Transcript Motivation, Addiction & Eating

Motivated Behaviors:
Addiction & Eating
Motivation
• There are several types of motivation:
– Basic needs
• Homeostasis: thirst, hunger, electrolyte balance, etc.
• Controlled by lower brain levels.
– “Pleasure” seeking
• Addictions, etc., also in lower or mid brain.
– Higher level
• Motivation to go to work, school, etc.
• Mostly controlled by cortex.
Addiction
• Addiction: the dependence on a substance.
• Dependence: the internal need or motivation
to seek out and use a substance regardless
of its benefits or harms.
Addiction
• Causes major social problems
– Increased crime
• Most corporate embezzlement due to gambling losses!
– Loss of productivity + increased health care costs
are estimated at nearly $150 Billion/year!
– Relationship problems, including abuse.
– Loss of life if user is responsible for others.
– Increases chances of HIV, STDs, cancer, and other
diseases.
Addiction
• Not a recent phenomenon - abuse of alcohol
and other substances are as old as history:
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Opium poppy by Indians
Coca leaves by South American natives
Tobacco by North American natives
Cannabis
• Not limited to humans - animals can also be
addicted and/or attracted to inebriation.
• This indicates an underlying biological basis.
Addiction
• Guwahati, India, December 17, 2003:
– At least six persons were crushed to death
by a gang that went amok after getting
drunk on rice beer near Guwahati, an
official said Tuesday. “They smashed huts
and plundered granaries and broke open
casks to drink rice beer. They went berserk
killing six persons," the official told reporter
by telephone from Tinsukia.
Addiction
– The culprits were ELEPHANTS!
“Pleasure”-Based Motivation
• James Olds and Peter
Millner (1950s)
– Rats were implanted with
electrodes.
– Rat received electrical
stimulation whenever it
pressed a lever.
– Some rats would press the
lever until exhaustion
(electrode in DA neurons).
“Pleasure”-Based Motivation
• One explanation of the Olds and Millner results
was that the rat experienced pleasure from the
stimulation, leading to the stimulation points
being labeled “pleasure centers.”
• Perhaps a more accurate view is that these are
“reinforcement centers.” (“wanting” vs. “liking”)
• There are also negative reinforcement areas.
Reward-Based Motivation
• Rats will self-administer drugs like humans.
• Several key sites of administration have been
mapped:
– Heroin (opiate) and nicotine (ACh) are readily
self-administered to the ventral tegmental area.
– Cocaine (DA reuptake) is readily selfadministered to the nucleus acumbens.
– Injections into mesotelencephalic structures, but
not other areas, produce place preference.
Reward-Based Motivation
Reward-Based Motivation
• Stimulation experiments in humans are much
more difficult, but there have been rare
opportunities with surgery (epilepsy) patients.
• The patients report pleasure from some sites.
• Patients will also continuously stimulate
certain areas that do not produce a pleasurable
experience. i.e. the reward is NOT pleasure!
Reward-Based Motivation
• One possible explanation for the scattered
sites of self-stimulation is that they are all
connected by a common pathway.
• As in rats, high rates of self-stimulation were
found in the medial forebrain bundle and
ventral tegmental area. These are both on the
dopaminergic pathways, leading to the
dopamine hypothesis of addiction.
Reward-Based Motivation
• Dopamine agonists (amphetamines, etc.)
cause increased self-stimulation rates.
• Dopamine antagonists (haloperidol, etc.)
decrease self-stimulation rates.
• Many addictive drugs such as heroin,
nicotine, cocaine enhance the efficacy of
dopamine and cause its release in the nucleus
acumbens of the thalamus.
Reward-Based Motivation
Reward-Based Motivation
• All natural reinforcers studied so far cause the increase
of dopamine in the nucleus accumbens.
– Heroin, nicotine, cocaine, amphetamines, and morphine are all
highly addictive, but have different mechanisms:
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Heroin acts on opiate receptors to ↑ DA neuron firing in VTA.
Nicotine acts on cholinergic receptors to ↑ DA neuron firing in VTA.
