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 –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 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 ???
Caffeine - Studies Tolerance 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, mg = decrease, mg = adverse - occurs in 100% of heavy coffee drinkers ( mg/day) - occurs in 45% of moderate coffee drinkers ( 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 sleep- wake 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 (Wilcox, 1988) Birth defects Weight-loss Pancreatic Cancer
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.
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
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 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