And third generic levonorgestrel 0.18 mg, neural communication which directly prepares the body for action (dilating blood vessels to the muscles discount 0.18mg levonorgestrel visa, constricting blood vessels to the skin levonorgestrel 0.18mg with visa, etc) order 0.18 mg levonorgestrel free shipping. Of particular interest in the current chapter (which attempts to integrate the immune and neuroendocrine systems) are chemicals (neurotransmitters purchase 0.18 mg levonorgestrel overnight delivery, hormones and cytokines) which are released by the cells of one system and impact on the cells of the other. Instead, some examples are offered, which support the notion that these systems are highly integrated. Future research can be expected to provide additional details and open new therapeutic avenues. The immune modulating the neuroendocrine system: examples 1. Cytokines, interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor-alpha (TNF- alpha) and interferon-gamma (IFN-gamma) pass through the circumventricular organs and impact on the hypothalamus, leading to fever and sickness behavior. Cytokines impacting on the HPA lead to cortisol release from the adrenal cortex (Chowers et al, 1996; Dunn et al, 1999). Immune cells synthesize IFN which passes the blood brain barrier, impacts on brain and may cause “depression” (Hauser et al, 2002). Elevated levels of C-reactive protein and IL-6 in children are associated with behavior problems (Slopen et al, 2013). Lymphocytes synthesize hormones including ACTH, prolactin and growth hormone (Wilder, 1995). Peripheral cytokines stimulate afferent pathways such as the vagus nerve which leads to the release of cytokine and stimulation of brain cells (McCusker and Kelley, 2013). Cytokines reduce the efficiency of glucocorticoid receptors (resistance) which reduce the negative feedback (which may have a role in depression) (Pace and Miller, 2009). Acetylcholine and adrenaline neurotransmitters, and hormones [recently, melatonin] are endogenously produced in the immune system (Blalock, 2005). For (simplified) details, see the following list: Source Hormone/neurotransmitters Lymphocytes Acetylcholine, melatonin T Lymphocytes ACTH, endorphins B Lymphocytes ACTH, endorphins Macrophages ACTH, endorphins Splenocytes Adrenalin, CRH, Megakaryocytes Neuropeptide Y The neuroendocrine modulating the immune system: examples 1. Sympathetic/noradrenergic nerve fibers innervate important organs and systems related to the immune system, including the liver, spleen, thymus, bone marrow, lymph nodes, skin, and digestive tract and respiratory apparatus (Montoro et al, 2009; Irwin and Cole, 2011). Adrenergic receptors are located on lymphocytes (Hadden et al, 1970). Catecholamines and corticoids suppress the production of IL-12 by immune cells (Elenkov and Chrousos, 1999). Increased cortisol suppresses immune function (McEwen et al, 1997). Cortical steroids directly affect immune cells, increasing the production of IL-4, 10 and 13 (DeKruyff et al, 1998). Neuropeptide, neurotransmitter and neuroendocrine hormone receptors are located on immune cells (Blalock, 2005). Neurotransmitters (acetylcholine, noradrenaline, serotonin, histamine, glutamic acid, GABA), neuropeptides (ACTH, Prolactin, Vasopressin, Bradykinin, Somatostatin, VIP, SP, Neuropeptide Y, encephalin, endorphin), neurological growth factors (NGF) and hormones (adrenalin and corticoids) modulate immune function (Montoro et al, 2009). Neurons synthesize IL-1 and other cytokines (Breder, 1988). Parental separation results in higher levels of C-reactive protein in the adult (Lacy et al, 2013). Exogenous administration of CRH and ACTH produce a substantial increase in IL-6 in the adrenal glands (Hueston and Deak, 2014). Marital distress has long-term immune consequences (Jaremka et al, 2013). Clinical aspects The Holy Grail The Holy Grail of PNI is around the question of whether psychological factors (presumably modifiable) can be employed to moderate the immune system and influence the onset and outcome of physical diseases. Diseases of particular interest include infections (such as hepatitis and AIDS), autoimmune diseases (such as rheumatoid arthritis and multiple sclerosis) and cancer. Possible psychological interventions include the talking and relaxation/hypnosis therapies and in the broader context, social engineering to reduce loneliness, isolation and poverty. Healthy students under examination stress manifest a decrease in indicators of cellular immune response (Glaser et al, 1986). Stressful life events can play a part in the onset and exacerbation of auto-immune diseases (Homo-Delarche et al, 1991; Nakata, 2012). Cognitive-behavioral interventions have been associated with improved physical symptoms of some auto-immune disorders (Radojevic, 1992). Some studies involving education and psychological treatment have demonstrated increased cancer survival (Spiegel et al, 1989; Fawzy et al, 1993). An important review (Miller and Cohen, 2001) somewhat unexpectedly, found that the immune system shows little response to psychological intervention, and another (Montoro et al, 2009) did not find chronic stress to be an intrinsic cause of allergy. Nevertheless, beneficial effects of social support and connectedness on the immune system continues to be anticipated (Audet et al, 2014).
