Lec07 - Addiction and Alcohol - Ch09 Ch10 (4) PDF

Administration of an M5 muscarinic receptor (excitatory) negative allosteric modulator reduces voluntary ethanol consumption in iP rats iP rats: strain genetically selected to consume ethanol voluntarily  What is an alcohol and where does it come from? An alcohol is an organic...

Administration of an M5 muscarinic receptor (excitatory) negative allosteric modulator reduces voluntary ethanol consumption in iP rats iP rats: strain genetically selected to consume ethanol voluntarily  What is an alcohol and where does it come from? An alcohol is an organic compound with –OH bound to a saturated C Ethyl alcohol, or ethanol, is the alcohol form in drinks; other types of alcohol are toxic o e.g., methanol causes blindness or death Ethanol: produced by fermentation of sugars by yeasts; produces alcohol and CO2 Alcohol has calories but no nutritional value; chronic heavy drinkers may suffer malnutrition. The pharmacokinetics of alcohol determines its bioavailability Ethanol is a small molecule that can’t be ionised; mixes readily with water; not very lipid soluble but reacts readily with polar lipid head Easily absorbed from the GI tract; diffuses throughout the body, entering most tissues, including the brain Behavioral effects are described according to blood alcohol concentration (BAC) rather than amount ingested The pharmacokinetics of alcohol determines its bioavailability Alcohol is mostly absorbed from the small intestine into the blood by passive diffusion; the higher the concentration in the drink, the faster the absorption Food in the stomach delays movement into small intestine and thus absorption Absorption in women is faster than in men on average because reduced gastric metabolism (less alcohol dehydrogenase) and smaller body size increase the concentration FIGURE 10.4 Blood levels of alcohol after oral administration The pharmacokinetics of alcohol determines its bioavailability About 95% of ingested alcohol is metabolised by the liver at a constant rate (1 to 1.5 ounces/hour); about 5% is excreted by the lungs—which can be measured with a Breathalyzer Alcohol is oxidized by alcohol dehydrogenase and aldehyde dehydrogenase (ALDH) About 10% of Asians have genes that code for an inactive form of ALDH o Drinking alcohol causes build-up of toxic acetaldehyde o Flushing, nausea and vomiting, tachycardia, headache, dizziness, etc  FIGURE 10.5 Metabolism of alcohol Flushing depends on ALDH genotype The pharmacokinetics of alcohol determines its bioavailability Enzymes in the cytochrome P450 family also convert alcohol to acetaldehyde and metabolise many other drugs If alcohol is consumed with other drugs, they compete for the same enzymes; could lead to dangerously high levels of the other drugs Induction: when alcohol is consumed on a regular basis, these liver enzymes increase in number, which increases the rate of metabolism of alcohol and other drugs  Chronic alcohol use leads to tolerance Tolerance: effects of alcohol reduced when administered repeatedly Cross-tolerance with other drugs in the sedative–hypnotic class, including barbiturates and benzodiazepines Acute tolerance: in a single exposure; effects are greater while blood level is rising and smaller while blood level is falling; may lead to driving while intoxicated Metabolic tolerance: increase in P450 liver microsomal enzymes that metabolise alcohol Pharmacodynamic tolerance: neurons adapt to continued presence of alcohol by making compensatory changes in cell function Behavioral tolerance: practicing behaviors while under the influence of alcohol allows adjustment and compensation FIGURE 10.6 Tolerance to alcohol before 7-day drinking period after 7-day drinking period  Chronic alcohol use leads to both tolerance and physical dependence Physical dependence: intensity and duration of withdrawal is dependent on amount and duration of drug taking Alcohol shows cross-dependence with other drugs in the sedative- hypnotic class Hangover may be evidence of withdrawal or a sign of acute toxicity Withdrawal symptoms include tremor, anxiety, high blood pressure, rapid heart rate, sweating, rapid breathing, nausea, vomiting; some people experience delirium tremens (DT)  Alcohol affects many organ systems Dose-dependent effects on the CNS include relaxation, reduced anxiety, intoxication, impaired judgment, impaired memory, blackouts, and sleep Alcohol use increases risk of automobile accidents, violent crimes, and aggression High doses can cause alcohol poisoning, coma, and death due to respiratory depression  Alcohol affects many organ systems – vitamin B1 deficiency Heavy long-term alcohol use causes a vitamin B1 (thiamine) deficiency leading to cell death in the periaqueductal gray, medial thalamus, and mammillary bodies, causing Wernicke’s encephalopathy (WE) Korsakoff syndrome: permanent damage to thalamic nuclei and brain regions involved in memory subsequent to vitamin B1 deficiency Alcohol affects many organ systems – brain and glutamatergic neurons Multiple brain regions may be damaged by