3Local inhabitants consume cocaine by chewing leaves. going back yearsCoca chewers often combine the leaves with lime or ashThis promotes absorption
4Late 1850s German chemists had isolated pure cocaine Became immensely popular over the next 30 yearsProbably the most famous advocate was Sigmund Freud
51886 John Pemberton introduced Coca-Cola By 1885 Parke Davis & Co. pharmaceuticals was manufacturing 14 different forms of cocaine1886 John Pemberton introduced Coca-ColaCocaine containing tooth drops were even given to infants when teethingCocaine is a local anesthetic1914 Harrison Narcotic Act was the beginning of restrictions on cocaineOver time more and more restriction were put into place
61970s was the first wave of cocaine use increase – snorting cocaine From the 1920s-1960s cocaine was limited among a small group of artists, musicians, and other performers1970s was the first wave of cocaine use increase – snorting cocaine1980s (second wave)crack cocaineAbout 2 million people reported being current users (within the previous month)About 6 million within previous year34 million (14% of population) used at least once during lifetime
7Coca leaves contain about 0.6-1.8% cocaine Initial extraction of the leaves results in a paste that is about 80% cocaineThen converted to cocaine HCL a crystallized versionReadily water solubleCan be taken orallyIntranasallyIV
8Cocaine HCL is vulnerable to heat so that ruled out smoking Old way Can be converted back to cocaine freebaseOld wayDissolve cocaine HCL in waterAdd alkaline solution (ammonia)Extract cocaine with an organic solvent (ether)Freebasing refers to smoking cocaine obtained this wayEther is highly flammablePreparation and smoking is dangerousNew wayMix dissolved cocaine HCL with baking sodaHeat and then dryChunks of cocaine known as crackPopping noise when smoked.
10Smoked probably an understimate The different routes of administration yield somewhat different levels of plasma cocaineSmoked probably an understimate1-3 puffs of vapor heated in a flaskA few hours of coca leaf chewing produces plasma concentrations equivalent to a modest dose taking intranasally or orally
11Cocaine is fat solublePasses readily through the blood-brain barrierWhen smoked the brain is exposed to a very large surge in the brain that is not reflected in the peripheral venous systemOnce absorbed into circulation cocaine is rapidly broken down by enzymes in the bloodstream and liverHalf life hoursThus, subjective high is briefSmoking may produce only a 30 minute highThe breakdown products can persist longerBenzoylecgonine and be detected in urine for a number of days following the last dose in a heavy user
12Cocaine is often taken with depressant drugs to take the edge off the extreme arousal produced by cocaine aloneCocaine and alcohol when taken together produce a unique metabolite called cocaethyleneHas biological activity similar to cocaineHas a longer half lifeThe combination of cocaine and alcohol may increase the toxic effects of cocaine on the heart and other organs
13Cocaine interacts with several neurotransmitter systems Blocks the reuptake of three monoamine neurotransmittersDopamineNorepinephrineSerotoninBinds to and blocks the transporter
15Cocaine does not affect all monoamine transporters equally Has highest affinity for 5-HT transporter, followed by DA transporter, and NE transporterNevertheless, it is blockade of the DA transporter that plays the biggest role in the stimulating, reinforcing, and addictive properties of cocaineMany drugs used to treat depression block the 5-HT and NE transporterDo not have strong arousing effectsDo not have abuse potential
16At high concentrations cocaine inhibits voltage-gated NA+ channels in nerve cell axons Blocks conductionProduces local anesthesiaNovocaine (procaine)Xylocaine (lidocaine)Developed from cocaine
17Acute behavioral effects of cocaine Cocaine high (mild to moderate effects)Feelings of exhilaration and euphoriaSense of well beingEnhanced alertnessHeightened energyGreat self confidenceSmoking produces a “rush”Intense sense of great pleasure and powerIncreases sociability and talkativenessHeightened sexual interestCan increase aggression
18Note – how the effects become more negative as dose and duration of use go up. mq-table jpg
19Cocaine affects the behaviors of other animals as well Cocaine can cause psychosis at high enough doses (we’ll talk more about this later).Cocaine affects the behaviors of other animals as wellLab mice and rats are activated by low doses of cocaineLocomotionRearingSniffingHigher doses are replaced by focused stereotypiesStereotypy to stimulants in rats and miceIntense sniffingContinuous head and limb movementsLickingBitingHumans sometimes show stereotypy as wellRepetitive picking and scratching
20Monkeys have been trained to smoke cocaine freebase All animals tested so far readily learn to self-administer cocaine I.V.Monkeys have been trained to smoke cocaine freebaseIf cocaine is made freely available the animals health deterioratesHigh mortality ratesPoints to the powerful reinforcing properties of the drugAnimals trained to discriminate cocaine from vehicle readily learnLearning generalizes to amphetamineIndicates the two drugs are similarMuch less generalization to caffeineIndicates the two drugs are not as similar.
