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A low dose of nicotine is sufficient to produce nicotine withdrawal in mice  [PDF]
Besson Morgane, Suarez Sandra, Changeux Jean-Pierre, Granon Sylvie
Health (Health) , 2010, DOI: 10.4236/health.2010.21001
Abstract: The objective of our study was to investigate whether the chronic administration of a low dose of nicotine can be followed by a withdrawal syndrome at cessation of nicotine delivery. Pre-vious studies showed various results, depend-ing in the doses of nicotine, species, ways of administration and behavioural paradigms, but all emphasized a withdrawal effect on some or all of the following spontaneous behaviours: grooming, rearing, body shake or tremor, body scratching, abdominal constriction, jumping. However, it is not clear which behaviour is ex-actly altered, as a global behavioural index is most frequently used. This is not clear either if anxiety modulates the behavioral expression of withdrawal or which factors contribute to its locomotors effect, if any. To distant-angle these processes, we scored each of these behaviours individually before nicotine exposure, during continuous nicotine delivery and at cessation of nicotine delivery after precipitated withdrawal by mecamylamine injection. We also measured locomotor activity and anxiety levels in the same animals. We used a low dose of nicotine (2.4 mg/kg/day as free base) that has been pre-viously shown to produce nicotinic receptors up-regulation, both in the brain and in blood cells. With such a low dose, nicotine withdrawal didn’t affect locomotion nor anxiety levels but increased the number of rearing, jumping, and marginally, body-scratching. Other behaviours, classically considered to contribute to with-drawal syndrome, were unaffected, e.g., groom- ing, body or forelimb shakes. Our results show that anxiety may be dissociated from the be-havioural withdrawal syndrome. Also, the se-verity of the syndrome produced by nicotine withdrawal is qualitatively and quantitatively different from the one induced by other drugs of abuse and also by the one produced by nicotine at higher doses.
Nicotine withdrawal and agitation in ventilated critically ill patients
Olivier Lucidarme, Amélie Seguin, Cédric Daubin, Michel Ramakers, Nicolas Terzi, Patrice Beck, Pierre Charbonneau, Damien du Cheyron
Critical Care , 2010, DOI: 10.1186/cc8954
Abstract: We conducted a prospective, observational study in two intensive care units (ICUs). The 144 consecutive patients admitted to ICUs and requiring mechanical ventilation for >48 hours were included. Smoking status was assessed at ICU admission by using the Fagerstr?m Test of Nicotine Dependence (FTND). Agitation, with the Sedation-Agitation Scale (SAS), and delirium, with the Intensive Care Delirium Screening Checklist (ICDSC), were tested twice daily during the ICU stay. Agitation and delirium were defined by SAS >4 and ICDSC >4, respectively. Nosocomial complications and outcomes were evaluated.Smokers (n = 44) were younger and more frequently male and were more likely to have a history of alcoholism and to have septic shock as the reason for ICU admission than were nonsmokers. The incidence of agitation, but not delirium, increased significantly in the smoker group (64% versus 32%; P = 0.0005). Nicotine abstinence was associated with higher incidences of self-removal of tubes and catheters, and with more interventions, including the need for supplemental sedatives, analgesics, neuroleptics, and physical restraints. Sedation-free days, ventilator-free days, length of stay, and mortality in ICUs did not differ between groups. Multivariate analysis identified active smoking (OR, 3.13; 95% CI, 1.45-6.74; P = 0.003) as an independent risk factor for agitation. Based on a subgroup of 56 patients, analysis of 28 pairs of patients (smokers and nonsmokers in a 1:1 ratio) matched for age, gender, and alcoholism status found similar results regarding the role of nicotine withdrawal in increasing the risk of agitation during an ICU stay.Nicotine withdrawal was associated with agitation and higher morbidities in critically ill patients. These results suggest the need to look specifically at those patients with tobacco dependency by using the FTND in ICU settings. Identifying patients at risk of behavioral disorders may lead to earlier interventions in routine clinical practice.C
Nicotine Reward and Affective Nicotine Withdrawal Signs Are Attenuated in Calcium/Calmodulin-Dependent Protein Kinase IV Knockout Mice  [PDF]
Kia J. Jackson, Sarah S. Sanjakdar, Xiangning Chen, M. Imad Damaj
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051154
Abstract: The influx of Ca2+ through calcium-permeable nicotinic acetylcholine receptors (nAChRs) leads to activation of various downstream processes that may be relevant to nicotine-mediated behaviors. The calcium activated protein, calcium/calmodulin-dependent protein kinase IV (CaMKIV) phosphorylates the downstream transcription factor cyclic AMP response element binding protein (CREB), which mediates nicotine responses; however the role of CaMKIV in nicotine dependence is unknown. Given the proposed role of CaMKIV in CREB activation, we hypothesized that CaMKIV might be a crucial molecular component in the development of nicotine dependence. Using male CaMKIV genetically modified mice, we found that nicotine reward is attenuated in CaMKIV knockout (?/?) mice, but cocaine reward is enhanced in these mice. CaMKIV protein levels were also increased in the nucleus accumbens of C57Bl/6 mice after nicotine reward. In a nicotine withdrawal assessment, anxiety-related behavior, but not somatic signs or the hyperalgesia response are attenuated in CaMKIV ?/? mice. To complement our animal studies, we also conducted a human genetic association analysis and found that variants in the CaMKIV gene are associated with a protective effect against nicotine dependence. Taken together, our results support an important role for CaMKIV in nicotine reward, and suggest that CaMKIV has opposing roles in nicotine and cocaine reward. Further, CaMKIV mediates affective, but not physical nicotine withdrawal signs, and has a protective effect against nicotine dependence in human genetic association studies. These findings further indicate the importance of calcium-dependent mechanisms in mediating behaviors associated with drugs of abuse.
