Lecture21-Drug Abuse (1)

Lecture21-Drug Abuse (1) - Drug abuse • Opiate use Tests...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Drug abuse • Opiate use Tests • Tests of drug abuse in the lab in The • The role of dopamine dopamine The • The role of the nucleus accumbens nucleus Theories • Theories of why we get addicted get Relative danger and abuse potential Heroin • Heroin is widely considered to be the most harmful abused drug drug In the US, heroin is a In Schedule I narcotic Schedule In the US, Morphine is In schedule II schedule In the UK, heroin is a In legal prescription drug… so it is schedule II schedule • • • History of opiate abuse Derived • Derived from opium plants plants Used • Used to make pain medication medication nitially, • IInitially, morphine was the most common pain medication medication Morphine • Morphine is named after Morpheus.. The Greek god of dreams Greek History of opiate abuse By • By the end of the 1800s, China produced and consumed >90% of the world opium of Over 25% of the adult Over population in China at this time was opioid dependent dependent Smoking opium plant Smoking still extremely common in middle east east • • Afghanistan Now, • Now, over 90% of the worlds the 10’s • 10’s of billions of dollars go to farmers, warlords, and drug traffickers and Over • Over 200,000 families in Afghanistan are supported by the opium trade Opiate use in the US… 1800s Post • Post civil war morphine dependence was common ‘the Soldier’s Disease’ was Heroin and other opiates nitially • IInitially marketed as less addictive than morphine… but is largely metabolized into morphine into Illegal since 1924 • Opioid abuse Abuse • Abuse of prescription opioids is a major problem problem Dependence on opioid Dependence based pain medication is very common is Opiates can have both Opiates stimulant and depressant effect (stimulant effects at low doses… depressant effects at high doses) high • • Opioid abuse Direct • Direct injection of opioid into the VTA causes a robust stimulant effect robust But these stimulant But effects are masked at higher doses that act to reduce behavioral activation activation Once drug leaves the Once system, animal will experience withdrawal experience Withdrawal symptoms Withdrawal are opposite of acute effects effects • • • Heroin self­administration (rats) Rats • Rats self administering 0.1 mg/kg heroin (i.v.) for the first 6 days of training first Then dose is cut in half Then (0.05 mg/kg) for the last 6 days days Note that rats nearly Note double the number of lever presses so that they can get more infusions of the lower dose lower In this way, they make sure In they get the ‘desired’ amount of drug amount • • • Increased dopamine following morphine Microdialysis • Microdialysis is used to sample the neurochemical environment is specific brain regions following drug infusions infusions Dopamine (or other Dopamine molecules) will diffuse through the dialysis membrane and samples are collected (usually every 10 min) and measured later in an HPLC system an • Increased dopamine following morphine Many • Many microdialysis studies have been conducted to measure how drugs alter dopamine signaling in different striatal subregions Increased dopamine following morphine Many • Many microdialysis studies have been conducted to measure how drugs alter dopamine signaling in different striatal subregions different Morphine injections cause Morphine greater increases in dopamine transmission within the nucleus accumbens shell compared to the nucleus accumbens core • Place conditioning f • IIf a drug is reinforcing, it may facilitate a conditioned place preference. Aversive events, drugs, etc… can cause a conditioned place avoidance conditioned Dopamine in the shell mediates morphine reinforcement Blocking • Blocking D1 dopamine • (but not D2 dopamine) receptors within the nucleus accumbens shell prior to morphine injections… prevents morphine induced conditioned place preference preference This effect is specific This to the shell… since D1 blockade in the core has no effect has Increased dopamine is a final common pathway All • All abused drugs, not just opiates, increase dopamine signaling within the nucleus accumbens accumbens Cocaine also Cocaine increases dopamine signaling preferentially within the nucleus accumbens shell Morphine Cocaine • Real­time dopamine measurements While • While microdialysis studies measure dopamine once every 10 min or so… fast-scan cyclic voltammetry measures dopamine 10 times per second 10 Microdialysis Fast-scan cyclic voltammetry Real­time dopamine measurements Voltammetry • Voltammetry utilizes micro electrodes made from a single strand of carbon fiber strand Real­time dopamine measurements