21Cocaine is considered a sympathomimetic drug Produces symptoms of sympathetic nervous system activationIncreased heart rateVasoconstrictionHypertensionHyperthermiaAt low doses these effects are usually not harmful.At high doses these effects can be fatalSeizuresHeart failureStrokeIntracranial hemorrhage
2211.8 Computerized tomographic (CT) scan of a thalamic hemorrhage in a crack cocaine smoker mq-fig jpg
23DA plays a key role in the subjective and behavioral effects of Cocaine Dopamine plays a central role in the behavioral response of animals to cocaine and amphetamineTable 11.2
25Subsequent work points to different regions of nucleus accumbens Note in Table 11.2 (previous slide) that amphetamine but not cocaine microinjected in the nucleus accumbens is reinforcing (Goeders & Smith, 1983)Surprising findingNot known whyDifferences in how cocaine and amphetamine work at the synapse?Anesthetic effects of cocaine?Subsequent work points to different regions of nucleus accumbensThere is evidence that rats will Self administer in to the NA shell rather than NA core (Rod-Henricks et al, 2002).
26Led to some confusing results Knock out miceMore recently the neurochemical mechanisms of cocaine action have been studied in genetic knock out miceLed to some confusing resultsMay say more about the knock out model than about the mechanism of cocaineNotice in the next slide that knockout mice for the dopamine transporter, still self-administer cocaine.FR 2 schedule
28This finding implies that the DAT is not the only mechanism of reward. Could be trueAlso could be that knockout mice adapt to the lack of dopamine transporterThere is some evidence that serotonin blockade may play a greater role in the reinforcing effects of cocaine in knockout miceFluoxetine (Prozac; 5-HT reuptake inhibitor) doesn’t support self-administration in wild-type miceDoes in knock out miceFluoxetine also was found to stimulate DA release in the mesolimbic pathwayin knock out mice; but not in wild type miceAdds to already high levels (because no DAT)Perhaps this mediates reward
29Neural mechanisms of psychostimulants in humans Brain imaging studies show that once a certain minimum level of DAT occupancy is achieved (40-60%) the subject may experience a “high”Studied with PET scan[11C]d-threo-methylphenidatea radiotracer which binds rapidly to the DAT in vivoSee how much cocaine (or methylphenidate) reduced [11C]d-threo-methylphenidate bindingUse methylphenidate, which also binds to DAT because it can be used in participants that have not previously used cocaine
30The intensity of the high depends on two other things besides drug occupancy of DAT 1) The rate at which the transporter occupancy occursIV and smoking = quick occupancyMore intense high2) The baseline of DA activityIf DA release is lowblockade of DAT may not have that much of an effectIf DA release is highblockade of DAT seems to have a much greater effectSee next slide.May explain individual differences in the high that people feelSome subjects with 60% DAT occupancy failed to report a highPerhaps they have low baseline DA levels
32The role of DA receptor subtypes in the effects of psychostimulants There are 5 different subtypes of DA receptorsD1 and D5 (D1-like family)D2, D3, and D4 (D2-like family)Studies have shown that antagonism of D1-like or D2-like families can reduce behavioral activation and reinforcing properties of psychostimulantsNonselective antagonistsSo we don’t know which member or members of the families are actually controlling the effects
33Genetic knockouts and cocaine Knockout mice lacking D1 receptorsAre not activated by cocaineWon’t self-administer cocaineThough they will work for food and for opiatesCaine et al. (2007)Also blocked self-administration of D2 agonistsKnockout mice lacking D2 receptorsAre activated by cocaineDo self administer cocaine
34What do the results on the previous slide mean? D1 receptors may play a bigger role in the activational and rewarding effects of cocaine than do D2 receptorsPerhaps D1 receptors play a permissive role for Dopamine agonists (Caine et al.)This would explain why D2 agonists were not effective in D1 knockout mice
35Implicates the D3 receptor in rewarding properties of cocaine D3 receptors?D3 receptor antagonist (SB A) blocks the enhancement of brain reward (ICSS) that normally occursImplicates the D3 receptor in rewarding properties of cocaine