Differential changes in amygdala and frontal cortex Pde10a expression during acute and protracted withdrawal  [PDF]
Marian L. Logrip,Eric P. Zorrilla
Frontiers in Integrative Neuroscience , 2014, DOI: 10.3389/fnint.2014.00030
Abstract: Alcohol use disorders are persistent problems with high recidivism rates despite repeated efforts to quit drinking. Neuroadaptations that result from alcohol exposure and that persist during periods of abstinence represent putative molecular determinants of the propensity to relapse. Previously we demonstrated a positive association between phosphodiesterase 10A (PDE10A) gene expression and elevations in relapse-like alcohol self-administration in rats with a history of stress exposure. Because alcohol withdrawal is characterized by heightened anxiety-like behavior, activation of stress-responsive brain regions and an elevated propensity to self-administer alcohol, we hypothesized that Pde10a expression also would be upregulated in reward- and stress-responsive brain regions during periods of acute (8–10 h) and protracted (6 weeks) alcohol withdrawal. During acute withdrawal, elevated Pde10a mRNA expression was found in the medial and basolateral amygdala (BLA), as well as the infralimbic and anterior cingulate subdivisions of the medial prefrontal cortex, relative to alcohol-na?ve controls. The BLA was the only region with elevated Pde10a mRNA expression during both acute and protracted withdrawal. In contrast to the elevations, Pde10a mRNA levels tended to be reduced during protracted withdrawal in the dorsal striatum, prelimbic prefrontal cortex, and medial amygdala. Together these results implicate heightened PDE10A expression in the BLA as a lasting neuroadaptation associated with alcohol dependence.
The Endocannabinoid System as Pharmacological Target Derived from Its CNS Role in Energy Homeostasis and Reward. Applications in Eating Disorders and Addiction  [PDF]
Maria-Paz Viveros,Francisco-Javier Bermúdez-Silva,Ana-Belén Lopez-Rodriguez,Edward J. Wagner
Pharmaceuticals , 2011, DOI: 10.3390/ph4081101
Abstract: The endocannabinoid system (ECS) has been implicated in many physiological functions, including the regulation of appetite, food intake and energy balance, a crucial involvement in brain reward systems and a role in psychophysiological homeostasis (anxiety and stress responses). We first introduce this important regulatory system and chronicle what is known concerning the signal transduction pathways activated upon the binding of endogenous cannabinoid ligands to the G i/0-coupled CB1 cannabinoid receptor, as well as its interactions with other hormones and neuromodulators which can modify endocannabinoid signaling in the brain. Anorexia nervosa (AN) and bulimia nervosa (BN) are severe and disabling psychiatric disorders, characterized by profound eating and weight alterations and body image disturbances. Since endocannabinoids modulate eating behavior, it is plausible that endocannabinoid genes may contribute to the biological vulnerability to these diseases. We present and discuss data suggesting an impaired endocannabinoid signaling in these eating disorders, including association of endocannabinoid components gene polymorphisms and altered CB1-receptor expression in AN and BN. Then we discuss recent findings that may provide new avenues for the identification of therapeutic strategies based on the endocannabinod system. In relation with its implications as a reward-related system, the endocannabinoid system is not only a target for cannabis but it also shows interactions with other drugs of abuse. On the other hand, there may be also a possibility to point to the ECS as a potential target for treatment of drug-abuse and addiction. Within this framework we will focus on enzymatic machinery involved in endocannabinoid inactivation (notably fatty acid amide hydrolase or FAAH) as a particularly interesting potential target. Since a deregulated endocannabinoid system may be also related to depression, anxiety and pain symptomatology accompanying drug-withdrawal states, this is an area of relevance to also explore adjuvant treatments for improving these adverse emotional reactions.
