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Caffeine & Nicotine Diani Amaranath & Shareen Han Caffeine - Content Item Item Size Caffeine Content(mg) coffee 150 mL 60-150 coffee, decaf 150 mL 2-5 tea 150 mL 40-80 chocolate milk 150 mL 2-7 Mountain Dew 355 mL 54 Coca Cola 355 mL 46 Diet Coca Cola 355 mL 46 Sprite and 7-UP 355 mL 0 chocolate bar 50 g 3-63 peanut butter cup 51 g 5.6 chocolate chip cookie 30 g 2-5 MIDOL 1 tablet/capsule 32 *ANACIN 1 tablet/capsule 32 Caffeine - Prevalence • Worldwide, 120,000 tons of caffeine are consumed each year • The highest coffee consuming countries are Finland, Sweden, Denmark, Norway and Belgium. • The average daily consumption of caffeine among adults is 200 mg/day in the United States and Canada and more than 400 mg/day in Sweden and Finland. • Women metabolize caffeine about 25% faster than men • Why drink coffee?! (most popular source) - Need for a stimulant - Preference for coffee - Knowledge for coffee • Non-coffee drinkers even get plenty of caffeine: former coffee drinkers get about 107 mg per day and people who have never had coffee get about 91 mg per day Caffeine – ”Comorbidity” • • • • smokers =? = mood disorders substance abuse disorders Caffeine, drug withdrawal and dependence??? Caffeine - Symptoms • • • • • • Reduce fine motor movement Causes insomnia Headaches, nervousness and dizziness Pupil dilation Liver releases sugar into the bloodstream Blood vessels near the surface of the skin constricts • Increases heart rate • Bathroom breaks!!! (diuretic) Caffeine - Neuroanatomy Prefrontal Cortex http://www2.onu.edu/%7Eksehlhor/lecture.html#mesolimb Caudate Nucleus Caffeine –Adenosine • methylxanthine • caffeine increases the turnover of many transmitters, incl. monoamines (NE, 5-HT) and acetylcholines (ACh) • adenosine-ant. = DA , Adrenaline • adenosine decreases the firing rate of neurons and exerts an inhibitory effect on synaptic transmission and on the release of most neurotransmitters • acts on the A1 and A2a adenosine receptor subtypes • A1 (at high doses) - linked to adenyl cyclase - high levels in the hippocampus, cerebral and cerebellar cortex and thalamus • A2a (at low to moderate doses) - interaction with D2 receptors - almost exclusively located in the striatum, nucleus accumbens and olfactory tuburcle Caffeine – Monoamines • DA nucleus accumbens ??? • DA prefrontal cortex - Mesocortical subsystem • DA caudate nucleus - Nigrostriatal subsystem • expression of early genes in these areas with administration of caffeine • administer an adenosine A2a agonist, decrease the affinity of DA binding to D2 receptors in the striatal regions • caffeine leads to the inhibition and blockage of adenosine A2a receptors, leading to a potentiation of dopaminergic transmission • 5-HT later!!! Caffeine - Studies Withdrawal • Headaches, feelings of weariness, impaired concentration, fatigue, anxiety, irritability, increased muscle tension • onset of caffeine withdrawal effects usually occurs 24 h and peaks around 24-48 h (can appear within 3-6 h) • Experiment - Headaches B4 and After Surgery - Before and after surgeries, patients are usually told to fast for “X” amount of time - For every 100 mg increase in daily coffee consumption, the risk of headaches immediately before and after surgery is increased by 12-16% respectively, and also correlates with the duration of fasting - Risk of headaches reduce with caffeine substitutes (pills) - Caffeine withdrawal symptoms disappear soon after the absorption of caffeine in the blood - caffeine withdrawal, headaches and cerebral blood flow ??? Tolerance Caffeine - Studies • Seen in monkeys, mice, cats and squirrels • Reinforcement threshold for electrical brain stimulation • Tolerance development for animals and humans, including the effects of caffeine on blood pressure and heart rate, plasma adrenaline and NE levels and renin activity • Some indications of tolerance of caffeine in sleep: heavy coffee drinkers vs. non-coffee drinkers No tolerance development for caffeine??? • Limited evidence for tolerance in caffeine-induced alertness and wakefulness • Lack of tolerance of cerebral energy metabolism to caffeine: subjects had the same metabolic increases when administered of 10 mg/kg caffeine daily for 15 days (controls were injected with saline) Tolerance for caffeine remains unclear • Speculated that if tolerance to caffeine does exist it does not involve the adaptive changes in adenosine receptors but rather the DA system as a result of the chronic adenosine receptor blockage Caffeine - Studies Reinforcement • in rats, intravenous self-administration of caffeine via a lever (some of these studies, only a subset of the subjects pressed the lever) • in nonhuman primates, self administration was sporadic: periods of high frequency followed by periods of low frequency • caffeine was able to reinstate an extinguished cocaine self-administrating behaviour • dose dependent: 20-25mg = reinforcing properties, 50100mg = decrease, 400-600mg = adverse - occurs in 100% of heavy coffee drinkers (1020-1530 mg/day) - occurs in 45% of moderate coffee drinkers (128-595 mg/day) Caffeine - Studies Dependence • 99 subjects (U.S.) • 16 of which filled the criteria for caffeine dependence • dependence was not related to the amount of caffeine consumed daily • ranged from 129 to 2548 mg/day, median 360 mg • of the 16 subjects who were diagnosed as having a “caffeine dependence”… - 10 had a history of substance abuse disorder - 7 had a history of a mood disorders • these results are concurrent with other findings in the past where caffeine use was more prevalent in those who