The • The dopamine measurements are fast enough to resolve dopamine release from dopamine uptake dopamine ­0.4V 1.3V ­0.4V 500nM Cocaine­evoked dopamine release Blockade • Blockade of dopamine autoreceptors increases the frequency of dopamine release events (well established) established) And… cocaine slows And… dopamine uptake and increases the duration of dopamine release events (well established) established) raclopride • cocaine Cocaine­evoked dopamine release Most • Most recent evidence (published in 2008 and 2009; just two weeks ago) shows that cocaine also directly increases the frequency of dopamine release events Only, within the nucleus Only, accumbens shell… cocaine causes release events that resemble those evoked by autoreceptor blockade (via raclopride infusion) (via • Cocaine­evoked dopamine release For • For 2 to 3 minutes, the frequency of dopamine release events within the shell (following cocaine) are equal to reached following autoreceptor blockade Cocaine­evoked dopamine release The • The effect is prevented by preventing activation of dopamine neurons within the VTA. Thus, cocaine increases the activation of dopamine neurons Learning about cocaine n • IIn this study, a cue light (plus a tone) predicted a cocaine infusion. Following 10 to 20 cue/cocaine pairings… rats begin to approach the cue light Learning about cocaine When • When cue presentation leads to behavioral approach and investigation of the cue… more dopamine release occurred upon cue presentation within the core, not the shell of the nucleus accumbens Learning about cocaine Thus, • Thus, conditioned dopamine release caused by cue onset occurred within the core within This did not happen early This in training (B)… but did late in the training (C) late Unconditioned dopamine Unconditioned release following cocaine infusion occurred specifically within the shell (both early and late in training; D and E) in • • core shell Cocaine self administration in influenced by emotion Rats • Rats were given grape or orange kool-aid. Initially both flavors elicited positive hedonic reactions (lateral tongue protrusions; licking) protrusions; 30 min after the taste was administered, rats could either 30 self administer cocaine or saline self The taste that predicted cocaine self-administration soon The caused aversive taste reactivity (gapes) • • Cocaine self administration in influenced by emotion There • There was a relationship between the magnitude of aversive taste reactivity and motivation to take cocaine cocaine One possibility is that the One taste served as a cue to signal that cocaine will not be available for 30 min not Which caused a negative Which affective state Rats then took more Rats cocaine to alleviate their negative affect • • • Cocaine, emotion, and dopamine Tastes • Tastes that elicit positive taste reactivity increase dopamine signaling… tastes that are disliked decrease dopamine signaling Saccharin Quinine Cocaine, emotion, and dopamine • • • Questions: Can drugs change how much a rat likes or dislikes a reward? Is this reflected in rapid dopamine signaling? • 45 infusions (200ul/inf) of flavored 0.15% s infusions • 45 accharin (200ul/inf) of •flavored 0.15% saccharin Cocaine or saline injections • Cocaine or saline injections Electrochemical • •Electrochemical recordings in r dorsal shell of dorsal theecordings in thethe NAc shell cocaine pairings. after 10of the NAc after 10 cocaine pairings. Cocaine, emotion, and dopamine The • The same taste cue (saccharine) causes a decrease in dopamine signaling if it predicts cocaine dopamine Cocaine, emotion, and dopamine Again, • Again, the more aversive taste reactivity that is shown, the more • cocaine the rats take cocaine Since the taste cue is decreasing dopamine signaling, the Since increased cocaine seeking could be a compensation for that Why do some people abuse drugs? Almost • Almost everyone tries • • • drugs drugs But few get addicted Addiction is when Addiction drugs are taken compulsively, despite negative consequences consequences Often, people can quit Often, taking drugs for long periods of time… but then relapse (fall of the wagon)… why? the Why do some people abuse drugs? • Some primary explanations nitial • IInitial exploration… just • • • giving it a try etc Hedonics… enjoy the rush Hedonics… and pleasurable effects and Medication… drugs relieve Medication… unpleasant states such as anxiety, stress, depression, and pain and Then, something changes Then, and the person takes more and more and The nature of drug withdrawal Drugs • Drugs cause physical changes and the body adapts adapts For some drugs such For as opiates and alcohol, there are robust physical withdrawal symptoms and related tolerance and However, these