Drugs & the BrainPart 6

Stimulants

What Are Stimulants?

• A group of drugs with many potential therapeutic uses, but also widely used and abused recreationally

• Improve mood, quicken intellect, enhance alertness, some relieve depression

• Includes more than one biochemical group with similar effects on the brain

• All produce dependence, though degree varies

Cocaine

• Coca leaves, the source of cocaine, have been ingested for their psychoactive effect for a thousand years

• The drug action of the leaves is the same as that of the pure chemical

• More gradual & less intense only because leaves are chewed, passing through the digestive system to the blood stream, while pure cocaine is snorted or injected, a more direct route

History of Cocaine

• Ancient Inca society considered coca a symbol of divinity. – Use was confined to royalty and priests.– After Spanish conquest, coca use became

widespread among Peruvian commoners

• Mid 19th C. coca became popular in Europe

• Pure cocaine has been a drug of abuse for at least 100 years

Vin Mariani

• 1863- Corsican chemist Angelo Mariani patented Vin Mariani, a coca extract in wine

• Became Europe’s most popular beverage

• Thought to have wide-ranging curative powers

• Also developed coca tea & coca lozenges

• Awarded a medal by the Pope

The Coca-Cola Connection

• Mariani was the inspiration for Georgia pharmacist John Pemberton

• Developed Coca-Cola in 1886– Original preparation contained wine– Later substituted kola nut extract, a source of

caffeine– In 1888 substituted soda water for plain water– This is basically “classic” coke – but today without

the cocaine

Things Go Better With Coke

• 1892- rights were purchased by Asa Candler who founded the Coca-Cola Co.

• Led to widespread distribution and the development of soda fountains.

• Further mixed the pursuit of health and the pursuit of pleasure

Isolation of Pure Cocaine

• Cocaine abuse was not a significant problem until the development of the drug in pure form

• 1860- a chemist obtained pure cocaine by mixing plant juices into organic solvents

• 2 years later another chemist determined its chemical formula

Molecular Structure of Cocaine

Analyze This

• Sigmund Freud was one of the first to investigate medical use of purified cocaine

• Thought cocaine might be used to treat nervous exhaustion

• Obtained samples from Merck Pharmaceuticals• Ingested them himself• Conducted several medical studies• Demonstrated apparent increase in muscular strength• Published an article which initiated widespread

prescription of cocaine for anxiety & depression

“Cocaine brings about an exhilaration and lasting euphoria which in no way differs from the euphoria of the healthy person . . .You perceive an increase of self-control and possess more vitality and capacity for works . . . In other words you are simply normal, and it is soon hard to believe that you are under the influence of any drug . . . Long intensive mental or physical work is performed without any fatigue . . .This result is achieved without any of the unpleasant after effects that follow exhilaration brought about by alcohol.”

Sigmund Freud

An Error in Judgment

• Freud recommended cocaine to relieve morphine addiction

• A close friend had developed a morphine addiction following use to combat pain associated with amputation of his thumb

• Freud substituted cocaine• The patient was soon injecting larger and larger doses• Ultimately he developed cocaine psychosis• Similar experiences occurred throughout Europe• Freud was heavily criticized in the medical community

for his initial embrace of cocaine

Medical Uses of Cocaine• Cocaine was the first effective local anesthetic• Local anesthesia is safer than general anesthesia• Local anesthesia is required for some types of

surgery• Cocaine injected into the peripheral nerves of an

are creates a nerve-block• Use for local anesthesia prompted drug companies

to develop related compounds that could be synthesized– These include procaine, lidocaine & tetrocaine– These are still used for local anesthesia

Caffeine• Caffeine in coffee, tea, &

many soft drinks is a member of a group of molecules called xanthines

• Other xanthines are theophylline & theobromine

• Causes stimulation, alertness, elevation of mood

• Caffeine containing compounds in use since 900 A.D.

