UW BIOLOGY OF ADDICTION UNIT IV: STIMULANTS

LECTURE 17: COCAINE

LT FOR LESSON 17 COCAINELT=I CAN EXPLAIN HOW COCAINE WORKS AT THE LEVEL OF THE MOLECULE, THE NEURON, THE BRAIN, AND BEHAVIOR.

SUCCESS CRITERIA

• TO EVALUATE THE INFLUENCE THAT METHOD OF INTAKE HAS ON DRUG EXPERIENCE.

• TO UNDERSTAND THE BASIC PRINCIPLES OF ACID/BASE CHEMISTRY AND HOW THEY IMPACT THE COCAINE STORY.

• TO UNDERSTAND THE REWARD PATHWAY AND HOW THIS PARTICULAR DRUG STIMULATES IT.

• TO BE ABLE TO RELATE THESE INTERACTING MOLECULES WITH THE GENES THAT ENCODE THEM AND DEVELOP AN UNDERSTANDING OF HOW GENETIC DIFFERENCES CAN INFLUENCE DRUG EXPERIENCE.

• TO BE ABLE TO WEIGH RISKS AND BENEFITS OF THIS DRUG IN A KNOWLEDGEABLE WAY THAT ASSISTS IN WISE DECISION MAKING.

WHAT IS COCAINE? WHY IS IT USED?

• EXTRACTED FROM ERYTHROXLON COCA PLANT 2% OF THE LEAF IS COCAINE

HOW IS COCAINE ADMINISTERED?

INTENSITY AND DURATION OF COCAINE’S IMPACT DEPEND COMPLETELY UPON THE METHOD OF DELIVERY.

• COCA LEAVES ARE CHEWED, COCAINE IS EXTRACTED FROM COCA LEAVES.

• CONVERTED TO WATER SOLUBLE HYDROCHLORIDE SALT (ACIDIC). EXPORTED THIS WAY.

HOW IS COCAINE ADMINISTERED?

• FREEBASE MORE PURE AND ALKALINIZES COCAINE WHICH MAKES IT STRONGER.

• MADE BY DISSOLVING IN ALKALINIZING SOLVENTS (LIKE NAOH) AND THEN EXTRACT IT IN PETROLEUM OR ETHER.

• CRACK COCAINE TREATED WITH A BASIC SUBSTANCE (LIKE BAKING SODA) MAKES IT MORE ALKALINE AND LESS WATER SOLUBLE.

• CRACK IS LESS EXPENSIVE AND LESS DANGEROUS THAN FREEBASE.

• FREEBASE IS MORE DIFFICULT TO PRODUCE THAN CRACK

• BOTH ARE SMOKED RAPID ONSET

HOW IS COCAINE ADMINISTERED?

• POWDERED COCAINE

• INSUFFLATION

• SLIGHTLY SLOWER ONSET OF SYMPTOMS RELATED TO COCAINE USE

HOW IS COCAINE ADMINISTERED?

TEST OF CONTENT

Q: CRACK COCAINE IS MERELY PROCESSED COCAINE EXTRACT. IT IS NO LESS PURE. BUT CRACK COCAINE COSTS A FRACTION OF THE COST THAT CRYSTALLINE COCAINE COSTS. WHY MIGHT THIS BE A PARTICULARLY WISE MARKETING DECISION?

A: GET PEOPLE ADDICTED BY MAKING IT AFFORDABLE – REPEAT CUSTOMERS!

COCAINE DOSAGEDosage can vary considerably dependent on the method of administration and tolerance of the individual • A “line” of cocaine is about

50 – 75 mg• A dose of Crack is closer to

150 mg

The lethal dose of cocaine also depends upon the method of administration. • Snorted cocaine is lethal if

over 500 mg• Injected cocaine is lethal if

20 mg are administered.

COCAINE DOSAGE: TEST OF CONTENT

Why might it be untrue that one can more easily overdose (die) on crack than cocaine?