glutamate-induced excitotoxicity Other brain areas often show cell loss unrelated to diet: large ventricles indicate tissue shrinkage, small brain mass, cerebellar cell loss Alcohol affects many organ systems – circulatory systems Alcohol dilates peripheral blood vessels (seminar); in the brain vasodilation may improve cognitive function in older adults Low-to-moderate alcohol use increases the amount of “good” cholesterol in the blood while reducing the “bad”; may reduce incidence of blood clots and stroke Alcohol use disorder increases the risk of high blood pressure, stroke, and heart enlargement  Alcohol affects many organ systems – gastric system Alcohol increases sexual arousal while decreasing performance, increases appetite, and aids digestion by increasing gastric secretions Alcohol has a diuretic effect, by reducing secretion of antidiuretic hormone Liver damage associated with alcohol use disorder includes fatty liver, alcohol-induced hepatitis and cirrhosis  Alcohol affects many organ systems – development Alcohol passes through the placental barrier and the fetus quickly reaches the same BAC as the mother Fetal alcohol spectrum disorders (FASD) and the more severe fetal alcohol syndrome (FAS): intellectual disability and developmental delays, low birthweight, neurological problems, head and facial malformations Prenatal Alcohol Exposure (PAE) ➔ Ethanol is a teratogen, potential to cause developmental abnormalities in a fetus ➔ Widespread effects depending on factors such as chronic/acute dosing, timing of exposure, amount of exposure, and sex of offspring Fetal Alcohol Spectrum Disorders Physical Manifestations Behavioural and Cognitive Challenges (Williams et al., 2015) (Almeida et al., 2020) Dopaminergic System ➔ Regulates movement, Mesolimbic Mesocortical reward, motivation, and mood ➔ Significant changes during adolescence ➔ Dopamine neurons in the VTA innervate: NAc, amygdala, hippocampus Amygdala PFC 19 Social reward Crucial in forming and maintaining adaptive social relationships Period of adolescence characterized by increased social interaction  Adolescent Can be described as a unique period of increased vulnerability to social behaviour Development dysfunction Weaning Early Adolescence Mid Adolescence Late Adolescence Adulthood Postnatal day Postnatal day Postnatal day Postnatal day Postnatal day 21 30 40 50 60 McCormick & Mathews (2010) Social motivation operant conditioning task Behavioural Procedure Male and female Sprague Dawley early adolescence (P30), mid (P40), late (P50), and adulthood (P70) Training Days Progressive Extinction Tissue Fixed ratio (1:1) ratio test days collection (Steps of 5) 1 2 3 4 5 6 7 Days Early adolescent PAE rats displayed greatest social preference Control Male Control Female PAE Male P30 P40 PAE Female Social Preference Social Preference Non-social Preference Non-social Preference  Late adolescence and adult PAE rats displayed similar behaviour to controls Control Male across training days Control Female PAE Male P50 P70 PAE Female Social Preference Social Preference Non-social Preference Non-social Preference PAE rats continued to display greater social preference in early adolescence during progressive ratio Social Preference * Non-social Preference  PAE rats display reduced preference reversal during Control Male extinction Control Female PAE Male P30 P40 PAE Female Social Preference Social Preference Non-social Preference Non-social Preference PAE rats display reduced preference reversal during Control Male extinction Control Female P50 P70 PAE Male PAE Female Social Preference Social Preference Non-social Preference Non-social Preference What’s next These results resemble previous PAE research suggesting a lack of impulse control and altered reward sensitivity. Behavioural results inform potential for motivational circuitry deficits that require more research to determine the mechanism underlying the observed increased social motivation. Dopamine Receptors ➔ D1-like (D1 and D5) Stimulates cAMP production ➔ D2-like (D2, D3, and D4) Inhibits cAMP production  DR density plasticity throughout development (Andersen & Teicher, 2000) More to come! Receptor expression in the PFC, NaC, and MeA is being analyzed using Western blots D1 receptor density in prefrontal cortex D2 receptor density in prefrontal cortex D3 receptor density in prefrontal cortex  Animal models are vital for alcohol research Animals don’t naturally develop alcohol use disorder (AUD), there is no direct animal model; only specific components of AUD can be modeled Rodent models exist for acquisition and maintenance of drinking, physical dependence, relapse (alcohol seeking), compulsive drinking, and binge-type drinking Selectively bred alcohol-preferring (AP) and high-alcohol-drinking (HAD) rodents are used to evaluate behavior, neural mechanisms, and genetics of AUD FIGURE 10.13 Average daily alcohol consumption for selected generations of rats Alcohol-preferring (AP) Alcohol non-preferring (NP)  Animal models are vital for alcohol research Alcohol-preferring (AP) and high-alcohol-drinking rat