Neurobiology of Addiction. Ai-Min Bao M.D. Ph.D Neurobiology Department of Zhejiang University School of Medicine

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1 Neurobiology of Addiction Ai-Min Bao M.D. Ph.D Neurobiology Department of Zhejiang University School of Medicine

2 Addiction Addiction is a brain disease Addictive disorders are common and have vast consequences Every medical discipline is affected by addictive disorders Treatment for addictive disorders works

3 What can you become addicted to? Alcohol Tobacco Stimulants Marijuana Prescription Drugs Behaviors Gambling, Sex, Video Games, Shopping, Work Opiates Hallucinogens

4 Definitions 1. Addiction: a recurring compulsion to engage in a specific activity, despite harmful consequences to the individual's health, mental state or social life. Sometimes divided into substance addiction and "process addictions for gambling, shopping, sexual activity, eating, or other activities that become compulsive. 2. Tolerance: Pharmacological term for a decrease in drug potency after chronic use. Metabolic/pharmacokinetic tolerance - up-regulated drug metabolism and functional or pharmacodynamic tolerance as a result of reduced activity not attributable to enhanced metabolism.

5 Definitions 3. Cross-Tolerance: occurs between drugs in the same class e.g. LSD( Lysergic acid diethylamide,d- 麦角酸二乙胺, 半人工致幻剂 ) and psilocybin( 光盖伞素 ), alcohol and benzodiazepines or methadone and morphine. 4. Sensitization: increase in behavioral response to a drug as a result of a prior exposure to the drug - generally locomotion and in rodents. 5. Withdrawal: a syndrome observed after stopping a drug - generally resulting in physiological and psychological effects opposite to the acute effects of the drug e.g. seizures after stopping benzodiazepines or alcohol, diarrhea and hyperalgesia after stopping opiates and dysphoria after stopping most drugs of abuse. A manifestation of opponent processes.

6 What is Addiction?- some details from The American Society of Addiction Medicine ( 美国成瘾药物协会 ): A primary, chronic disease of brain reward, motivation, memory and related circuitry. characteristic biological, psychological, social and spiritual manifestations. reflected in the individual pursuing reward and/or relief by substance use and other behaviors. characterized by impairment in behavioral control, craving, inability to consistently abstain, and diminished recognition of significant problems with one s behaviors and interpersonal relationships. Like other chronic diseases, addiction can involve cycles of relapse and remission. Without treatment or engagement in recovery activities, addiction is progressive and can result in disability or premature death.

7 Symptoms of addiction Denial Loss of control Urges / cravings Irrational beliefs Compulsive thinking Impaired decision-making Relapse

8 Brain stimulation reward (BSR, 脑刺激奖赏 ) Direct stimulation of regions of the brain through either electrical or chemical means is rewarding and can serve as an operant reinforcer. The stimulation activates the reward system and establishes response habits similar to those established by natural rewards such as food and water. Electrical brain stimulation and intracranial drug injections are among the most powerful rewards because they activate the reward circuitry directly rather than through the peripheral nerves. Found in all vertebrates tested, including humans, providing a useful tool for understanding how natural rewards are processed by the brain as well as the anatomical structures and the neurochemistry associated with the brain's reward system.

9 Electrical stimulation of specific brain areas is associated with pleasurable sensations and animals will self-stimulate these areas repeatedly Olds et al (1954)

10 Dopamine (DA) is released in the nucleus accumbens (NAC) during cocaine self-administration Time (min) DA Drug self-administration paradigm Microdialysis to measure DA release in vivo

11 DA neurons are located in the substantia nigra ( 黑质 ) & ventral tegmental area ( 腹侧被盖区 ) in the midbrain Substantia nigra Ventral tegmental area

12 Dopaminergic Pathways Major targets include: Frontal cortical regions, limbic cortex (temporal lobe), striatum (caudate, putamen, accumbens), amygdala and hippocampus

13 Mesolimbic DA may mediate rewarding effects of naturally rewarding stimuli. Many abused drugs promote DA release

14 DA terminal fields: Caudate( 尾状核 ) Putamen ( 壳核 ) (Nigro Striatal) Nucleus accumbens ( 伏隔核 ) (ventral striatum) important in reward (VTA) (meso limbic)