36Cocaine abuse and the effects of chronic cocaine exposure People usually begin taking cocaine intranasallyMost who try cocaine do not continue to a pattern of drug abuseSome report anxiety responseAvailability of drug may be limitedCost may be too muchSocial and legal consequencesFear of addictionApproximately 10-15% of initial users eventually become abusers
37Social reinforcement may also play a role Initial use may be reinforced by the powerful rewarding aspects of the drugSocial reinforcement may also play a roleFriends enjoy newfound energy and enthusiasmTransition to smoking or IV is often a significant event in drug historyMuch greater highOften develop cocaine bingesBouts of drug use lasting from hours to daysNothing is more important than maintaining the high3-day freebasing binge could involve consuming as much as 150 g of cocaine
38Tolerance and Sensitization Psychostimulants cause tolerance, but they often also cause sensitization.sensitization can occur after a few exposurescan last for weeks or monthsWhy sometimes tolerance and sometimes sensitization?Not fully understoodPattern of drug use may play a roleChronic exposure (continuous infusion)more likely to elicit toleranceAcute exposures (once daily)more likely to elicit sensitizationSee following graphs
3911.12 Chronic cocaine administration can produce tolerance or sensitization (Part 1) mq-fig jpg
4011.12 Chronic cocaine administration can produce tolerance or sensitization (Part 2) mq-fig jpg
41SensitizationSensitization can increase in strength after the last drug use (that is during withdrawal).Presumably due to ongoing neurochemical changes.In some cases researchers have observed acute tolerance along with long-term sensitization.Bradberry (2000)Monkeys self administering cocaine over 6 month test periodMeasured DA levels in the striatumIf the monkeys injected themselves twice during a session,the DA response to the second dose was reduced (acute tolerance)However, the DA response to the first dose each session gradually escalated over the 6 month period (long-term sensitization).
42These acute tolerance and long-term sensitization effects may help us understand patterns of drug use in humansThe long-term sensitization may underlie the increased craving that users experience (like the incentive sensitization model we discussed in Ch 8).Users also report that during a cocaine or amphetamine binge, they need more drug later to obtain the high they had at the beginningThus, there may be a short-term tolerance that wears off prior to the next binge.
43Sensitization can be divided into two phases Induction Establishment of sensitizationNMDA receptors (glutamate) seem to be involvedRemember tolerance to opiates?ExpressionChanges in reactivity of DA nerve terminals in the nucleus accumbens seem to be involvedA given dose of cocaine causes greater increases in synaptic DA levels
44Health Consequences of chronic cocaine use As we stated before a single high dose can cause a stroke or seizureWhat about chronic use?Effects on the bodyHeart problemsChest painsCardiac arrhythmias (irregular hear rate)Cardiac myopathy (damaged heart muscles)Myocardial infarction (heart attack)There can also be adverse effects on the lungs, GI system, and kidneys.Snorting can lead to perforation of the nasal septum
45The old correlation causation issue Maternal Cocaine useEffects on fetusNot completely understoodSome children turn out okayOthers have attentional deficitsSome show Cognitive deficitsMay increase prenatal mortalityThe old correlation causation issue
46Chronic cocaine and the brain Check out Box 11.1 in your book for an in depth discussion.In general there is evidence that chronic cocaine use can alter DA functioning in the brainOf course we already expected this from the animal work that showed tolerance and sensitization effectsThere is also some evidence for decreased grey matter in brain areas associated with cognitive functioningPrefrontal and temporal areasThere is some evidence that there may be behavioral consequencesImpaired verbal memoryImpaired attentionImpaired motor functionBut….keep in mind…we have the old correlation vs. causation issue again.
47Pharmacotherapy for cocaine? Are there drugs we can use to treat cocaine abuse?Desipramine (tricyclic antidepressant)Mainly inhibits NE uptakeMost widely used drug to treat cocaine addictionUsed in adjunct with traditional therapiesUsed most often with those that have been diagnosed as also having depression (comorbid).Used for those diagnosed with cocaine abuse more than the more severe cocaine dependence.