Behavioral, Biochemical, and Molecular Indices of Stress are Enhanced in Female Versus Male Rats Experiencing Nicotine Withdrawal  [PDF]
Oscar V. Torres,Luis A. Natividad,Luis M. Carcoba,Laura E. O’Dell
Frontiers in Psychiatry , 2013, DOI: 10.3389/fpsyt.2013.00038
Abstract: Stress is a major factor that promotes tobacco use and relapse during withdrawal. Although women are more vulnerable to tobacco use than men, the manner in which stress contributes to tobacco use in women versus men is unclear. Thus, the goal of this study was to compare behavioral and biological indices of stress in male and female rats during nicotine withdrawal. Since the effects of nicotine withdrawal are age-dependent, this study also included adolescent rats. An initial study was conducted to provide comparable nicotine doses across age and sex during nicotine exposure and withdrawal. Rats received sham surgery or an osmotic pump that delivered nicotine. After 14 days of nicotine, the pumps were removed and controls received a sham surgery. Twenty-four hours later, anxiety-like behavior and plasma corticosterone were assessed. The nucleus accumbens (NAcc), amygdala, and hypothalamus were examined for changes in corticotropin-releasing factor (CRF) gene expression. In order to differentiate the effects of nicotine withdrawal from exposure to nicotine, a cohort of rats did not have their pumps removed. The major finding is that during nicotine withdrawal, adult females display higher levels of anxiety-like behavior, plasma corticosterone, and CRF mRNA expression in the NAcc relative to adult males. However, during nicotine exposure, adult males exhibited higher levels of corticosterone and CRF mRNA in the amygdala relative to females. Adolescents displayed less nicotine withdrawal than adults. Moreover, adolescent males displayed an increase in anxiety-like behavior and an up-regulation of CRF mRNA in the amygdala during nicotine exposure and withdrawal. These findings are likely related to stress produced by the high doses of nicotine that were administered to adolescents to produce equivalent levels of cotinine as adults. In conclusion, these findings suggest that intense stress produced by nicotine withdrawal may contribute to tobacco use in women.
Fatty Acid Amide Hydrolase (FAAH) Inhibitors Exert Pharmacological Effects, but Lack Antinociceptive Efficacy in Rats with Neuropathic Spinal Cord Injury Pain  [PDF]
Aldric T. Hama, Peter Germano, Matthew S. Varghese, Benjamin F. Cravatt, G. Todd Milne, James P. Pearson, Jacqueline Sagen
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096396
Abstract: Amelioration of neuropathic spinal cord injury (SCI) pain is a clinical challenge. Increasing the endocannabinoid anandamide and other fatty acid amides (FAA) by blocking fatty acid amide hydrolase (FAAH) has been shown to be antinociceptive in a number of animal models of chronic pain. However, an antinociceptive effect of blocking FAAH has yet to be demonstrated in a rat model of neuropathic SCI pain. Four weeks following a SCI, rats developed significantly decreased hind paw withdrawal thresholds, indicative of below-level cutaneous hypersensitivity. A group of SCI rats were systemically treated (i.p.) with either the selective FAAH inhibitor URB597 or vehicle twice daily for seven days. A separate group of SCI rats received a single dose (p.o.) of either the selective FAAH inhibitor PF-3845 or vehicle. Following behavioral testing, levels of the FAA N-arachidonoylethanolamide, N-oleoyl ethanolamide and N-palmitoyl ethanolamide were quantified in brain and spinal cord from SCI rats. Four weeks following SCI, FAA levels were markedly reduced in spinal cord tissue. Although systemic treatment with URB597 significantly increased CNS FAA levels, no antinociceptive effect was observed. A significant elevation of CNS FAA levels was also observed following oral PF-3845 treatment, but only a modest antinociceptive effect was observed. Increasing CNS FAA levels alone does not lead to robust amelioration of below-level neuropathic SCI pain. Perhaps utilizing FAAH inhibition in conjunction with other analgesic mechanisms could be an effective analgesic therapy.