15 The DA synapse Vesicular Monoamine Transporter (VMAT, 囊泡单胺转运体 ) Dopamine Transporter (DAT, 多巴胺转运体 ) Different drugs will target different transporters

16 Evidence in support of the role of DA neurons in Intracrainial Self-Stimulation (ICSS) 1. Mapping - Electrical self-stimulation is intense in the VTA regions that contain the highest concentrations of DA neurons. 2. DA release - Stimulation of the cells of the VTA increases DA release. Results obtained with microdialysis show increase in DA release in the NAC when rats engaged in VTA stimulation. Chemical lesion with 6-OHDA of neurons of the VTA reduces ICSS in that side. ICSS remains intense on the other non-lesioned side. 3. Pharmacology of ICSS - DA agonists and antagonists have opposite effects on brain self-stimulation.

为了帮助保护您的隐私,PowerPoint 禁止自动下载此外部图片若要下载并显示此图片, 请单击消息栏中的选项, 然后单击启用外部内容 Cocaine (benzoylmethylecgonine): a crystalline tropane alkaloid ( 莨菪烷类生物碱 ) obtained from the leaves of the coca plant.

17 为了帮助保护您的隐私,PowerPoint 禁止自动下载此外部图片若要下载并显示此图片, 请单击消息栏中的选项, 然后单击启用外部内容 Cocaine (benzoylmethylecgonine): a crystalline tropane alkaloid ( 莨菪烷类生物碱 ) obtained from the leaves of the coca plant. It is a CNS-stimulant, an appetite suppressant, and a topical anesthetic. Specifically, it is a serotonin norepinephrine dopamine reuptake inhibitor, which mediates functionality of these neurotransmitters as an exogenous catecholamine transporter ligand. Because of the way it affects the mesolimbic reward pathway, cocaine is addictive. Cocaine is ranked both the 2nd most addictive and the 2nd most harmful of 20 popular recreational drugs (Nutt et al., The Lancet 369 (9566): 1047)

18 Cocaine increases alertness, feelings of well-being and euphoria, energy and motor activity, feelings of competence and sexuality. Athletic performance may be enhanced in sports where sustained attention and endurance is required. Anxiety, paranoia and restlessness are also frequent. With excessive dosage - tremors, convulsions and increased body temperature are observed. Health problems from the use of legal substances, particularly alcohol and tobacco, are greater than health problems from cocaine use. Occasional cocaine use does not typically lead to severe or even minor physical or social problems.

19 Strong imbalances of transmitter levels Receptors disappear from the cell surface or reappear on it, resulting more or less in an "off" or "working mode" respectively, or they change their susceptibility for binding partners (ligands) mechanisms called down-/upregulation.

20 Finally, a loss of vesicular monoamine transporters (VMT), neurofilament proteins, and other morphological changes appear to indicate a long term damage of DA neurons. All these effects contribute to a rise in tolerance thus requiring a larger dosage to achieve the same effect. The lack of normal amounts of serotonin and DA in the brain is the cause of the dysphoria ( 烦躁不安 )and depression felt after the initial high. Cocaine dependence (or addiction) is psychological dependency on the regular use of cocaine, which may result in physiological damage, lethargy, psychosis, depression, akathisia ( 静坐不能 ), and fatal overdose.

Amphetamine is a psychostimulant drug of the phenethylamine ( 苯乙胺 ) class which produces increased wakefulness and focus in association with decreased fatigue and appetite.

21 Amphetamine is a psychostimulant drug of the phenethylamine ( 苯乙胺 ) class which produces increased wakefulness and focus in association with decreased fatigue and appetite. Side effects - Dependence and addiction Tolerance is developed rapidly - periods of extended use require increasing amounts of the drug in order to achieve the same effect. Abuse results in a stimulant psychosis: i.e. paranoia, hallucinations, delusions.