Cocaine blocks reuptake of NE and D in nucleus acumbens.
Amphetamines 1) cause leakage, 2) ↑ release and 3) block reuptake of
E, NE, D and 5-HT.
• The release of dopamine is a necessary, but not
necessarily sufficient, condition for positive
reinforcement.
Reward-Based Motivation
• Dopamine is not the complete answer.
– Cutting the medial forebrain bundle reduces, but does not
cause cessation of self-stimulation responses.
– Destruction of ascending dopaminergic axons reduces food
seeking behaviors, but does not reduce the pleasurable
responses to food.
– The ventral tegmental to nucleus acumbens dopamine
neurons are mostly associated with the “want” compulsion.
– Hedonic “liking” is related to and connected to the “want”
circuits, but is separate.
Negative Reinforcement
• Makes a response to an aversive stimulus
more likely (punishment = less likely).
• Positive reinforcement from drugs provokes
their continued use, but negative
reinforcement from withdrawal symptoms
inhibits quitting.
• Negative reinforcement also explains some
addictions that come from the use of drugs
to overcome unpleasant conditions.
Craving
• Cannot be completely explained by
withdrawal symptoms because it can occur
long after a person stops taking the drug.
• PET studies of cocaine addicts show that
cravings increased activity in the dorsolateral
prefrontal cortex, the amygdala and parts of
the cerebellum.
• Evidence of increased D3 receptors.
• Drug abuse changes the brain!
Addiction Terms
• Tolerance
– A decreased sensitivity to a drug caused by its
continued use.
– Metabolic tolerance
• Tolerance that results from changes that let less drug
reach the sites of action.
• Ex: alcohol abuse ↑ alcohol dehydrogenase
– Functional tolerance
• Tolerance that results from changes that decrease the
reactivity of the sites of action.
• Up- or down- regulation
• Most tolerance to psychoactive drugs is functional.
Addiction Terms
• Withdrawal syndrome
– The effects of the sudden withdrawal of the drug.
– Usually occur after tolerance.
– Typically the opposite effects of drug, suggesting
the same neural mechanisms that produce
tolerance are responsible.
– Ex. Heroin – symptoms include euphoria &
constipation, withdrawal includes dysphoria and
diarrhea.
Addiction Terms
• Physical dependence (Eddy 1965) “an adaptive
state that manifests itself by intense physical
disturbances when the administration of a drug
is suspended.”
• Psychological dependence (Eddy 1965) “a
feeling of satisfaction and a psychic drive that
requires periodic or continuous administration
of the drug to produce pleasure or to avoid
discomfort.”
Addiction
• It was previously thought that all addiction
required physical dependence (withdrawal
effects), but:
– People are not dependent when they start,
something else causes approach.
– Cocaine, which is highly addictive, has minimal
withdrawal effects/minor physical dependence.
• Do not underestimate the importance of
psychological dependence!
Substance Abuse Genetics
• Society has recognized for centuries that
alcoholism runs in families.
• Is this because of genetics, or shared values,
traditions, etc.?
• MZ = 50%, DZ = 30% for Type II males.
– Largely genetic, at least in males.
Substance Abuse Genetics
• Definitely polygenetic
• Vulnerability genes proposed on chromosomes 1, 2,
7, and 11 (DRD2, smoking also).
• Protection gene on chromosome 4.
– 50% of NE Asians do not have mitochondrial aldehyde
dehydrogenase 2 isoenzyme, which breaks down alcohol.
– Only 2% of NE Asian alcoholics have this defect.
– The lack of this enzyme causes alcohol hypersensitivity
and avoidance.
Alcohol Abuser Types
Type I
Type II
Genetics
Less dependent
Stronger genetic basis
Onset
Start drinking in response
to severe events
Drinking heavily by 25,
drink regardless of events
Susceptibility
Equal in men and women
Overwhelmingly men
Severity
Less severe
More severe
Personality
Tend to be anxious, shy,
emotionally dependent
Tend to be aggressive,
impulsive risk takers
Dependence
Drinking relieves anxiety,
but this is a + reinforcer
Very dependent, usually
abuse drugs, too
Digestion Review
• Mouth – predigestion and size
reduction
• Esophagus – tube to stomach
• Liver/Gall bladder – produce
digestive enzymes
• Stomach – protein and
carbohydrate digestion
• Small intestines – fat digestion
and nutrient absorption
• Large intestines – water
absorption
• Energy storage
– Lipids - from excess fats and glucose.