48BP 897 a D3 receptor partial agonist reduces cocaine-seeking in rats Researchers are working on developing drugs that might reduce cocaine’s euphoric effectsPartial agonists of the DA receptor especially D1 and D3 are gaining a lot of interestWould compete with DA for access to the receptorWould have lower efficacyPossibly blunt the effects of cocaineBP 897 a D3 receptor partial agonist reduces cocaine-seeking in ratsIs currently in clinical trials
49Animals can be immunized against cocaine Cocaine vaccine?Animals can be immunized against cocaineCreate antibodies that attack the cocaine moleculeLess cocaine will get to the brainSeems to work with animals (see following figures).Has been tried with humans, but the antibodies gradually disappeared over time
5011.14 Reduction in behavioral responses to cocaine in vaccinated (immunized) rats (Part 1) mq-fig jpg
5111.14 Reduction in behavioral responses to cocaine in vaccinated (immunized) rats (Part 2) mq-fig jpg
52True amphetamine comes in 2 forms AmphetaminesAmphetamine is the parent compound of a family of synthetic psychostimulantsTrue amphetamine comes in 2 forms1-amphetamine (Benzedrine)d-amphetamine or dextroamphetamine (dexedrine)Other members of amphetamine-like psychostimulantsMethamphetamine3,4-methylenedioxymethamphetamine (MDMA)3,4-methylenedioxyamphetamine (MDA)3,4-metheylenedioxy-N-ethylamphetamine (MDE)As can be seen in the following slide all of these compounds are structurally quite similar to dopamine
5311.15 Amphetamine and related psychostimulants mq-fig jpg
54History of Amphetamine Ephedrine and Cathinone are naturally occurring plant compounds that are similar to amphetaminechemical structure presented in previous slideCathinone is primary active ingredient in khat (qat)Shrub native to East Africa and Arabia
55History of Amphetamine Ephedrine comes from the herb Ephedra vulgaris.Ephedrine (Ephedra) is obtained from the dried branches of this plantChinese have used Ephedra for more than 5000 years as an herbal remedyReduces appetiteHeightened energyBeen marketed as a weight loss product in health food storesWas very popular
56History of Amphetamine Side effects of ephedraElevated blood pressureIncreased risk for heart attack or strokeIn 2003 Baltimore Orioles pitcher Steve Bechler collapsed and died during spring training in FloridaHad been taking high doses of ephedra containing supplement to control weightCoroner ruled ephedra as a likely contributor to his deathFDA banned the sale of ephedra containing supplements in 2004.
57History of Amphetamine Ephedra played a role in the initial development of amphetaminePurified ephedrine was used to treat asthma in 1920sPseudoephedrine is a modern decongestantSimilar compound but with less side effectsThere was concern that demand may be greater than supply of the plantAmphetamine was used as a synthetic substitute.Smith, Kline, & French pharmaceuticals created an amphetamine-containing inhaler in 1932Effective treatment for nasal or bronchial congestion
58History of Amphetamine Some patients began to overuse the inhalersOften available without prescriptionContained a cotton plug which contained the amphetamineSome folks began to open the inhalers and either chew or swallow the cotton plug, or extract the amphetamine for injection.Amphetamine tablets were marketed in 1935 as a treatment for narcolepsy.Amphetamines are still used for this purpose today.1940s amphetamine was widely embraced by medical professionAmerican military personnel were given amphetamine to maintain alertness and forestall sleep while on duty
59History of Amphetamine After WWII there was a surge in street use of amphetamine1950s and 60s students used amphetamines as study aidsThe peak of use occurred in early 70sSince then cocaine use has surpassed amphetamine useAn exception to this trend is the recent upsurge in methamphetamine use
60Amphetamine/Methamphetamine Amphetamine and Methamphetamine are quite similar pharmacologicallyAmphetamine is typically taken PO, IV, or SCAKA: uppers, bennies, dexies, black beauties, diet pillsMethamphetamine is more potent than amphetamineTypically taken PO, Intranasally, IV, or smoked.AKA: meth, speed, crank, zip, goSmoking can be done with a glass pipe, or by heating on a piece of aluminum foil (“chasing the dragon”)
61Began showing up in Hawaii in the 1980s. Crystal Meth/IceMethamphetamine HCL is a crystal form that is particularly suitable for smokingAKA ice or crystal methBegan showing up in Hawaii in the 1980s.Now spread to many parts of the country.Especially west, south, and midwestInexpensive to make and highly addictive
62Little sleep or eating occurs during a run Patterns of useUse of amphetamine/methamphetamine often occurs in binges “speed freaks”Can last for daysLittle sleep or eating occurs during a runCheck out “Spun”Metabolized by the liver at a slow rateVery long half-life, so the high from amphetamine/methamphetamine lasts much longer than that of cocaine