A. Because crack is smoked, much is lost from burning

B. Because crack is smoked, it gets into the blood faster

C. Because crack is smoked, we are protected from gastrointestinal effects

D. Because cocaine is snorted, it gets into the blood faster

E. Because cocaine is snorted, it has a shorter half life

BIOAVAILABILITYCOCAINE AVAILABILITY DEPENDS ON ADMINISTRATION

• CHEWED= SEVERAL MINUTES TO REACH THE BRAIN

• SNORTED (INSUFFLATION)= TAKES 3 MINUTES

• AN INSUFFLATED COCAINE HIGH LASTS APPROXIMATELY 30 – 60 MINUTES.

• INJECTED COCAINE = 15 SECONDS

• SMOKING COCAINE= 5 SECONDS

• THE HIGH FROM SMOKING CRACK IS VERY BRIEF (10 MINUTES) BUT MORE INTENSE THAN OTHER ADMINISTRATION METHODS

• CAUSES USERS TO “CHASE” THEIR HIGH, SEEKING MORE BECAUSE THEIR HIGH WAS INTENSE BUT BRIEF.

HOW IS COCAINE METABOLIZED?

Cocaine• Half life= ~

1hr

CYP2A4

Metabolite= Benzolecgonine• Half life 2-3 days as long as 8 days

BIOAVAILABILITY: TEST OF CONTENT

Q: BENZOYLEGONINE CAN BE DETECTED UP TO 8 DAYS AFTER COCAINE USE IN THE URINE. HOW DOES KNOWING ABOUT DRUG METABOLISM AFFECT THE TYPES OF DRUG TESTING THAT CAN BE DONE?

A: PREFER TO TEST FOR METABOLITE, NOT DRUG ITSELF

Q: LIDOCAINE IS A COCAINE-RELATED ANALGESIC THAT IS METABOLIZED BY CYP1A2 AND CYP3A4. REGULAR USERS OF WHAT TWO DRUGS MIGHT REQUIRE HIGHER DOSES OF LIDOCAINE?

A: OTHER DRUGS METABOLIZED BY THESE ENZYMES. CYP1A2 – CAFFEINE AND ECSTASY. CYP3A4 METABOLIZES NEARLY HALF OF ALL PRESCRIPTION DRUGS.

HOW DOES COCAINE BIND?

COCAINE BINDS TO RECYCLING TRANSPORTERS

IT INHIBITS ALL MONOAMINES, BUT PRIMARILY IMPACTS DOPAMINE REUPTAKE

HOW DOES COCAINE BIND?• WHEN BOUND TO THE

RECYCLING TRANSPORTER, TWO THINGS HAPPEN:

1. DOPAMINE CAN’T BE RECYCLED AND INTERNAL STORES OF DOPAMINE GET RELEASED.

2. THE DOPAMINE RECYCLER BECOMES SO OCCUPIED WITH ALLOWING DOPAMINE TO FLOW OUT OF THE NEURON THAT IT IS UNABLE TO RECYCLE DOPAMINE BACK IN.

HOW DOES COCAINE BIND?

• SYNAPSE IS FLOODED WITH DOPAMINE USER FEELS EUPHORIA

• BECAUSE DOPAMINE CAN’T BE RECYCLED, THE SUPPLY RUNS OUT OVER TIME

• LEADS TO USERS FEELING MORE DEPRESSED AFTER USE

• NOT JUST RELATIVE TO WHEN THEY ARE HIGH BUT RELATIVE TO PRE-DRUG USE.

• ORDINARY ACTIVITIES THAT ARE PLEASURABLE DUE TO DOPAMINE RELEASE DO NOT HAVE THE SAME IMPACT BECAUSE THERE LESS DOPAMINE AVAILABLE.

• THIS “BLAH” FEELING ABOUT THINGS THAT USED TO GIVE PLEASURE IS CALLED ADHEDONIA

AFFECTS ON THE CELLS AND TISSUES?COCAINE (LIKE NOVACAINE) IS AN ANESTHETIC.