22 Mechanism of Amphetamine action Modulate several key neurotransmitters in the brain, including dopamine, serotonin, and norepinephrine. Region-dependent? certain receptors that respond to amphetamine in some regions of the brain tend not to do so in other regions. For instance, dopamine D2 receptors in the hippocampus, a region of the brain associated with forming new memories, appear to be unaffected by the presence of amphetamine. The major neural systems affected by amphetamine are largely implicated in the brain s reward circuitry. Moreover, neurotransmitters involved in various reward pathways of the brain appear to be the primary targets of amphetamine. DA, heavily active in the mesolimbic and mesocortical reward pathways - including the striatum, the NAC, and the ventral striatum, the primary sites of amphetamine action.

23 Amphetamine increases DA concentrations in the synaptic cleft, thereby heightening the response of the post-synaptic neuron, a specific action that hints at the hedonic response to the drug as well as to the drug s addictive quality. Two major hypotheses which are not mutually exclusive: 1) amphetamine s actions on the vesicular level, increasing DA concentrations in the cytosol of the pre-synaptic neuron. - backed by data demonstrating that injections of amphetamine result in rapid increases of cytosolic DA concentrations. Amphetamine is believed to interact with DA-containing synaptic vesicles in the axon terminal, a substrate for a specific neuronal synaptic vesicle uptake transporter called VMAT2. When amphetamine is taken up by VMAT2, the vesicle releases DA molecules into the cytosol in exchange. The redistributed DA is then believed to interact with DA transporter (DAT) to promote reverse transport. Calcium may be a key molecule involved in the interactions between amphetamine and VMATs.

24 2) the role of the DAT - amphetamine may interact with DAT to induce reverse DA transport from the presynaptic neuron into the synaptic cleft. there might be a direct interaction between amphetamine and DAT. DAT activity is believed to depend on specific phosphorylating kinases, such as protein kinase c, specifically PKC-β. Upon phosphorylation, DAT undergoes a conformational change that results in the transportation of DAT-bound DA from the extracellular to the intracellular environment. In the presence of amphetamine, however, DAT has been observed to function in reverse, spitting DA out of the presynaptic neuron and into the synaptic cleft. Thus, beyond inhibiting reuptake of dopamine, amphetamine also stimulates DA release into the synapse. - it has been found that PKC-β inhibitors eliminate the effects of amphetamine on extracellular DA concentrations in the striatum of rats.

25 Amphetamines and methylphenidate (Ritalin) block dopamine uptake and promote release 酪氨酸

Cocaine binds directly to the DAT1 transporter, inhibiting reuptake with more efficacy than amphetamines; Amphetamines phosphorylate DAT causing internalization - primarily

26 Cocaine binds directly to the DAT1 transporter, inhibiting reuptake with more efficacy than amphetamines; Amphetamines phosphorylate DAT causing internalization - primarily releasing DAT (while cocaine does not do) and secondary inhibiting its reuptak (and much more minor) in a different manner of cocaine: from the opposite conformation/orientation to DAT.

27 Serotonin Amphetamine has been found to exert similar effects on serotonin as on DA. Like DAT, the serotonin transporter SERT can be induced to operate in reverse upon stimulation by amphetamine. This mechanism is thought to rely on the actions of calcium ions, as well as on the proximity of certain transporter proteins. The interaction between amphetamine and serotonin is only apparent in particular regions of the brain, such as the mesocorticolimbic projection.

28 Other relevant neurotransmitters Extracellular levels of glutamate, the primary excitatory neurotransmitter in the brain, have been shown to increase upon exposure to amphetamine, an effect found in the areas of the brain implicated in reward - namely, the NCA, striatum, and PFC. Increased levels of norepinephrine in response to amphetamine, which is believed to occur via reuptake blockage as well as via interactions with the norepinephrine neuronal transport carrier. The long-term effects of amphetamines use on neural development in children has not been well established. Based on a study in rats, amphetamine use during adolescence may impair adult working memory.