Excitability of jcBNST Neurons Is Reduced in Alcohol-Dependent Animals during Protracted Alcohol Withdrawal  [PDF]
Attila Szücs, Fulvia Berton, Pietro Paolo Sanna, Walter Francesconi
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042313
Abstract: Alcohol dependence and withdrawal has been shown to cause neuroadaptive changes at multiple levels of the nervous system. At the neuron level, adaptations of synaptic connections have been extensively studied in a number of brain areas and accumulating evidence also shows the importance of alcohol dependence-related changes in the intrinsic cellular properties of neurons. At the same time, it is still largely unknown how such neural adaptations impact the firing and integrative properties of neurons. To address these problems, here, we analyze physiological properties of neurons in the bed nucleus of stria terminalis (jcBNST) in animals with a history of alcohol dependence. As a comprehensive approach, first we measure passive and active membrane properties of neurons using conventional current clamp protocols and then analyze their firing responses under the action of simulated synaptic bombardment via dynamic clamp. We find that most physiological properties as measured by DC current injection are barely affected during protracted withdrawal. However, neuronal excitability as measured from firing responses under simulated synaptic inputs with the dynamic clamp is markedly reduced in all 3 types of jcBNST neurons. These results support the importance of studying the effects of alcohol and drugs of abuse on the firing properties of neurons with dynamic clamp protocols designed to bring the neurons into a high conductance state. Since the jcBNST integrates excitatory inputs from the basolateral amygdala (BLA) and cortical inputs from the infralimbic and the insular cortices and in turn is believed to contribute to the inhibitory input to the central nucleus of the amygdala (CeA) the reduced excitability of the jcBNST during protracted withdrawal in alcohol-dependent animals will likely affect ability of the jcBNST to shape the activity and output of the CeA.
The Associations between Self-Consciousness, Depressive State and Craving to Drink among Alcohol Dependent Patients Undergoing Protracted Withdrawal  [PDF]
Philippe de Timary, Mariana Cordovil de Sousa Uva, Catherine Deno?l, Ludger Hebborn, Marc Derely, Martin Desseilles, Olivier Luminet
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0071560
Abstract: Context In order to understand how certain personality traits influence the relation between depression symptoms and craving for alcohol, trait self-consciousness (trait SC) was examined during a withdrawal and detoxification program. Methods Craving (Obsessive and Compulsive Drinking Scale), depressive state (Beck Depression Inventory) and trait SC (Revised Self-Consciousness Scale) were assessed in alcohol-dependent inpatients (DSM-IV, N = 30) both at the beginning (T1: day 1 or 2) and at the end (T2: day 14 to18) of protracted withdrawal during rehabilitation. Results A significant decrease in craving and depressive symptoms was observed from T1 to T2, while SC scores remained stable. At both times, strong positive correlations were observed between craving and depression. Moreover, regression analyses indicated that trait SC significantly moderated the impact of depression on cravings for alcohol. Limitations This study was performed on a relatively small sample size. Administration of medications during detoxification treatment can also be a confounding factor. Finally, craving could have been evaluated through other types of measurements. Conclusions During protracted withdrawal, alcohol craving decreased with the same magnitude as depressive mood. Depressive symptoms were related to alcohol craving but only among patients with high trait SC scores. Our results suggest that metacognitive approaches targeting SC could decrease craving and, in turn, prevent future relapses.
Personality Dimensions and Nicotine Dependence and Withdrawal Symptoms: the Mediating Role of Self-Directness
Sybilla Schiep, Katarzyna Cie lik
Polish Psychological Bulletin , 2011, DOI: 10.2478/v10059-011-0022-x
Abstract: We analyzed the relationship between personality traits and smoking status and nicotine withdrawal symptoms using two comprehensive models of personality: the Five-Factor Model and the Cloninger's Temperament and Character Inventory. In total 295 people were examined, 149 smokers and 146 who have never smoked. To measure the severity of the nicotine dependence we used the Fagerstroem Tolerance Questionnaire and the DSM-IV criteria of nicotine dependence and to measure the nicotine withdrawal symptoms the Nicotine Dependence History. The results showed significant differences between the groups in particular dimensions: Neuroticism, Agreeableness and Conscientiousness. The analyse of the TCI demonstrate, that smokers are higher in Novelty Seeking and lower in Reward Dependence than never smokers and show less Self-Directness and Cooperativeness. The mediation analyses showed that Self-Directness is the significant mediator between Extra-Introversion and nicotine withdrawal symptoms measured by NDHIS and between Neuroticism and DSM-IV criteria of nicotine dependence.
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