• IT CAUSES NUMBING WHEN APPLIED DIRECTLY TO MEMBRANES OF THE MOUTH OR NOSE CAUSED BY A BLOCKAGE OF A SUBSET OF ION CHANNELS (SOME VOLTAGE-GATED SODIUM CHANNELS).

• BLOCKING THESE CHANNELS INHIBITS ACTION POTENTIALS ALTHOUGH DIFFERENT TYPES OF CHANNELS ARE IMPACTED AND NOT THOSE OF THE REWARD PATHWAY

• IT TURNS OUT THAT THERE ARE OTHER (NON-NEURAL) TISSUES WHOSE FUNCTION DEPENDS UPON SODIUM CHANNELS BLOCKING SODIUM CHANNELS IN THE HEART CAN LEAD TO HEART FAILURE.

AFFECTS ON THE CELLS AND TISSUES?

TEST OF CONTENT

Q: IMAGINE YOU USE ALUMINUM TO PACKAGE YOUR PRODUCT. YOUR ALUMINUM INPUT IS FROM MINING OR RECYCLING. YOUR ALUMINUM OUTPUT IS IN MAKING YOUR PACKAGE. IF THE USERS OF YOUR PACKAGE ARE UNABLE TO RECYCLE THE PACKAGE, HOW MIGHT THIS IMPACT THE SPEED OF YOUR PACKAGING? HOW MIGHT THIS RELATE TO COCAINE USER? EXPLAIN.

A: MUST RELY ON MINING, NOT RECYCLING. THIS WILL RESTRICT THE NUMBER OF CANS YOU CAN MAKE. SIMILARLY, COCAINE INHIBITS DOPAMINE RECYCLING SO THE ONLY DOPAMINE RELEASE THAT CAN HAPPEN RESULTS FROM NEWLY-MANUFACTURED DOPAMINE.

ADDICTION?

DRUGS THAT STIMULATE EUPHORIA ARE MORE LIKELY TO RESULT IN ADDICTION…LIKE COCAINE.

• THIS INTENSE FEELING OF EUPHORIA IS COMMUNICATED TO THE PREFRONTAL CORTEX AND HIPPOCAMPUS CAUSING A USER TO “LEARN” AND “DECIDE” THAT COCAINE USE IS WORTH REPEATING.

• BECAUSE USERS ARE DEPLETING THEIR DOPAMINE RESERVES WITH REPEATED USE OF COCAINE, THE POST-HIGH DEPRESSION CAUSES THEM TO WANT TO “CHASE” THAT HIGH BY USING THE DRUG AGAIN…

ADDICTION?DEPENDENCE CAUSES THEM TO SUFFER WITHDRAWAL SYMPTOMS WHEN THEY STOP USING THE DRUG. SO WHAT SYMPTOMS DO COCAINE USERS FEEL WHEN THEY STOP USING?

• A LOT OF PEOPLE WILL SAY THAT WITHDRAWAL SYMPTOMS FOR COCAINE ARE “ONLY PSYCHOLOGICAL”.

• THIS MEANS THAT THE USER CRAVES THE DRUG WHEN IT IS GONE.

• WHILE IT IS LARGELY TRUE THAT THERE ARE NO PHYSIOLOGICAL SYMPTOMS OTHER THAN CRAVING (NO GASTRO-INTESTINAL SYMPTOMS, NO ACHES, NO SHAKES), KEEP IN MIND THAT THE BRAIN IS THE ORGAN THAT DETERMINED “PSYCHOLOGICAL” MATTERS AND THE BRAIN IS AN ORGAN OF THE BODY.

• HAVING CRAVINGS IS INDEED A WITHDRAWAL SYMPTOM AND DEPENDING UPON THE USER AND CIRCUMSTANCES, IT CAN BE IMPOSSIBLE TO IGNORE.

