in rats and 60.2% for orally inhaled electronic vapor product in humans. A marked absorption of nicotine from the upper respiratory tract and the gastrointestinal tract for inhaled aqueous aerosol contributed to the differential systemic pharmacokinetics in rats and humans. The PBPK model derived dosimetry shows that the current aerosol dosimetry models with their posteriori application using independent aerosol physicochemical characterization to predict aerosol deposition are insufficient and will need to consider complex interplay of inhaled aerosol evolutionary process. While the study highlights the needs for future research, it provides a preliminary framework for interpreting pharmacokinetics of inhaled aerosols to facilitate the analysis of in vivo exposure-responses for pharmacological and toxicological assessments.

Adolescent nicotine administration increases nicotinic acetylcholine receptor binding and functional connectivity in specific cortico-striatal-thalamic circuits.

Nicotine exposure is associated with regional changes in brain nicotinic acetylcholine receptors subtype expression patterns as a function of dose and age at the time of exposure. Moreover, nicotine dependence is associated with changes in brain circuit functional connectivity, but the relationship between such connectivity and concomitant regional distribution changes in nicotinic acetylcholine receptor subtypes following nicotine exposure is not understood. Although smoking typically begins in adolescence, developmental changes in brain circuits and nicotinic acetylcholine receptors following chronic nicotine exposure remain minimally investigated. Here, we combined in vitro nicotinic acetylcholine receptor autoradiography with resting state functional magnetic resonance imaging to measure changes in [3H]nicotine binding and α4ß2 subtype nicotinic acetylcholine receptor binding and circuit connectivity across the brain in adolescent (postnatal Day 33) and adult (postnatal Day 68) rats exposed to 6 weeks of nicotine administration (0, 1.2 and 4.8 mg/kg/day). Chronic nicotine exposure increased nicotinic acetylcholine receptor levels and induced discrete, developmental stage changes in regional nicotinic acetylcholine receptor subtype distribution. These effects were most pronounced in striatal, thalamic and cortical regions when nicotine was administered during adolescence but not in adults. Using these regional receptor changes as seeds, resting state functional magnetic resonance imaging identified dysregulations in cortico-striatal-thalamic-cortical circuits that were also dysregulated following adolescent nicotine exposure. Thus, nicotine-induced increases in cortical, striatal and thalamic nicotinic acetylcholine receptors during adolescence modifies processing and brain circuits within cortico-striatal-thalamic-cortical loops, which are known to be crucial for multisensory integration, action selection and motor output, and may alter the developmental trajectory of the adolescent brain. This unique multimodal study significantly advances our understanding of nicotine dependence and its effects on the adolescent brain.

Catechol-O-Methyltransferase Effects on Smoking: A Review and Proof of Concept of Sex-Sensitive Effects.

This article reviews recent research on how catechol-O-methyltransferase (COMT) may impact cigarette smoking behavior, and how effects may be sex-sensitive. Preliminary data are presented on sex-sensitive effects of COMT on response to short-term abstinence in individuals who smoke. Although research is mixed, functional variants in the COMT gene have been linked with smoking behavior, cessation outcomes and nicotine abstinence-related symptoms. Our proof-of-concept preliminary data from a human laboratory study of individuals who smoke cigarettes found that those with the high COMT enzyme activity genotype (Val/Val) reported more severe smoking urges and withdrawal symptoms following overnight abstinence than Met carriers. These effects were present in women, but not in men and were abstinent-dependent, in that they dissipated following nicotine administration. The preliminary data showing sex-sensitive pharmacogenetic effects may shed light on mechanisms contributing to sex differences in barriers to smoking cessation or potential sex-specific treatment options.

Additional studies on nicotine exposure in horses: Accurate quantification and elimination profiles of potential biomarkers in plasma and urine.