– Glucose - from carbohydrates in stomach.
Ingestive Behaviors
• Why do we eat and drink?
– Primary function is to supply the body with the
nutrients it needs to survive and function.
– Secondary functions can be social or hedonistic.
• What regulates our eating and drinking?
• Why can’t we control our eating?
– 65% of adults are overweight, 30+% obese
– 15% of kids are overweight
Regulation of Eating
• Eating behaviors are evolutionarily ancient.
– Programming hasn’t caught up to reality yet!
• Largely controlled by the brainstem.
– Suckling behaviors appear prenatally.
– Decerebrate animals will not approach
food, but can taste and swallow/spit
and regulate salt and sucrose intake.
– Large cortex allows for modification of
lower brain controls.
Regulation of Eating
• Eating is controlled by two opposite forces:
– Hunger - the drive to eat
• Physiological
• Psychological
– Satiety - a feeling of having eaten enough
– Ideally the two should balance out.
Regulation of Eating
• Animals tend to eat according to their needs.
– In rats, size of meal dictates time until next meal.
– Fat stores are kept constant.
• Humans
– Hardwired to eat when food is available.
– Tend to eat on fixed schedules.
– Will still modulate meal size according to amount
and time of last meal.
– Will also eat because of smell, sight, etc.
Regulation of Eating
• Dual Center Theory
– Hunger center in lateral hypothalamus controls
feeding behaviors. Lesions cause anorexia.
– Satiety center in ventromedial hypothalamus
inhibits eating behaviors. Lesions cause obesity.
– This is correct, but a little simplistic.
Regulation of Eating
• Set-Point Assumption (1950s-60s)
– Body tries to maintain constant energy state.
– Glucostatic (short-term) theory
• Set-point is based on glucose levels
• Responsible for short-term regulation
– Lipostatic (long-term) theory
• Kennedy (1953)
• Set-point is based on fat levels
• Responsible for long-term regulation
Regulation of Eating
• Long-term regulation of eating seems to
depend on the amount of stored energy (fats).
• The understanding of long-term regulation of
eating took a jump ahead in 1994 with the
discovery of leptin, a hormone released by fat
tissues that decreases eating and increases
metabolism.
Regulation of Eating
1994 Massively obese ob/ob mice were found
to have a genetic defect in the code for
leptin. Leptin injections reduce weight.
Leptin does not help
humans as much, at
least not adults.
Human leptin is 84%
similar to mouse
leptin (167 AAs).
Regulation of Eating
• Too much fat
– Adipose tissue releases more leptin.
– Leptin receptors in the arcuate nucleus of the
hypothalamus increase release of TSH and ACTH
from PVN, raising metabolism.
– SNS causes increased temperature and
metabolism.
– Increased αMSH and CART production causes
decreased feeding behaviors.
Regulation of Eating
• Too little fat
– Adipose tissue releases less leptin.
– Leptin receptors in the arcuate nucleus of the
hypothalamus increase release of NPY and
AgRP (αMSH opposite), which decreases TSH
and ACTH release, lowering metabolism.
– Decreased MCH and orexin production in
lateral hypothalamus cause increased feeding
behaviors.
Regulation of Eating
• Satiety factors:
– Gastric factors
• Short-term: distension factors
• Long-term: nutrient sensors, not volume!
– Intestinal factors
• Duodenum nutrient nerves, fats release CCK.
– Liver factors
• Senses glucose levels early (insulin). Fructose does
not cross the blood-brain barrier, but will stop eating.
– Head factors
• Brain estimates needs due to satiety time delay.
Regulation of Eating
• CCK reception seems to be mediated by
serotonin (5-HT).