effects However, are not the entire story… story… ‘Bubbles’ heroin addict from ‘the Wire’ • • The nature of drug withdrawal People • People and other animals will self administer opioids at doses that are too low to produce clear dependence dependence Further, withdrawal will Further, last days to weeks… and yet the liability to relapse lasts for years (may never go away) (may But, there is withdrawal But, other than the obvious physical signs physical • • ‘Bubbles’ heroin addict from ‘the Wire’ The nature of drug withdrawal The • The physical symptoms of withdrawal are past… yet avoiding relapse is a constant struggle Stress causes relapse to drug taking Two • Two primary environmental contributors to relapse… cues previously paired with drug use and stress previously Stress enhances drug related memories • • • • • • Human subjects… over 100 Human abstinent heroin addicts abstinent Asked to learn a list of words, Asked some related to heroin use, some were not some Prior to learning the words, Prior subjects were stressed (TSST social stress challenge) social Tell subject they have to give a Tell speech to a panel and measure their cortisol levels their Exogenous administration of Exogenous cortisol also enhances memory for drug words for Beta adrenergic antagonists Beta prevent enhanced memory by TSST and cortisol TSST Withdrawal ­ learning and memory Thus, • Thus, cues produce rapid withdrawal symptoms mediated by memory that drive resumption of drug use use Just the sight of heroin can Just induce negative affective state… that is relieved by drug use drug Thus, drug influence on Thus, learning and memory systems allow relapse liability to persist longer than withdrawal symptoms • • Incentive sensitization The • The learning and memory systems accessed by drug cues are not just activated… they have been pathologically strengthened by the associative processes and drug reinforcement drug Drug cues cause ‘craving’ Drug which is an abnormally strong wanting that results from sensitized associative motivational systems motivational Elegant behavioral evidence Elegant for sensitized motivational brain circuitry brain • • Incentive sensitization Neural • Neural restructuring is associated with behavioral sensitization by amphetamine and cocaine amphetamine By enhancing dopamine By transmission, abused drugs engage brain mechanisms normally used for reinforcement driven learning driven So… drugs usurp the So… neural machinery of learning (alter synaptic strength) • • Cocaine and neural plasticity Within • Within the nucleus accumbens… tests of neural plasticity show that long term depression (LTD) is a common neural adaptation neural LTD is a reduction in EPSP LTD amplitude following the training stimulation training Can be caused by a reduced Can number of synapses number Or a weakening of existing Or synapses (smaller or perhaps fewer receptors) fewer • • • Cocaine self administration and learning Rats • Rats were trained to self administer cocaine and then the ability to induce LTD in specific brain regions was assessed to Cocaine self administration and learning Drug • Drug seeking resulted in a reduction in the plasticity potential specifically within the nucleus accumbens core following 21 days of drug abstinence days Cocaine and neural plasticity At • At the level of the dopamine cells within the VTA… a single injection of cocaine strengthens glutamate synapses on the dopamine neurons that project to the nucleus accumbens Cocaine and neural plasticity • • • This effect persists for 5 but not 10 days And does not occur within all brain regions, for example, it does not And occur within the hippocampus occur Further, this effect does not occur at non-dopaminergic neurons Further, within the VTA (the absence of plasticity at GABAergic cells within the VTA is shown below) the Cocaine and neural plasticity This • This plasticity at dopamine neurons within the midbrain may explain why there is also sensitization at the level of increased dopamine concentration following amphetamine injections injections fmol/min DA Summary Drug • Drug abuse is very complicated and cannot be explained • • • • • by any single theory by Drugs usurp adaptive neural mechanisms that evolved to Drugs mediate motivated behavior critical for survival and reproduction reproduction Drugs target brain circuitry critical for emotion and Drugs motivation And have massive impact on neural mechanisms of And learning and memory learning Associative mechanisms become sensitized while Associative hedonic set points are reduced such that drug cues more easily evoke negative affect easily The result is persistent relapse and drug addiction ...
View Full Document

Ask a homework question - tutors are online