29 Neurotransmitters in Addiction Neurochemical Main Region Role Dopamine NAc; SN Motivation, pleasure Serotonin Dorse Raphe Mood, pain, impulsivity Opioid Everywhere Pain, pleasure Glutamate (+) Hippocampus Learning, memory GABA (-) Everywhere Alertness

30 Alcohol: Neurotransmitters Neurotransmitter Increases Dopamine Decreases Serotonin Effects Pleasure, reward, craving Impulsivity, disinhibition + Opiates Euphoria + GABA Sedation, Hypnotic, Inhibits Glutamate Amnesia, Learning Impairments

31 THC( 四氢大麻酚 )and the Brain Binds to cannabinoid receptors CB1: hippocampus, cortex, basal ganglia, cerebellum and spinal cord CB2: Peripheral NS, immune system THC binds and activates CB1/2 and inhibits synaptic transmission

32 What are Opioids? Anything that binds to opioid receptors Endogenous (dynorphins, enkephalins, endorphins) Naturally-derived (opium) Semi-Synthetic (Heroin, Oxycodone( 羟考酮 )) Fully Synthetic (Methadone)

34 Drug ACUTE USE Like it or not? Decision to repeat? New User Genetics (impulsive?) Mood (depressed/anxious?) Peers (taking drugs?) Medicine (in pain/can t sleep?)?? DEPENDENT USER Adaptations (molecular, cellular and behavioral e.g.tolerance) Less euphoria from drug/natural rewards Loss of prefrontal cortical control of drug-behaviors (switch to habit circuitry) WITHDRAWAL Often opposite effects of acute drug (dysphoria) PROLONGED ABSTINENCE

35 New User Genetics (impulsive?) Mood (depressed/anxious?) Peers (taking drugs?) Medicine (in pain/can t sleep?) Drug DEPENDENT USER Adaptations (molecular, cellular and behavioral e.g.tolerance) Less euphoria from drug/natural rewards Loss of prefrontal cortical control of drug-behaviors (switch to habit circuitry) ACUTE OPIOID USE Euphoria Calm Analgesia Constipation Antitussive Respiratory Depression Druginduced adaptations and opponent processes OPIOID WITHDRAWAL Dysphoria Anxiety Hyperalgesia Diarrhea Sweating/chills Runny nose

Comparison of the perceived harm for twenty various psychoactive drugs from a poll among medical psychiatrists specialized in addiction treatment.

36 Comparison of the perceived harm for twenty various psychoactive drugs from a poll among medical psychiatrists specialized in addiction treatment. The physical harm was assigned a value from 0 to 3 for acute harm, chronic harm and intravenous harm. Shown is the mean physical harm. Not shown, but also evaluated, was the social harm.

Areas of the brain affected in Addiction Brain Regions Changes seen Symptoms Seen Orbitofrontal Cortex Anterior Cingulate Decreased activity at rest

37 Areas of the brain affected in Addiction Brain Regions Changes seen Symptoms Seen Orbitofrontal Cortex Anterior Cingulate Decreased activity at rest Increased activity when presented with drugs Anhedonia, Lack of pleasure from normal rewards Compulsive drive, increased saliency( 显著性 ) 情感和行为被此控制, 无法获得时, 体会到强烈的渴望

38 Stimulants & Blood Flow High blood flow Healthy Control Cocaine-dependent Gottschalk, 2001, Am J Psychiatry Low blood flow

40 Why does addiction begin in adolescence? Brains are not fully developed Brains react differently to drugs of abuse ETOH <14 = 4x risk as compared to ETOH >20

41 Why do some people become addicted? Biological risk factors Psychological risk factors Social risk factors

42 Biological Risk Factors 40-60% of vulnerability is genetic Metabolism Reinforcing effects Responses to the environment Neurochemicals Neurocircuits

43 Psychological Risk Factors Risk-taking Sensation-seeking Impulsive No coping skills Psychiatric conditions

44 Treatment Approaches to Addictive Disorders 1. Medications (Bio) 2. Therapy (Psycho) 3. Lifestyle changes (Social) BPS treatment

45 Medications of the future Vaccines: (Cocaine and Methamphetamine ( 甲基苯丙胺脱氧麻黄碱 )) Create antibodies that bind to abused drug Prevents effects of drugs Pharmacogenetic Matching Medications that promote compliance Long-acting Decreased side effects Ease of administration

Classes of Neurotransmitters. Neurotransmitters

Classes of Neurotransmitters. Neurotransmitters 1 Drugs Outline 2 Neurotransmitters Agonists and Antagonists Cocaine & other dopamine agonists Alcohol & its effects / Marijuana & its effects Synthetic & Designer Drugs: Ecstasy 1 Classes of Neurotransmitters