– Increased 5-HT reduces feeding.
– Eating, especially of carbohydrates, increases 5HT levels.
• 5-HT agonists are powerful appetite
supressors. 5-HT agonists are also used as
anti-depressants, hence their use for obesity.
Hedonic Eating Behaviors
• Humans don’t only eat out of necessity.
• There is a hedonic (pleasurable) aspect to
eating as well.
• The mechanism is separate from feeding
motivation, and relies on stimulation of the
mesocorticolimbic dopamine system, which
has long been associated with reinforcing
behaviors.
UPDATE: Cannabinoid Receptors
• Cannabis-induced “munchies” have been known
for hundreds of years.
• Receptors activated by cannabis metabolites
(cannabinoids) have recently been identified
(CB-1 and CB-2).
• Several types of endogenous cannabinoids have
also been identified.
• Agonists cause eating, antagonists inhibit eating.
UPDATE: Cannabinoid Receptors
• CB receptors are found throughout the body:
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Hypothalamus – eating regulation
Limbic system – hedonic value
Intestines – satiety and lipid regulation
Liver, adipose tissue – fat storage
Pancreas – sugar regulation
UPDATE: Cannabinoid Receptors
• Engeli, Jordan (2006) CB1 antagonists act in
periphery to increase lipid metabolism and
decrease lipid formation.
• Ward, Dykstra (2005): CB1 receptors are
involved in the preferential reinforcement of
eating preferred vs. bland foods.
• Cota, et al. (2005) Chronic CB1 antagonist
TX only temporarily inhibits eating, but
weight loss continues.
UPDATE: Cannabinoid Receptors
• Rimonabant (Acomplia/Zimulti), a CB1
antagonist, is now in clinical trials. FDA
decision expected summer 2007.
• Suppresses appetite transiently
– Initial suppression lessens with time
– CB1 receptors in hypothalamus
• Weight loss continues
– CB1 receptors in liver and adipose tissue curtail
lipogenesis.
• Energy regulation, not orexigenesis
Eating Disorders
• Anorexia nervosa – “no appetite”
• Bulemia nervosa – “binge and purge”
– AN and BN are often comorbid & family
studies indicate a common genetic etiology.
• Obesity – overweight
• All are highly (50-80%) genetic.
• Probably involve metabolism efficiencies.
Eating Disorders
• Anorexia nervosa
– Most common in adolescent females - societal
pressures play a large role.
– Genetics also plays a large role (probably
around 50-60%), anorexia is 8 times more
common in relatives of anorexics.
• Anorexic’s genetics make them more metabolically
efficient than normal people.
Eating Disorders
• Anorexia nervosa – “no appetite”
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Mechanisms are not understood.
Unresponsive to drugs.
Therapy is not effective long-term.
Often exercise to excess, even though they lose
weight faster. It releases fatty acids into blood
and reduces feelings of hunger.
– Studies show their bodies respond to food
stimuli with increased insulin levels.
Eating Disorders
• Anorexia nervosa
– Anorexics have a higher than normal incidence
of mother’s difficult pregnancies.
– Anorexics often have gastric and intestinal
problems as children.
– NE, 5-HT and opioid abnormalities found.
– High co-morbidity of depression.
Eating Disorders
• Bulimia nervosa = “binge and purge”
– About 80% genetic predisposition.
– Not related to weight:
• 19% undereat, 37% normal, 44% overeat
– Often also found in anorexics.
– NE, 5-HT and opioid abnormalities found.
Eating Disorders
• Bulimia nervosa
– Depression is very often comorbid.
– Can be seasonally modulated like depression.
– Light therapy can help those who are seasonally
modulated, just like depression.
– 5-HT agonists (Prozac, etc.) often help.
Eating Disorders
• Obesity
– Heritability of weight is 60-90%.
– There is little evidence of leptin problems.
• Obese people generally have high leptin levels.
• But also no indication of leptin receptor problems.
– Probably more due to a less efficient
metabolism, along with possibly defective
satiety signals.
– Environmental and societal effects are large.