Motivated Behaviors: Addiction & Eating. Motivation There are several types of motivation: –Basic needs Homeostasis: thirst, hunger, electrolyte balance,

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:– 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 self-

administered 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:• 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

• 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.

• Eating behaviors are evolutionarily ancient.– Programming hasn’t caught up to reality yet!

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 Eating1994 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 5-

HT 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:– 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”– 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.