As many as one-third to one-half of adolescents ceptors after nicotine use (43) buy 0.18mg levonorgestrel visa. One theory linking schizo- experimenting with cigarettes become regular smokers buy 0.18 mg levonorgestrel free shipping. Adolescents have less interest in treatment order 0.18 mg levonorgestrel amex, high treat- diated by functions of the -7 nicotinic cholinergic receptor ment dropout rates buy discount levonorgestrel 0.18mg on line, and low quitting rates (20) purchase 0.18mg levonorgestrel free shipping. Cigarette smoking and nicotine improve abnormal of adolescent tobacco smoking conclude that better charac- sensory gating in humans and animals. The abnormality of terization of nicotine dependence (35) and assessment of sensory gating in schizophrenia has been linked to the gene pharmacotherapies are needed, given the almost epidemic also encoding the -7 subunit (45). Dependence on alcohol, heroin, cocaine, and other drugs frequently coexists with nicotine addiction (4). Alcohol and nicotine addiction have common heritability (46,60). Stim- RISK FACTORS ulant drug exposure may cross-sensitize to neurochemical effects of other stimulants, so nicotine and other stimulants Comorbidity enhance the effects of one another (14,48). Because all ad- Some smokers report that smoking helps relieve their dicting drugs release dopamine in the mesolimbic system, depression and other mood disorders. Others become se- drugs may be interacting or substituting for one another to verely depressed when they stop smoking (16,52). Smokers produce common changes in dopamine-related reinforce- are more likely to have experienced major depression, and ment. Several mechanisms may link smoking and depression (16). Genetics Depression sensitizes patients to the dysphoric effects of stressful stimuli. Nicotine-related decreases in 5-HT formation and cant proportion in the variation in the use of tobacco in release in the hippocampus could be a factor. Stopping ad- twin studies, with heritabilities estimated to be as high as Chapter 107: Therapeutics for Nicotine Addiction 1537 84% and 82% for liability to lifetime and current tobacco The alterations in synaptic function plausibly would ac- use, respectively (9), influencing both initiation and mainte- count for associated behavioral disruptions evident in hu- nance of tobacco smoking (60). Another twin pair study mans (98) and in animal models (1,62,89). The fetal effects of nicotine may be (72% versus 28%). Genetic factors also appeared important greater during the later stages of pregnancy, a finding sug- for the appearance of alcohol dependence (55% versus gesting the first trimester is the most desirable period for 45%), consistent with a common genetic vulnerability and NRT during pregnancy. Based on the rat data, it may be showing that nicotine and alcohol dependence occur to- preferable to introduce NRTs early in pregnancy to try to gether (60). Environmental factors more strongly deter- reduce the fetal exposure to nicotine before the second or mined age of first use of tobacco and alcohol, whereas la- third trimester. In the rat models, episodic nicotine delivery, tency between first use and patterns of regular use were as happens with smoking, is associated with less nicotine more genetically determined (54). A major genetic influence exposure to the fetus than continuous exposure from a nico- accounting for about 70% of the variance in risk in a group tine patch. Of course, fetal exposure to tobacco smoke pre- of Vietnam era twin pairs is consistent with other studies sents a host of other toxins besides nicotine. Cognitive defi- Genetically determined dopamine receptor functional cits, behavioral problems in childhood, particularly atten- differences and genetic variation in hepatic enzyme activity tion-deficit/hyperactivity disorders, conduct disorders, and important in metabolizing nicotine suggest possible mecha- substance abuse in the exposed children are associated with nisms. Individuals with TaqIA alleles (A1 and A2) and maternal smoking. Children whose mothers smoked ten or TaqIB (B1 and B2) of the D2 dopamine receptor gene had more cigarettes daily during pregnancy had a fourfold in- earlier onset of smoking, smoked more, and made fewer creased risk of prepubertal-onset conduct disorder in boys attempts to quit (58). Specific gene mutations, including and a fivefold risk in adolescent-onset drug dependence in those associated with dopamine D2 receptors (23) and do- girls (98). The outcomes are not explained by other risk pamine transporter proteins (95), have been implicated as factors. Maternal prenatal smoking appeared to be related possible determinants for nicotine addiction. People lacking to future criminal behavior in male children, with a a fully functional genetically variable enzyme CYP2A6 im- dose–response relationship between intensity of third portant in the metabolism of nicotine to cotinine are slow trimester smoking and arrest history of 34-year-old men nicotine metabolizers (30). This genotype may be important whose mothers smoked during pregnancy (63). Although in protecting against tobacco dependence because of im- such studies are limited by retrospective maternal reports paired nicotine metabolism and may be important as well of smoking behaviors during pregnancy, there is a consis- in determining dose and response to NRTs. Tobacco and Nicotine Exposure During Pregnancy MANAGEMENT AND THERAPEUTICS OF In the United States, about 25% of pregnant women smoke NICOTINE ADDICTION cigarettes, and so each year about 1 million babies are ex- posed in utero to tobacco smoke (89). Within those countries, smokers Tobacco smoking has long been known to present consider- have the lowest income, are the least educated, and have able fetal risks (59). Less well appreciated is that nicotine the poorest access to health care. Thus, from a world view, itself is a neuroteratogen (89).