For the purpose of doping control, this is the first report of accurate quantification of four critical structural isomers of nicotine metabolites (trans-3'-hydroxycotinine, cis-3'-hydroxycotinine, 5'-hydroxycotinine, and N'-hydroxymethylnorcotinine) in equine plasma and urine for the establishment of their elimination profiles. Besides, the pharmacokinetic studies of trans-3'-hydroxycotinine and N'-hydroxymethylnorcotinine in equine plasma and urine are also presented for the first time. The accurate quantification methods of the aforementioned four structural isomers in horse plasma and urine were successfully developed and validated using the solid-phase extractions followed by liquid chromatography/tandem mass spectrometry analysis. Baseline chromatographic separation was achieved to completely differentiate these isomers, which shared the same selected reaction monitoring transition. Such methods were applied to post-administration samples obtained from the nicotine and tobacco leaf administration studies for the establishment of pharmacokinetic profiles. N'-Hydroxymethylnorcotinine could be quantified for the longest period, ranging from 48 to 72 h in plasma and 96 h in urine after a single administration of 250 mg of nicotine and an equivalent amount of nicotine in tobacco leaves. In terms of detection, both N'-hydroxymethylnorcotinine and trans-3'-hydroxycotinine could be detected up to the last sample collection time point (96 h), indicating that they are the most appropriate biomarkers for nicotine exposure. N'-Hydroxymethylnorcotinine and trans-3'-hydroxycotinine were detected longest in plasma and urine samples after both nicotine and tobacco leaf administrations, and N'-hydroxymethylnorcotinine was deemed most appropriate as a monitoring target due to its relatively higher abundance and slower elimination rate. These two biomarkers could also be used to differentiate sample contamination by tobacco products and genuine nicotine exposure to horse regardless of intentionality.

Impact of acute nicotine exposure on monoaminergic systems in adolescent and adult male and female rats

Adolescence is a period of risk for beginning tobacco addiction. Differential neural response to nicotine in adolescents vs. adults may help explain the increased vulnerability to nicotine self-administration seen with adolescent onset. We indexed the effects of acute nicotine ditartrate (0.4 mg/kg, salt weight) administration on dopamine (DA) and serotonin (5HT) as well as the DA metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in several brain regions (nucleus accumbens, striatum and frontal cortex) of 6-week old (adolescent) and 10-week old (young adult) Sprague-Dawley rats. When nicotine was administered DA concentrations in the accumbens were significantly higher in adults than in adolescents, whereas there was no age-related difference without nicotine. However neither age group showed a significant effect of nicotine vs. age-matched controls. DA turnover in the accumbens was significantly greater in adolescent females in response to nicotine, but adult females did not show this effect and neither did males of either age group. DA turnover in the striatum was significantly higher in adolescents than adults regardless of nicotine administration. In the frontal cortex, there was a more complex effect. Without nicotine, adult male rats had higher DA concentrations than adolescent males, whereas female rats did not differ from adolescent to adult ages. When given nicotine, the age effect was no longer seen in males. However, there was not a significant effect of nicotine vs. age-matched controls in either age group. No age or nicotine effects were seen in females. 5HT in the accumbens was significantly increased by nicotine administration in adults but not in adolescents. Altered neural responsivity of adolescents to nicotine-induced neural effects particularly in accumbens DA and 5HT may be related to the increased nicotine dose concentrations they self-administer.

The rat takes the cheese: a novel model of CFTR-dependent chronic bacterial airway infection

Pharmacological mechanisms involved in nicotine-induced seizures were investigated in mice by testing the ability of several nicotinic agonists in producing seizures after peripheral administration. In addition, nicotinic antagonists such as hexamethonium, mecamylamine, dihydro-β-erythroidine, and methyllycaconitine citrate (MLA) were used in combination with nicotine. We also examined the involvement of calcium channels, <i>N</i>-methyl-d-aspartate receptors, and nitric oxide formation in nicotine-induced seizures. Our results showed that the peripheral administration of nicotine produced seizures in a stereospecific and mecamylamine-sensitive manner. Nicotine-induced seizures are centrally mediated and involve the activation of α7 along with other nicotinic receptor subunits. Indeed, MLA, an α7-antagonist, blocked the effects of nicotine after peripheral and central administration. The extent of α4β2-receptor subtype involvement in nicotine-induced seizures was difficult to assess. On one hand, we observed that dihydro-β-erythroidine (a competitive antagonist) failed to block the effects of nicotine. In addition, a poor correlation was found between binding affinity for³H-nicotine-labeled sites (predominantly α4β2) and seizures potency for several nicotinic agonists. On the other hand, mecamylamine, a noncompetitive antagonist, blocked nicotine-induced seizures more potently than MLA. Furthermore, its potency in blocking seizures was in the same general dose range of other nicotinic effects that are not α7 mediated. These results suggest that this receptor subtype does not play a major role in nicotine-induced seizures. Our findings also suggest that nicotine enhances the release of glutamate either directly or indirectly (membrane depolarization that opens L-type calcium channels). Glutamate release in turn stimulates<i>N</i>-methyl-d-aspartate receptors, thus triggering the cascade of events leading to nitric oxide formation and possibly seizure production.