63mechanism of action (a triple whammy) Amph./methamp. are indirect agonists of the catecholaminergic systemEnter the terminal button (via DAT) and cause release of catecholamines from terminal button2 mechanisms involved1) DA molecules are released from synaptic vesicles into the cytoplasm2) the dopamine transporter moves the DA out into the synapse (reverse transport)This reverse transport prevents reuptake.Very high doses can also inhibit monoamine oxidase
64Amphetamines do have therapeutic uses Used to treat narcolepsySome forms are also used to treat ADHDLow doses of psychostimulants can cause a calming effect in ADHD childrenUsually combined with counseling (therapy) of some sortMethylphenidate is available in several forms to treat ADHDRitalin (immediate release form)Works 3-4 hoursRitalin SRLasts 6-8 hoursRitalin LA and ConcertaCan last an entire day
65How can stimulants be calming? Human adults given low doses of methylphenidate are more likely to show arousal and hyperactivityBut young people appear to be calmedSome have speculated that this response is specific to children with ADHDOther researchers have shown that even children that don’t have ADHD have increased attention and lower activity levels to therapeutic doses of amphetamineLeading to speculation that this response to amphetamine is a general developmental phenomenon
66Apparently low doses can reduce activity in young rats as well. Kuczenski and segal (2002) – graphOral doses of methylphenidate during active part of cyle (night)Not shown in graph is that high doses (5 mg/kg) caused increased activity
67High doses and chronic use of amphetamine Amphetamines can cause psychotic reactionsSame sorts of symptoms that we discussed for cocaine psychosisThese kinds of effects usually require chronic high doses in order to develop.After a few “speed runs”Perhaps may cause “flash backs”Triggered by stressful eventsPerhaps previous drug use caused heightened stress sensitivity?
68Amphetamine Neurotoxicity Animals exposed to multiple doses of methamphetamineLong-lasting reductions inDA levelsTyrosine hydroxylaseRemember key enzyme in DA synthesisDopamine transporterIndicates damage to DA axons and terminalsHistology experiments show degenerating axonsAlso causes damage to serotonergic axons
69Amphetamine neurotoxicity in humans? PET scan data indicate large losses of DAT in the striatum for previous methamphetamine users.Doesn’t necessarily mean loss of axons, but animal data would imply that it mightNotice the lack of DAT in parkinson’s patients (PD) compared to controlThen compare the slides for methamphetamine usersGiven that striatal DA activity occurs during normal aging, if nothing else these findings might imply an increased susceptibility to Parkinson’s disease
70Developed by Merck pharmaceutical company in 1914 MDMA (Ecstasy)Developed by Merck pharmaceutical company in 1914Forgotten for decades, but reemerged in the 1970sSome psychotherapists began to give MDMA to clients during therapyCaused clients to communicate betterOpen up their emotions, experience greater closeness and empathy for othersPeople began to use it recreationallyAKA: Ecstasy, XTC, Adam1985 the DEA made MDMA a schedule 1 drug
71Psychological effects of MDMA Produces mild euphoriaIncreased energyEnhanced sensory perceptionFeelings of well being and self-confidenceDesire to interact with other people
72Physical effects of MDMA Increased heart rateIncreased blood pressureElevated body temperatureSweatingSalivationTremorTightening of jaw musclesTeeth grindingMDMA was closely associated with Rave sceneThis led to concern about heatstroke and dehydrationCould be fatal
73Mechanism of action of MDMA Acts at DA and serotonin neuronsEnhances release and blocks reuptake of both NTsThe primary mechanism of action appears to be activation of the serotonergic system.Probably explains the subjective and physiological differences between MDMA and amph./methamp.
74MDMA toxicity?Animal studiesRepeated high doses have been shown to damage serotonergic pathways in the brainDecreased serotonin levels and pruning (loss of terminal button branches) of serotonin axons in the the cortex and hippocampusThere is evidence of regrowth, but the regrowth is not always normalSome show long lasting deficits (see next figure)Some studies have actually shown development of excessive serotonergic input
75Monkeys stained for serotonergic neurons in neocortex Control monkey – left columnMiddle column5 mg/kg MDMA twice daily for 4 daysSacrificed 2 weeks laterRight columnSacrificed 7 years laterFrom what I can gather – (don’t hold me to this).A pretty high dose for humansAbout 2.5 mg/kgTypical dose?About mg/kg
76Does this sort of toxicity occur in humans? Critics say pretty high doses in animal studiesHumans may not typically expose themselves to such levelsHowever, there are signs of deficits in heavy usersReduced 5-HIAA (principle metabolite) of serotoninDecreased 5-HT transporter densitySome signs of cognitive deficitsDecreased performance on memory testsAgain…..correlational (poly drug use; preexisting conditions)Also typically study people that are chronic heavy users of MDMAHard to say what the long-term effects of a few doses of MDMA are.