Coffee, Caffeine & Society

The Down Side of “Up”

• Excess caffeine produces symptoms of anxiety neurosis– Can induce panic attacks in

some subjects

• Is addicting & produces tolerance

• Though from a different chemical family, effects are similar to amphetamines

Action of Caffeine

• Blocks the brain’s receptors for adenosine– Adenosine is an inhibitory transmitter– Inhibits the release of other neurotransmitters

• Thus caffeine is a stimulant because it blocks the inhibiting action of adenosine

• Arousal effect of caffeine is the result of increased norepinephrine in the cerebral cortex

Nicotine• Found in tobacco• Increases arousal, alertness, mental

efficiency• Is highly addictive & produces tolerance• Mimics acetylcholine in the brain• One type of acetylcholine receptor is

called “nicotinic” because it binds nicotine

• In the brain leads to release of many neurotransmitters, including endorphins & dopamine in the reward pathway

Understanding Nicotine

• Radiolabeled acrtylcholine incubated with brain slices – autoradiograph then slows where receptors are located by lighting up on x-ray film

• Comparison of brains of smoker & non-smokers showed that smokers had more nicotinic receptors– Nicotine desensitizes receptors– This stimulates brain cells to produce more

receptors

Mode of Action of Nicotine

• Nicotine is a cholinergic agonist

• It acts by stimulating nicotinic acetylcholine receptors.

Structure of Caffeine & Nicotine

Genesis of Amphetamines

• Developed to treat asthma

• Epinephrine was a common effective treatment for asthma– Epinephrine is a bronchial dilator– But cannot be taken orally

• Chemists were looking for a derivative that could be taken by mouth

The Herbal Connection• Investigated ma huang (Ephedra vulgaris),

a plant used in Chinese herbal medicine to treat asthma

• Ephedrine was the first successful asthma medication which could be taken orally

• Ma huang was scare• Chemists attempted to create synthetic

substitutes• Mid 1930s – synthesized amphetamine

Benzedrine

• Amphetamine could be dispensed in a volatile form that could be inhaled directly

• Marketed as Benzedrine• Benzedrine inhalers were a non-prescription item widely

marketed in the 1930’s & 1940’s• Usefulness to prevent sleepiness and increase mental

alertness was quickly recognized by the general population, especially college students

• People opened the inhalers & ingested the contents orally• Amphetamine abuse was also wide spread by service men

from many countries during WW II

Multiple Effects

• Besides their stimulant effects, cocaine, amphetamines and other stimulant drugs suppress appetite

• Amphetamines were widely used for appetite suppression until dangers were recognized

• Are the stimulant & euphoric effects of these drugs directly related to appetite suppression?

• Led to development of many new amphetamines

Attention Deficit Disorder

• Amphetamines have a claming effect on younger patients with attention deficit disorder (ADD)

• Seems counter-intuituive

• Actually, effect is not ‘calming’, but focusing – increases ability to concentrate

Stimulant Psychosis

• Cocaine & amphetamines induce identical psychoses• A functional psychosis: conscious and aware• Closely resembles paranoid schizophrenia

– Auditory hallucinations– “idea of reference” (everything has to do with them)– Paranoid ideation (everyone is out to get them) – Touch hallucinations are unique to this condition

• Symptoms relieved by neuroleptic (anti-schizophrenic) drugs– Barbiturates make the psychoses worse

• Schizophrenics in remission experience return of psychosis with small doses of amphetamine

The Norepinephrine Connection• Amphetamines closely resemble norepinephrine &

dopamine• Norepinephrine neurons originate in the locus coeruleus in

the brainstem• The norepinephrine system forms many branching

connections– Axons from the locus coeruleus branch out to contact several

billion neurons – 1/3 to ½ of the cells in the brain– Norepinephrine neurons touch cells in the cerebral cortex in a

non-specific manner

• Norepinephrine neurons are most highly concentrated in the limbic system

Mode of Action of Amphetamines• The major action of amphetamines is to release

norepinephrine & dopamine from storage vesicles • Because amphetamines resemble

neurotransmitters, they displace those molecules from their storage sites

• Both inhibit the pump that ordinarily inactivates norepinephrine & dopamine – same action as tricyclic anti-depressants

• Schizophrenia-like psychosis is due to increase in dopamine release

Mode of Action of Cocaine

• Molecular action of cocaine is not known, but may be same as amphetamines

• Cocaine’s stimulant effects are closely associated with inhibition of dopamine reuptake

• Stimulant effects of both amphetamines & cocaine are due to increased norepinephrine activity in the cerebral cortex

Comparing Molecules

ephedrine

amphetamine

methamphetamine

dopamine

norepinephrine