Mechanism of Electroacupuncture Analgesia on Nicotine Withdrawal-Induced Hyperalgesia in a Rat Model.

Purpose This study aimed to investigate the analgesic effect and mechanism of electroacupuncture (EA) in nicotine withdrawal-induced hyperalgesia rats. Methods Behavioral testing was conducted twice a week for 7 weeks during nicotine administration using von Frey filaments. Electroacupuncture at the bilateral “Zusanli” and “Taichong” points was applied daily for 3 days during nicotine withdrawal. Western blot analysis and immunohistology were used to determine expression levels of pain-related factors in the spinal cord and midbrain periaqueductal gray (PAG). Results Behavioral tests showed that electroacupuncture had a significant analgesic effect on nicotine withdrawal-induced hyperalgesic rats. Western blot results demonstrated that, in hyperalgesic rats, the expressions of nicotinic acetylcholine receptors (subunits: nAChR α7, α4, or β2) decreased in the spinal cord, nAChR α7, and β2 decreased in PAG. The proinflammatory factor cyclooxygenase 2 (COX2) and the activated microglia (ionized calcium-binding adaptor molecule 1, Iba1 positive cells) increased in the spinal cord and PAG compared to controls. After electroacupuncture treatment, nAChR α7 and nAChR β2 expressions increased significantly, and COX2 and Iba1 expressions decreased in the spinal cord. Compared with the nonelectroacupuncture nicotine withdrawal group, electroacupuncture stimulation increased the expression of nAChR α7 and nAChR α4 in the PAG of rats with electroacupuncture. Immunohistochemical results confirmed that electroacupuncture reversed nicotine withdrawal-induced changes in nAChR α7 positive neurons and Iba1-positive microglia in the dorsal horn of the spinal cord. Conclusion Electroacupuncture treatment has an analgesic effect on nicotine withdrawal-induced pain in nicotine-dependent rats. The mechanism of analgesia of the electroacupuncture treatment relates to the increased expression of nAChR α7 and nAChR β2 proteins in the spinal cord, nAChR α7 in the PAG, and decreased expression of Iba1 and COX2 protein in the spinal cord.

A Comparison of Vaping Behavior, Perceptions, and Dependence among Individuals Who Vape Nicotine, Cannabis, or Both.

Background: Electronic delivery systems (e.g., vapes, e-cigarettes) are now popular modes of cannabis and nicotine administration that are often used by the same individuals; however, we still know little about dual nicotine and cannabis vaping. Materials & Methods: An online convenience sample of adult nicotine and/or cannabis vape users residing in the United States completed a 60 min survey on sociodemographic characteristics, cannabis and/or nicotine vape use behaviors and dependence, reasons for vape use, and perceptions of benefits and harms. After data cleaning, we compared dual vs. nicotine-only and cannabis-only vape users with univariate statistics and step-wise hierarchical linear regression analyses. Additionally, we assessed the factor structure, internal consistency, and criterion and convergent validity of the Penn State Cannabis Vaping Dependence Index (PSCVDI). Results: The final sample included 357 dual, 40 cannabis, and 106 nicotine vape users. Compared to nicotine- and cannabis-only vapers, dual vapers started using their nicotine and cannabis vapes at a younger age (p < 0.001), used them for more years (p < 0.001), and were less likely to use their nicotine vape to replace combustible cigarettes (p = 0.047). Dual users vs. single-substance users did not have significantly higher nicotine or cannabis vape dependence scores after controlling for sociodemographic and use behaviors. The PSCVDI showed adequate validity for measuring cannabis vape dependence. Conclusions: This survey is the first to highlight important differences in vape use behaviors and reasons for use between dual vs. cannabis- and nicotine-only vape users.