EFFECTS OF COCAINE ADDICTION

• CONTINUED USE OF COCAINE HAS BEEN SHOWN TO REDUCE THE SIZE OF THE AMYGDALA (FEAR & STRESS) CAN RESULT IN REDUCTION OF INHIBITIONS ABOUT CONTINUED USE

• LONG TERM USE CAN ALSO RESULT IN CHANGES IN AREAS OF THE PREFRONTAL CORTEX RESPONSIBLE FOR PLANNING AND IMPULSE INHIBITION.

• THESE CHANGES RESULT IN LOWERED LEVELS OF PROTEINS IMPORTANT FOR REGULATING SYNAPSES, SO THE ABILITY TO RESIST CRAVINGS IS DIMINISHED.

TREATMENT OF COCAINE ADDICTION

SOME OPTIONS EXIST TO HELP MINIMIZE WITHDRAWAL SYMPTOMS.

• WELLBUTRIN INHIBITS MONOAMINE (DOPAMINE & NOREPINEPHRINE) REUPTAKE TRANSPORTERS AND AS SUCH ELEVATES MOOD

• KEEPS A MORE LIMITED SUPPLY OF DOPAMINE IN SYNAPSE LONGER LOWERS CRAVING

COCAINE ADDICTION: TEST OF CONTENT

Q: LIKE MOST STIMULANTS, COCAINE STIMULATES THE SYMPATHETIC NERVOUS SYSTEM, WHICH REDUCES URGE TO EAT / APPETITE. COCAINE FURTHER INHIBITS YOUR URGE TO EAT – WHY?

A: BY REDUCING DOPAMINE RESERVES, THE NORMAL “YAY” RESPONSE TO EATING IS DIMINISHED. BY NUMBING NOSE AND MOUTH, SENSORY EXPERIENCES WE ENJOY DURING EATING ARE MINIMIZED.

Q: LIKE MOST STIMULANTS, COCAINE CAUSES VASOCONSTRICTION. A PERSON WITH WHAT MEDICAL CONDITION(S) SHOULD NOT USE COCAINE?

A: HIGH BLOOD PRESSURE

BENEFITS?

COCAINE IS A SCHEDULE II DRUG CONSIDERED ABUSABLE BUT WHICH HAVE A RESTRICTED MEDICAL BENEFIT.

• MEDICAL BENEFIT OF COCAINE?

• USED AS AN ANESTHETIC THAT CAUSES VASOCONSTRICTION

• CAN BE USED FOR MINOR SURGERIES TO NUMB THE AREA AND REDUCE BLEEDING FROM THE SAME AREA.

• IN 1905, THE NOBEL PRIZE IN MEDICINE WAS AWARDED FOR THE DISCOVERY OF NOVOCAIN. NOVOCAIN IS A COCAINE DERIVATIVE THAT CAN SERVE AS AN ANESTHETIC WITHOUT GIVING PATIENTS ANY SENSE OF EUPHORIA, AND THEREFORE MINIMIZE ABUSE.

• KEEP THIS COCAINE/NOVOCAIN RELATIONSHIP IN MIND FOR LATER WHEN WE DISCUSS MEDICAL MARIJUANA.

HARMS?

COCAINE IMPACTS THE CARDIOVASCULAR SYSTEM

• CAUSED BY VASOCONSTRICTION

• PET SCANS OF COCAINE USERS SHOW REDUCED BLOOD FLOW AND GLUCOSE UTILIZATION IN THE BRAIN.

HARMS?

• VASOCONSTRICTION LEADS TO INCREASES IN BLOOD PRESSURE (HYPERTENSION)

• VASOCONSTRICTION ALSO LEADS TO STROKE AND HEART ATTACK BECAUSE BLOOD CLOTS ARE MORE LIKELY TO LODGE IN AND BLOCK NARROW BLOOD VESSELS.

• COCAINE IS ABLE TO BLOCK SODIUM CHANNELS NECESSARY FOR HEART FUNCTION.