It is popular and has been taken by 13% of 3000 UK university students (Webb generic levonorgestrel 0.18 mg overnight delivery, et al 0.18mg levonorgestrel, 1996) levonorgestrel 0.18 mg for sale, and 4 discount levonorgestrel 0.18mg with visa. Ecstasy causes the release of serotonin from nerve terminals buy levonorgestrel 0.18mg amex. It also inhibits tryptophan hydroxylase, the rate-limiting enzyme in serotonin synthesis, resulting in central serotonin depletion. Lowering of mood is frequently reported in the post use period, which is consistent with depletion of central serotonin. Ecstasy has both stimulant and hallucinogenic effects. It also causes an altered state of consciousness and profound feelings of attachment and connection. Physical effects are reminiscent of amphetamines use, with tachycardia, anorexia, increased motor activity, bruxism (teeth grinding), elevated temperature, and sweating. Animal evidence indicates MDMA is toxic to serotonergic neurons. Human neurotoxicity has not been conclusively demonstrated, but the evidence is strong (Gouzoulis-Mayfrank & Daumann, 2006). As mentioned above, Kish et al (2010) have shown reduced serotonin transporter density throughout the cortex of MDMA users compared to healthy controls. These losses are greatest in the insula and occipital cortex. Mental complication include anxiety and panic, major depression, prolonged depersonalization, suicidal ideation, and psychosis. Physical complications are more common when taken in combination with other substances and include hyperthermia, dehydration, idiosyncratic organ failure of heart and liver, and cerebral oedema. The serotonin and neuroleptic malignant syndromes have been described. The principal psychoactive component: delta-9-tetrahydrocannabinol (THC). Cannabis may be eaten, but the most efficient and common mode is smoking. A specific receptor (for the endogenous ligand anandamide) is located in regions associated with memory, reward, pain perception and motor co-ordination. A New Zealand study (Boden et al, 2006) found that by 25 years of age, 76. Acute mental effects include euphoria and relaxation, perceptual alterations (time distortion), intensification of ordinary sensory experiences (for example, while eating and listening to music) and impaired short-term memory and attention. Impairment in cognition and behavioural functions, such as driving are dose-related. The most commonly reported adverse mental effects are anxiety and panic reactions, and these may lead to discontinuation by naïve users. Earlier opinion was that cannabis was not a drug of dependence was incorrect. Tolerance (Adams & Martin, 1996) and withdrawal symptoms (Copersino et al, 2006) have been observed. Cannabis dependence, with inability to abstain is listed in the DSM-IV. It is not clear how cannabis dependence is best managed; some evidence indicates the use of CBT and social support. A major difficulty is that we do not know whether psychotic symptoms lead to cannabis abuse, or whether cannabis use causes psychosis (Ben Amar and Potvin, 2007; Mata et al, 2007). It is likely that the relationship is bidirectional (Hides et al, 2006). Recent work (Moore et al, 2007) finds that all those who use cannabis are at risk of psychosis. There is good evidence that cannabis can at least precipitate (bring forward) the first episode (which would otherwise have occurred later) of schizophrenia in a vulnerable person. Cognitive impairment, which is subtle and involves the higher functions of memory, attention and organization, and the integration of complex information, has been demonstrated in individuals with a long history of cannabis use (Solowij, 1998). High doses of cannabis have been reported to produce visual and auditory hallucinations, delusional ideas and thought disorder in normal volunteers. Cannabis use by people with schizophrenia is a major problem. Clinical experience indicates that cannabis is a potent cause of relapse and exacerbation of symptoms. Concurrent use of cannabis is associated with a worse prognosis for schizophrenia. Cannabis provides people who have lost much (career, prospects, income, family) with some comfort. Prevalence of use among people one year after first diagnosis of schizophrenia is 18.