Overdose symptoms and positive affect in never-established smokers are moderated by nicotine patch type: A between-subjects experimental investigation

Background: A growing number of studies have assessed the effects of acute nicotine on affect, cognition, and brain activity in never-established smokers in attempts to identify mechanisms by which nicotine promotes progression to dependence. However, these acute administration studies have not adequately addressed the problem of potential adverse side effects due to lack of tolerance, such as nausea, feelings of sickness, lightheadedness, and general negative affect and malaise – a term referred to as nicotine overdose events (NODEs). Thus, we report the first study to carefully characterize the prevalence, intensity, and effects of NODEs in never-established-smokers after acute nicotine administration. Methods: We compared the subjective effects of two different 7 mg nicotine patches that have different pharmacokinetics on never-established smokers (n = 67). One patch produces gradual increases in blood nicotine and the other produces more rapid increases in blood nicotine. Results: The findings suggest that in never-smokers, the lowest dose (7 mg) of rapid blood nicotine-rise patches are associated with a high prevalence of NODEs (45.83%) and decreased positive affect (PA) (54.17%) compared to a placebo patch (8.34% for NODEs and 33.34% for PA). The slow-rise patch did not significantly affect nicotine overdose symptoms or PA. Conclusions: Fast blood-rise nicotine patches may not be an ecologically valid method of nicotine delivery to never-smokers, while slow-rise nicotine patches, lower dose, and self-paced dosing may be more appropriate in this population. Findings also highlight the importance of the careful assessment of NODES in this population.

Tobacco/nicotine use among individuals using cannabis for therapeutic purposes.

While the relationship between recreational cannabis and nicotine use is well established, little is known about nicotine use among users of cannabis for therapeutic purposes (CTP). Patients attending a medical marijuana dispensary (N = 697; 75.3% White; 60.0% male) completed a survey examining nicotine use, motivation to quit cigarette smoking, routes of administration of nicotine and cannabis, and CTP qualifying conditions. More than one-third (39.3%) of participants reported current nicotine use. Compared to exclusive cigarette smokers, e-cigarette users and non-users of nicotine were approximately four times more likely to vape, rather than to smoke, cannabis. Furthermore, 46.8% of cigarette smokers reported plans to quit smoking in the next 6 months (but not in the next month) and an additional 31.6% planned to quit in the next month. Having a psychiatric condition was associated with nicotine use and higher motivation to quit smoking. Users of CTP are more likely to use nicotine products than the general population and the route of administration of nicotine products is related to the route of administration of CTP. If aerosolized CTP is a less harmful route of administration than smoked CTP, dispensary staff should be aware of this relationship and take this into account when recommending a noncombustible route. This study further characterizes nicotine use behaviors and motivation to quit smoking among users of CTP and may be among the first to examine nicotine use among patients of a medical marijuana dispensary.

Measurement of α-Synuclein Dynamics In Vivo Using Microdialysis with a Novel Homogeneous Immunoassay.

Understanding the regulation of α-synuclein release could be important in better understanding Parkinson's disease development, progression, and treatment. Advances in such studies are hindered by technical challenges that limit the ability to monitor α-synuclein concentration in vivo. We developed a novel α-synuclein microdialysis method coupled with a specific and sensitive immunoassay that requires a small sample volume (1 μL). Using this method, basal α-synuclein level was estimated at 254 ± 78 pM in the striatum of freely moving mice. Additionally, we observed that potassium (75 mM) and nicotine (0.5 mg/kg) administration significantly increased α-synuclein in dialysates. These results provide evidence that the methods we report here can be useful to investigate the physiological roles of α-synuclein and support the idea that α-synuclein is secreted to the extracellular space in a neuronal activity-dependent manner.