• BLOCKING ELECTRICAL EVENTS OF THE HEART IS A PRIMARY CAUSE OF COCAINE RELATED OVERDOSE DEATH.

• COCAINE USE LEADS TO TACHYCARDIA – ELEVATED PULSE RATE.

HARMS?

COCAINE USE CAN BE ASSOCIATED WITH SEVERAL LESSER SYMPTOMS.

• USERS CAN EXPERIENCE SLEEP DISTURBANCES, RESTLESSNESS¸ PARANOIA, DELUSIONS, AND SCHIZOID BEHAVIOR (SOME SYMPTOMS COMMON WITH SCHIZOPHRENIA WHILE SOME OF THESE SOUND VERY SERIOUS (AND CAN BE) ALL ARE REVERSIBLE.

• EROSION OF NASAL MEMBRANES OCCURS WHEN USERS REGULARLY SNORT THE DRUG

• HIV RISK IS ELEVATED AMONG FOLKS WHO INJECT THEIR COCAINE

• RESPIRATORY AILMENTS ARE OBSERVED IF USERS SMOKE CRACK COCAINE OR FREEBASE.

HARMFUL SIDE EFFECTSCOCAINE USE HAS SERIOUS SIDE EFFECTS FOR A USER’S UNBORN CHILD. SO CALLED “CRACK BABIES” ARE ASSOCIATED WITH:

• 4 – 5 FOLD INCREASED RISK OF LOW BIRTH WEIGHT

• “FAILURE TO THRIVE”

• PREMATURE BIRTH

• BEHAVIORAL PROBLEMS SUCH AS BEING TEMPERAMENTAL AND HAVING LEARNING DIFFICULTIES

HARMS? TEST OF CONTENT

Q: MANY OF THE PROBLEMS EXPERIENCED BY CRACK BABIES RESULTS FROM THE ABILITY OF COCAINE TO CAUSE VASOCONSTRICTION. WHY WOULD THIS RELATE TO FETAL DEVELOPMENT? WHY WOULDN’T OTHER VASOCONSTRICTORS, LIKE NICOTINE AND CAFFEINE CREATE SIMILAR PROBLEMS FOR A FETUS? REDUCE SIZE OF VESSEL, REDUCE RATE OF NUTRIENT DELIVERY.

A: OTHER VASOCONSTRICTORS DO HAVE A SIMILAR IMPACT (TRICK QUESTION).

HARMS? TEST OF CONTENT

Q: THE FETUS HAS NOT YET DEVELOPED A FULL FUNCTIONAL LIVER PRIOR TO BIRTH. HOW MIGHT THIS RELATE TO INCREASING THE IMPACT OF COCAINE ON A FETUS?

A: LACK OF LIVER DEVELOPMENT MEANS INADEQUATE AMOUNTS OF METABOLIC ENZYMES, COCAINE STAYS IN BODY LONGER.

Q: THINK OF YOUR IMAGE OF A CRACK USER. USING YOUR CONCEPTIONS (MISCONCEPTIONS) ABOUT THIS TYPE OF PERSON, WHY MIGHT THE EVIDENCE PERTAINING TO PREGNANCY BE OVER-BLOWN?

A: MOST CRACK USERS ALSO USE OTHER DRUGS. WHICH DRUG HAS BIGGEST IMPACT IS DEBATABLE, AND PERHAPS IT IS THE MIXUTURE.

INDIVIDUAL EXPERIENCES MAY VARY

THERE ARE FOUR MAIN CATEGORIES OF GENETIC INFLUENCE UPON THE COCAINE EXPERIENCE.

1. ONE RESULTS IN USERS FEELING MORE (OR LESS) PARANOID WHEN THEY USE THE DRUG THIS SYMPTOM IS CORRELATED WITH PARTICULAR VERSIONS OF THE DAT GENE (ENCODING THE DOPAMINE TRANSPORTER).