also consumed nicotine and alcohol Caffeine - Sleep • Areas that control mood and sleepwake functions are highly sensitive to caffeine • Regions include: 1. medial raphe (MRAP) 2. dorsal raphe (DRAP) 3. locus coeruleus (LC) • i.e. 200 lbs, 1 mg/kg = 1 cup of coffee • 5-HT: increase, promotes sleep decrease, reduces sleep • NE: increase, reduces sleep, inhibits REM sleep lesion LC, abolish muscle tone in REM sleep Caffeine – Sleep (again) • benefits of sleep… - restorative properties = helps the body recover from the activities during the day - deprived of stage 4 sleep, people complain about being physically tired - adaptive for animals who hibernate, are nocturnal or diurnal • shortens the time spent in various phases of slow wave sleep (repairing stages of sleep) • phases of REM sleep is preserved • prolongs sleep latency • caffeine withdrawal-induced behavioural changes usually last a dew days but the disruption in sleep-related signs have been shown to last up to 30 days after the onset of the withdrawal symptoms Caffeine – Long Term Aversive Effects • • • • • Caffeine dependence Infertility Birth defects Weight-loss Pancreatic Cancer (Wilcox, 1988) Caffeine – Benefits??? At low to moderate doses… • increases ACh synthesis (LTP and memory) • alertness (memory) • ability to concentrate • speeds up reaction time • Anacin – relieves vascular headaches Caffeine – Future Studies Parkinson’s Disease (Ross et al., 2000) • PD = decrease in DA BUT, caffeine increases DA • 8,004 Japanese American men, 102 developed PD • PD incidence, correlates negatively with the amount of coffee consumption • Caffeine from other sources such as green tea and chocolate were also associated with a lower risk in PD A little 4-1-1… + = Caffeine does NOT counteract the effects of alcohol!!! Drug tests include caffeine! Athletes are disqualified if their concentration exceeds 12 micrograms of caffeine per mL of urine. NICOTINE OVERVIEW • • • • • • • • • • Epidemiology Comorbidity Maternal Consequences Genetics Brain reward circuit Neurotransmitters Tolerance / Withdrawal Treatment Long-term effects / Benefits Conclusion EPIDEMIOLOGY • Lifetime prevalence - 24% • Highest risk for nicotine dependence occur in the first 16 yrs after smoking began • Gender differences COMORBIDITY • Comorbid with depression and schizophrenia • Psychiatric comorbidity in adolescents • Early onset of cigarette smoking and conduct problems- increased psychopathology Maternal Consequences • In utero nicotine exposure in animal models: – growth suppression – disturbances in neuronal pathfinding, – abnormalities in cell proliferation and differentiation – disruptions in the development of cholinergic and catecholaminergic systems. Maternal Consequences • Prenatal exposure to nicotine in humans: – – – – – risk of developing ADHD low birth weight elevated blood pressure dysregulation in neurodevelopment higher risk for psychiatric problems GENETICS • Family studies: – high vulnerability • Parental alcoholism and nicotine dependence – Adult children of alcoholics (ACOA) high risk of developing nicotine dependence (13.3%) – ACOA started regular nicotine use earlier Brain Reward Circuit • Nicotine receptors in the CNS found on presynaptic dopaminergic and serotonergic neurons in the brain • Neurons in Substantial Nigra and VTA are important in cigarette addiction Reward Pathway NEUROTRANSMITTERS Glutamate / GABA • Nicotine increases glutamate in the VTA, Nucleus accumbens, prefrontal cortex • Glutamate antagonist: – reduce nicotine self-administration in mice • GABA agonist: – reduce nicotine self- administration in rats Soluble Gases • Nicotine modulate effects on Nitric Oxide • increase Nitric oxide indirectly via glutamate receptors • increase in the cortex and hippocampus Dopamine • Increase extracellular dopamine concentration • inhibit uptake of dopamine through nicotinic acetylcholine receptors • increase release of dopamine in the nucleus accumbens Dynamics of Addiction Tolerance (Addiction Cycle) Tolerance • Repeated exposure to nicotine = increase nicotinic acetylcholine receptors • Tolerance builds up during the day • Night Abstinence : regain sensitivity to nicotine • Smokers use cigarettes to: – regulate amount of nicotine – stay in the neutral zone – avoid withdrawal symptoms Withdrawal Withdrawal Symptoms • • • • • • • Restlessness Irritability Anxiety Drowsiness Impatience Confusion Impaired concentration Withdrawal Symptoms • Physical signs – decreased heart rate – decreased urinary excretion of Epinephrine , Norepinephrine and Cortisol – gain weight (~ 5 pounds) • absence of anorexic effects of nicotine • decrease metabolic rate – craving persist for months to years Neurobiology of Withdrawal symptoms • Central and peripheral populations of nicotine acetylcholine receptors: involved in mediating SOMATIC signs • Only Central populations of nicotine acetylcholine receptors: involved in mediating AFFECTIVE signs Treatment • Oral nicotine solution • Nicotine replacement therapy (NRT) • Bupropoin SR – reduces withdrawal symptoms and weight gain • Behavioral Counseling • Antidepressants - Comorbidity Long-term Effects/ Benefits • Changes in nicotinic acetylcholine receptors (nicotine addiction) • elevation of nerve growth factor • enhance learning • protection of neuronal loss • preventive factor against neurodegenerative disease (Alzheimer’s and Parkinson’s disease) • Cognitive benefits in Schizophrenia Future Studies • Effectiveness of nicotine as treatment for neurodegenerative diseases • Is nicotine dependence a consequence or a cause of environmental factors versus biological factors