Neutrophil extracellular traps-mediated Beclin-1 suppression aggravates atherosclerosis by inhibiting macrophage autophagy

A growing body of evidence suggests that neutrophil extracellular traps (NETs) critically contribute to the development of atherosclerosis. However, the detailed mechanism of how NETs promote atherogenesis remains unknown. In this study, we explored the role of NETs for promoting atherosclerosis by modulating the activity of autophagy in macrophages. NETs were effectively induced by a nicotine administration to the HL-60 cell-derived neutrophil-like cells. Treatment with NETs markedly suppressed both autophagosome formation and autophagosome–lysosome fusion in 7-ketocholesterol-treated macrophages, which are accompanied by the enhancement of inflammasome activity. NETs upregulate epidermal growth factor receptor (EGFR) activity, which enhances Beclin-1 phosphorylation of the tyrosine residues of Beclin-1 by EGFR, inhibits the PI3 kinase activity of the Beclin1–Vps34 complex, and suppresses autophagosome formation in macrophages. Furthermore, NET-induced activation of EGFR allows Rubicon to increase its expression, thereby suppressing autophagosome-lysosome fusion. In vivo experiments revealed that the suppression of NET formation by ablating peptidyl arginine deiminase-4 in neutrophil leukocytes resulted in the attenuation of atherosclerotic plaques in a nicotine-administered HFD-fed ApoE −/− mice. Taken together, these results suggest that NET-mediated EGFR–Beclin-1 signaling in the macrophages promotes atherogenesis by autophagy inhibition-mediated inflammasome activation.

Nicotine Has a Therapeutic Window of Effectiveness in a Drosophila melanogaster Model of Parkinson's Disease.

Strong epidemiological evidence and studies in models of Parkinson's disease (PD) suggest that nicotine may be therapeutically beneficial in PD patients. However, a number of clinical trials utilizing nicotine in PD patients have had mixed results, indicating that either nicotine is not beneficial in PD patients, or an important aspect of nicotine therapy was absent. We hypothesized that nicotine must be administered early in the adult fly life in order to have beneficial effects. We show that continuous early nicotine administration improves both climbing and flight deficiencies present in homozygous park25 mutant PD model Drosophila melanogaster. Using a new climbing assay, we identify several climbing deficiencies in this PD model that are improved or rescued by continuous nicotine treatment. Amongst these benefits, it appears that nicotine improves the ability of the park25 flies to descend the climbing vial by being able to climb down more. In support of our hypothesis, we show that in order for nicotine benefits on climbing and flight to happen, nicotine administration must occur in a discrete time frame following adult fly eclosure: within one day for climbing or five days for flight. This therapeutic window of nicotine administration in this PD model fly may help to explain the lack of efficacy of nicotine in human clinical trials.

Pharmacological inhibition of eIF2alpha phosphorylation by integrated stress response inhibitor (ISRIB) ameliorates vascular calcification in rats.

Vascular calcification (VC) is an independent risk factor for cardiovascular events and all-cause mortality with the absence of current treatment. This study aimed to investigate whether eIF2alpha phosphorylation inhibition could ameliorate VC. VC in rats was induced by administration of vitamin D3 (3×10(5) IU/kg, intramuscularly) plus nicotine (25 mg/kg, intragastrically). ISRIB (0.25 mg/kg·week), an inhibitor of eIF2alpha phosphorylation, ameliorated the elevation of calcium deposition and ALP activity in calcified rat aortas, accompanied by amelioration of increased SBP, PP, and PWV. The decreased protein levels of calponin and SM22alpha, and the increased levels of RUNX2 and BMP2 in calcified aorta were all rescued by ISRIB, while the increased levels of the GRP78, GRP94, and C/EBP homologous proteins in rats with VC were also attenuated. Moreover, ISRIB could prevent the elevation of eIF2alpha phosphorylation and ATF4, and partially inhibit PERK phosphorylation in the calcified aorta. These results suggested that an eIF2alpha phosphorylation inhibitor could ameliorate VC pathogenesis by blocking eIF2alpha/ATF4 signaling, which may provide a new target for VC prevention and treatment.