2. SOME PEOPLE ARE MORE (OR LESS) DRIVEN TO USE COCAINE AT ALL DRUG-SEEKING BEHAVIOR IS CORRELATED WITH VARIATIONS OF D2DR GENE (ENCODING THE DOPAMINE RECEPTOR) .

• SOME VERSIONS OF THIS RECEPTOR ARE HYPOTHESIZED TO POORLY BIND DOPAMINE AND WHEN PEOPLE HAVE THIS VERSION, THEY CRAVE EXPERIENCES THAT LEAD TO DOPAMINE

INDIVIDUAL EXPERIENCES MAY VARY

3. SOME LABS ARE NOW INVESTIGATING AN ENDOGENOUS COCAINE/ AMPHETAMINE – LIKE SUBSTANCE.

• THE CARTPT (COCAINE AND AMPHETAMINE RELATED TRANSCRIPT PEPTIDE) ARE FOUND TO HAVE DIFFERENT VERSIONS IN POPULATIONS THAT DIFFER IN THEIR FREQUENCY OF COCAINE USE.

4. NEW STUDIES ARE FINDING THAT OUR BODIES MAKE A MICRO-RNA (212) WHICH SEEMS TO PROTECT PEOPLE WHO MAKE IT AGAINST COCAINE ADDICTION.

INDIVIDUAL EXPERIENCES MAY VARY: DRUG COMBINATIONS

• COMBINING DIFFERENT STIMULANTS TOGETHER (NICOTINE AND COCAINE, FOR INSTANCE) CAN EITHER ADDITIVELY, OR SYNERGISTICALLY, INCREASE THE RISK OF CARDIOVASCULAR ILLNESS.

• OTHERS MIGHT THINK THAT COMBINING ALCOHOL AND COCAINE MIGHT HELP THE ALCOHOL DRINKER TO STAY ALERT.

• AN UNEXPECTED OUTCOME RESULTS FROM COCAINE AND ALCOHOL USE THE BODY FORMS COCAETHYLENE WHEN COCAINE AND ALCOHOL ARE TAKEN SIMULTANEOUSLY

• THIS HAS BEEN SHOWN IN RODENTS TO BE VERY TOXIC TO CARDIAC FUNCTION

INDIVIDUAL EXPERIENCES MAY VARYQ: SINCE IT WOULD BE UNETHICAL TO ASK SOME PREGNANT WOMEN TO USE COCAINE AND OTHERS NOT, HOW WOULD YOU DESIGN A STUDY TO DETERMINE IF THE IMPACTS OF COCAINE ON FETAL DEVELOPMENT ARE COCAINE RELATED OR MULTI-DRUG RELATED?

A: USE AN ANIMAL STUDY. WANT A PLACENTAL MAMMAL.

Q: USING QUALITATIVE TERMS (GOOD TRANSPORTER – MOVES DOPAMINE EFFICIENTLY, GOOD RECEPTOR BINDS DOPAMINE TIGHTLY), WHAT VARIATIONS IN THESE FUNCTIONS DO YOU SPECULATE WILL LEAD TO PROTECTION FROM COCAINE ABUSE?

A: GOOD RECYCLER CRAVES MORE DOPAMINE IN SYNAPSE AND WILL BE MORE RESISTANT TO INHIBITION BY COCAINE.

THEY WANT TO USE MORE DRUG TO GET SAME EFFECT. BUT THEY MIGHT NOT FIND THE EFFECT AS PLEASURABLE, WHICH WOULD REDUCE THEIR LIKELIHOOD OF ADDICTION.

ERS FOR LESSON 17: COCAINE

REQUIRED READING:

• LISKA - SECTION 7.2 - 7.5 AND QUESTIONS 1- 6.

INTERNET

• HTTP://LEARN.GENETICS.UTAH.EDU/CONTENT/ADDICTION/DRUGS/DELIVERY.HTML

• HTTP://WWW.JUSTICE.GOV/DEA/CONCERN/COCAINE.HTML

• HTTP://WWW.DRUGABUSE.GOV/INFOFACTS/COCAINE.HTML