Potential Actions of Baicalein for Preventing Vascular Calcification of Smooth Muscle Cells In Vitro and In Vivo.

Vascular calcification (VC) is associated with cardiovascular disease. Baicalein, a natural flavonoid extract of Scutellaria baicalensis rhizome has several biological properties which may inhibit VC. We investigated whether baicalein suppresses Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein 2 (BMP-2) and upregulates smooth muscle 22-alpha (SM22-α) and alpha-smooth muscle actin (α-SMA). In an in vitro experiment, primary rat aortic vascular smooth muscle cells (VSMCs) were pretreated with 0.1, 1, and 5 μM baicalein, followed by β-glycerophosphate (β-GP) to induce calcification. In an in vivo experiment, VC was generated by vitamin D3 plus nicotine (VDN) administration to male Sprague Dawley (SD) rats randomly assigned into a control group, a VC group, a VC group pretreated with baicalein, and a baicalein alone group. Each group comprised 10 rats. Left ventricular (LV) morphology, function and performance were assessed by echocardiography. Calcium content was measured by Alizarin red S staining and alkaline phosphatase (ALP) activity assays. Apoptotic VSMCs were detected by flow cytometry. Protein levels and superoxide changes were evaluated using Western blotting and immunofluorescence assays respectively. Plasma malondialdehyde (MDA) was assayed. Baicalein pretreatment significantly reduced calcium content in calcified VSMCs (p < 0.001) as well as in VC rat aortic smooth muscle (p < 0.001). Additionally, ALP activity was decreased in calcified VSMCs and VC rat aortic smooth muscle (p < 0.001). Apoptosis was significantly attenuated by 1 μM baicalein pretreatment in calcified VSMCs. Runx2 and BMP-2 expressions were downregulated by the baicalein in calcified VSMCs. Baicalein pretreatment increased typical VSMCs markers SM22-α and α-SMA in calcified VSMCs. Baicalein pretreatment was associated with adverse changes in LV morphometry. Markers of oxidative stress declined, and endogenous antioxidants increased in VC rats pretreated with baicalein. Baicalein mitigates VC through the inhibition of Runx2/BMP-2 signaling pathways, enhancement of vascular contractile phenotype and oxidative stress reduction. However, our study is of basic experimental design; more advanced investigations to identify other molecular regulators of VC and their mechanisms of action is required.

An extended amygdala-midbrain circuit controlling cocaine withdrawal-induced anxiety and reinstatement.

SUMMARYAlthough midbrain dopamine (DA) circuits are central to motivated behaviors, our knowledge of how experience modifies these circuits to facilitate subsequent behavioral adaptations is limited. Here we demonstrate the selective role of a ventral tegmental area DA projection to the amygdala (VTADA→amygdala) for cocaine-induced anxiety but not cocaine reward or sensitization. Our rabies virus-mediated circuit mapping approach reveals a persistent elevation in spontaneous and task-related activity of inhibitory GABAergic cells from the bed nucleus of the stria terminalis (BNST) and downstream VTADA→amygdala cells that can be detected even after a single cocaine exposure. Activity in BNSTGABA→midbrain cells is related to cocaine-induced anxiety but not reward or sensitization, and silencing this projection prevents development of anxiety during protracted withdrawal after cocaine administration. Finally, we observe that VTADA→amygdala cells are strongly activated after a challenge exposure to cocaine and that activity in these cells is necessary and sufficient for reinstatement of cocaine place preference.

Evaluation of the effect of nicotine and O-acetyl-L-carnitine on testosterone-induced spatial learning impairment in Morris water maze and assessment of protein markers

The hippocampus has an essential role in learning and memory and is a target for androgen actions. Thus, the effect of testosterone and its metabolites on learning and memory has attracted researchers' attention.The present study aimed to identify the effects of four-day bilateral intra-hippocampal infusion of nicotine and o-Acetyl L-carnitine alone and in combination on testosterone enanthate (TE)-induced spatial learning deficits using Morris water maze (MWM). The expression of CREB, pCREB and BDNF proteins was quantified using western blots.We observed that bilateral intra-hippocampal infusion of TE significantly impaired spatial learning and a significant decrease in CREB, pCREB and BDNF protein markers compared to a control group that did not receive TE. In addition, administration of O-acetyl L-carnitine and/or nicotine reversed TE-induced spatial learning impairment in behavioural and molecular assessments.Thus, our findings suggest that administration of TE in the hippocampus of adult male rats impairs memory function, possibly via down-regulation of cAMP/PKA-CREB-BDNF signaling pathway.

Central Adenosine A1 Receptors Arbitrate the Nicotine Counteraction of Cardiovascular and Autonomic Dysfunctions in Septic Rats

The cholinergic anti‐inflammatory pathway plays a crucial role in improving end‐organ damage provoked by inflammatory disorders. Given the interplay between cholinergic and adenosinergic neuronal circuits in the central nervous system, we tested the hypothesis that central adenosine A1 receptors (A1Rs) modulate the offsetting action of nicotine on cardiovascular and inflammatory insults induced by sepsis. Pharmacologic agonistic and antagonistic studies were conducted in conscious rats, pre‐instrumented with femoral vessel and intracisternal (i.c.) catheters. Sepsis was induced by cecal ligation and puncture (CLP) 24 hr before cardiovascular measurements. Nicotine (25 or 100 µg/kg i.v.) dose‐dependently reversed septic manifestations of hypotension and concomitant reductions in time and spectral measures of heart rate variability (HRV) and cardiac sympathovagal balance (low‐frequency/high‐frequency ratio). Like nicotine, the i.c. administration of N(6)‐cyclopentyladenosine (CPA, AR1 agonist) to CLP rats caused significant increases in indices of HRV and sympathovagal balance and greater surges in these parameters were noted upon simultaneous administration of CPA plus nicotine. We also show that the favorable influences of nicotine on blood pressure and HRV in septic rats were significantly inhibited after central blockade of A1Rs by i.c. 8‐Cyclopentyl‐1,3‐dipropylxanthine (DPCPX). Immunohistochemically, the alleviation by nicotine of the upregulated myocardial expression of NFκB in septic rats disappeared upon prior exposure to DPCPX. The data suggest that central adenosine A1Rs act tonically to facilitate the ameliorative effect of nicotine against the inflammatory response of sepsis and interrelated cardiomyopathic and neuropathic hitches.

Ventral hippocampal NMDA receptors mediate the effects of nicotine on stress-induced anxiety/exploratory behaviors in rats

Brief exposure to stress increases the tendency to drug abuse, especially cigarette smoking. It seems that nicotine abuse alleviates some psychological and physiological stress symptoms. The present study investigated the effect of nicotine administration on stress-induced anxiety-like behavior in adult male Wistar rats. Also, the possible role of the ventral hippocampal (VH) glutamatergic NMDA receptors was examined in the stress-induced anxiety-like behavior under nicotine administration. The anxiogenic-like effects of forced swimming stress (10 min) were shown by decreases in the head-dipping behavior, rearing, and locomotor activity in a hole-board task. Interestingly, the administration of the different doses of nicotine (0.075 and 0.1 mg/kg, i.p.) inhibited stress-induced anxiogenic-like behaviors. Bilateral microinjection of NMDA (0.1 µg/rat) into the VH potentiated the response of an ineffective dose of nicotine (0.05 mg/kg, i.p.) on stress-induced anxiety-like behavior. The microinjection of D-AP5 (1.5 and 2 µg/rat) into the VH inhibited the response of an effective dose of nicotine (0.1 mg/kg, i.p.) on anxiety-like behavior induced by acute stress. Intra-VH microinjection of D-AP5 reversed the potentiating effect of NMDA on nicotine response. Intra-VH microinjection of NMDA or D-AP5 by itself did not affect stress-induced anxiety-like behavior. Taken together, we can conclude that nicotine inhibited stress-induced anxiogenic-like behaviors, possibly via the ventral hippocampal NMDA receptors mechanism.