strains have helped identify genes that influence alcohol consumption Experimental results indicate a role for the mGluR2 glutamate receptor in alcohol reinforcement mGluR2-knockout mice (Grm2) show increased alcohol consumption and preference over wild-type mice mGluR2 (Grm2)-knockout mice show increased alcohol consumption and preference  Alcohol acts on multiple sites and neurotransmitters Nonspecific actions: cell membrane lipids become more fluid; changes membrane relationship with membrane proteins Specific actions: influences ligand-gated channels and alters second- messenger systems FIGURE 10.15 Effects of alcohol on neuronal membranes  Alcohol use results in physiological dependence Acute alcohol reduces glutamate’s effect on NMDA receptors Alcohol reduces glutamate release in many brain areas Repeated use results in up-regulation of NMDA receptors During withdrawal, glutamate release increases, correlated with CNS hyperexcitability and seizures; excessive Ca2+ influx contributes to cell death o Why liquor stores were considered essential during pandemic! Frequently experienced withdrawal may be responsible for some irreversible brain damage FIGURE 10.16 Relationship between alcohol withdrawal and glutamate release behavioral rebound withdrawal hyperexcitability score  Alcohol acts on multiple neurotransmitters GABA: alcohol increases GABA-induced Cl− flux and hyper-polarization; also stimulates GABA release Some receptors respond to low doses of alcohol in a persistent fashion to the GABA that remains in the extracellular space; may have a role in reinforcing effects Repeated exposure to ethanol reduces GABAA-mediated Cl– flux; may contribute to tolerance and withdrawal Alcohol also impacts metabotropic GABAB receptors  Alcohol acts on multiple neurotransmitters Dopamine: activates dopaminergic cells in the VTA, causing release of DA in the NAcc, which is involved in positive reinforcement Increased dopaminergic transmission in the mesolimbic pathway occurs in response to most drugs of abuse, including alcohol In rodents, withdrawal after chronic alcohol use reduces firing rate of mesolimbic neurons and decreases DA release in the NAc Reduction in mesolimbic DA is also reflected in a rebound depression of reinforcement mechanisms  FIGURE 10.18 Dopamine turnover and alcohol withdrawal (Part 1) 3,4-Dihydroxyphenylacetic acid (DOPAC) Homovanillic acid (HVA) FIGURE 10.18 Dopamine turnover and alcohol withdrawal (Part 2) Rebound depression of reinforcement during withdrawal: more injected current is required to achieve reinforcement  Alcohol interacts with the opioid system Opioid systems: endorphins contribute to the reinforcing effects of alcohol; enhances release from the pituitary gland But chronic alcohol use reduces gene expression, less endogenous opioids are available for release Blocking opioid receptors reduces alcohol self-administration: μ-opioid receptor knockout mice do not self-administer ethanol High levels of μ-opioid receptors correlate with scores on craving AP rats release more opioids in response to alcohol and show enhanced opioid gene expression The causes of Alcohol Use Disorder (AUD) are multimodal No specific cause of AUD has been identified; a variety of factors contribute to vulnerability of any given individual Psychological factors: o Stress reduces or increases alcohol consumption under different conditions o Family history o Lifetime anxiety, especially early in life o Personality/novelty seeking and risk taking  Treatment strategies for rehabilitation Pharmacotherapeutic treatment includes two strategies: make drinking unpleasant and reduce alcohol’s reinforcing qualities Disulfiram (Antabuse) inhibits ALDH (converts acetaldehyde to acetic acid): o Drinking even 1 oz of alcohol results in flushing, pounding heart, nausea, vomiting, etc Naltrexone: an opioid receptor antagonist; reduces the “high” by blocking the effects of alcohol-induced endorphin release FIGURE 10.23 Effectiveness of naltrexone in treatment of AUD  Treatment strategies for rehabilitation Acamprosate: partial antagonist at glutamate NMDA receptors; significantly blocks the glutamate increase that occurs during alcohol withdrawal in rats  Possible new treatment strategies for rehabilitation CRF1 antagonists: repeated episodes of intoxication and withdrawal lead to increased CRF1 receptors in the amygdala, sensitisation of the reactivity to stressors, and significantly elevated rates of alcohol consumption Glucocorticoid receptor (GR) antagonist: reduced alcohol self- administration and craving Ketamine: NMDA glutamate receptor antagonist: could reverse the hyperexcitable state in withdrawal  Neurophysiology toolkit for psychopharmacology Contributions of distinct brain regions and pathways to learning and behaviour o Why does the potential for recreational drug use and addiction exist? Mechanisms of neural signal transduction and long-term changes Sites and mechanisms of cellular drug actions  Drug addiction is considered a chronic, relapsing behavioral disorder Early views emphasised physical dependence: abstinence from the drug leads to unpleasant withdrawal symptoms (but not for all drugs, e.g., cocaine) Modern focus is compulsive features of drug seeking and use, including craving (seminar) Individuals remain addicted for long periods of time; drug-free periods (remissions) are often followed by relapses The addictive potential of a substance is influenced by its route of administration Oral or transdermal: relatively slow absorption; slow drug availability to the brain IV or inhalation: rapid drug entry into the brain and a fast onset of drug action; but shorter duration of action Routes that cause fast onset of drug action have the greatest addiction potential: produce strongest euphoric effects and shortest latency Shorter latency between response and reinforcement would lead to stronger and faster drug conditioning FIGURE 9.5 Relationship between route of administration and addiction potential of opiates, cocaine, and nicotine levo-alpha-acetyl-methadol Most recreational drugs exert rewarding and reinforcing effects Positive reinforcers: consuming the drug strengthens whatever preceding behavior was performed by the organism (think of operant conditioning) Drug reward: the positive subjective experience associated with the drug – euphoria or the “high” Drug reinforcement is studied using self-administration tests; strong reinforcers in these tests have high addiction potential for humans, such as cocaine, heroin, and methamphetamine  Drug dependence leads to withdrawal symptoms when abstinence is attempted Development of addiction: drug-taking behavior progresses from an “impulsive” stage to a “compulsive” stage The process may be due to gradual recruitment of an “antireward” system in the brain (“neuroadapted state”) Rather than initial euphoria, antireward mitigates negative effects of lack of drug (‘least bad’ solution)  Genetic factors contribute to the risk for addiction Contribution of genetics to the risk for substance use disorder has been assessed using family, adoption, and twin studies Overall heritability of substance use disorders is in the range of 40% to 60% The remaining variability is due to environmental influences and gene- by-environment interactions (genetic component is only expressed in people with specific life events, such as stressful events) Sex differences in substance use, misuse, and addiction Biological sex and gender influence features of substance use, misuse, and addiction Men often begin use in a social context; women may begin in response to a negative life event and/or onset of depression or anxiety Women more often than men rapidly escalate substance use (“telescoping”) Many sex differences in substance use or addiction have been linked to female reproductive hormones or to differences in stress response  The neurobiology of drug addiction Development of addiction has been conceptualized as a repeating cycle of three stages (Figure 9.13 in text): o Preoccupation with and anticipation of obtaining and using the substance o Escalating use, which for some substances results in drug “binges” and intoxication o Withdrawal and the associated negative effects The model has been helpful for understand the neurobiology of addiction, including neural circuits and transmitters implicated in each stage Self-medication hypothesis applied to the development of alcohol dependence Transition from the impulsive to the compulsive phase of alcohol addiction The primary motivation for drug use over the progression from initial drug use to addiction Drug reward and incentive salience drive the binge/intoxication stage of drug use Reward circuit in the brain mediates the acute rewarding and reinforcing effects of most recreational drugs The mesolimbic DA pathway from the VTA to the NAc has a central role in the circuit; all recreational drugs activate this pathway Different locations in the circuit have receptors for each type of addictive drug Alternative viewpoint: neural circuit variation necessary for function results in an increased potential targets for many drugs  Brain pathways contributing to development and maintenance of addiction Mesocorticolimbic circuit includes: Dopaminergic projections from ventrotegmental area (VTA) Glutamatergic projections from hippocampus (HIPP) and amygdala (AMY) GABAergic projections from nucleus accumbens (NAc) https://upload.wikimedia.org/wikipedia/commons/9/98/Mesocorticolimbic_Circuit.png  Brain pathways contributing to development and maintenance of addiction Ventral tegmental area (VTA) VTA involved in reward responses and orgasms (pair bonding!) Rewards and drugs: VTA activation results in NAc receiving direct and indirect dopaminergic activation Mesolimbic (limbic/striatal projections) projections affect motivational behaviors Mesocortical (PFC) projections affect learning external cues  Brain pathways contributing to development and maintenance of addiction Striatum (Nucleus Accumbens, NAc) Broadly involved in acquiring and eliciting learned behaviors in response to rewarding cues: motivation, aversion, reinforcement VTA projections activate NAc: ~90% of NAc cells are GABAergic Behaviour affected by subregions (shell and core) and receptor type (D1 and D2)  Brain pathways contributing to development and maintenance of addiction Striatum (Nucleus Accumbens, NAc) Short-term rewards: shell projects to pallidum and VTA, regulating limbic and autonomic functions, modulates reinforcement Long-term rewards: core projects to substantia nigra (ST), development of reward- seeking behaviors NAc activation of dorsal striatum allows reward associated cues to activate dopaminergic system without reward being present: cravings, relapse  Brain pathways contributing to development and maintenance of addiction Prefrontal cortex (PFC) VTA dopaminergic projections activate glutamatergic projections to many regions, including dorsal striatum and NAc PFC mediates stimulus salience and conditional behaviors Abstinence activates PFC glutamatergic projection to NAc: cravings, addiction behaviours Mesocortical pathway enables associations of environmental cues with reward  Brain pathways contributing to development and maintenance of addiction Hippocampus (HIPP) ‘Switchboard’ of the brain: hippocampus indexes memory locations Contextualises reward memories and associated cues Triggers reward-seeking behaviors in responses to cues and contextual triggers  Brain pathways contributing to development and maintenance of addiction Amygdala (AMY) Involved in creation of strong cue-associated memories Mediates anxiety effects of withdrawal Mediates increased drug intake in addiction FIGURE 9.14 The neural circuit responsible for the acute rewarding and reinforcing effects of recreational drugs Drug reward and incentive salience drive the binge/intoxication stage of drug use The dopaminergic system is necessary for the rewarding effects of psychostimulants; for other drugs, it contributes to reward but is not required Role of DA neuronal firing may be to signal the difference between prediction of receiving a reward and actual occurrence of the reward (i.e., it encodes reward-prediction error) Other systems involved are the endogenous opioid and cannabinoid systems The withdrawal/negative affect stage is characterised by stress and by the recruitment of an antireward system Hyperkatifeia: negative emotional state evoked by drug withdrawal – proposed to be one of the core features of addictive disorders The transition from positive to negative reinforcement in the addiction cycle is mediated by neuroadaptations in multiple neural circuits The antireward system in the extended amygdala is gradually recruited; activated by NE, CRF, and dynorphin FIGURE 9.18 Neurochemical changes underlying the transition from positive to negative reinforcement in addiction The preoccupation/anticipation stage involves dysregulation of prefrontal cortical function and corticostriatal circuitry Dysfunction in the PFC and associated circuitry may play key role in preoccupation/anticipation stage, characterised by intrusive thinking, drug craving, and lack of impulse control Researchers have identified the neural circuitry underlying each of these processes Transition to uncontrolled drug use involves several brain areas: o Behavioral control shifts from striatal areas associated with goal- directed behavior to other areas associated with habitual behavior o Decrease in striatal DA neurotransmission  The persistence of addiction has been studied at both the molecular and synaptic levels Long-lasting changes in brain underlying persistence may result from altered gene expression and changes in synaptic plasticity/strength in the reward/antireward circuitry Epigenetic contributions: e.g., hyperacetylation of histones H3 and H4 in the dorsal striatum or NAc by several addictive drugs Drug-induced plasticity at excitatory (glutamatergic) or inhibitory (GABAergic) synapses: NAc glutamatergic synaptic plasticity mediated by altered AMPA receptor subunit composition is a key component of an animal model of drug craving incubation  Molecular mechanisms of addiction Synaptic changes in nucleus accumbens result from amphetamine overuse, leading to addiction ΔFosB is considered a master regulator of addiction o Overexpression is necessary and sufficient to induce addiction Amount of ΔFosB accumulation in nucleus accumbens (half-life of weeks or more) may be biomarker for drug addictiveness  Endogenous opioids regulate pain relief in males but not females Females display increased prevalence of chronic pain and weaker analgesic efficacy of opioid therapies Sex-specific differences may be driven by dimorphic endogenous opioidergic responses In rodents, male but not female analgesia was reversed by inhibiting endogenous opioidergic reception In humans, sex-specific endogenous analgesic system(s) have not been identified Jon G Dean, Mikaila Reyes, Valeria Oliva, Lora Khatib, Gabriel Riegner, Nailea Gonzalez, Grace Posey, Jason Collier, Julia Birenbaum, Krishnan Chakravarthy, Rebecca E Wells, Burel Goodin, Roger Fillingim, Fadel Zeidan. Self-regulated analgesia in males but not females is mediated by endogenous opioids. PNAS Nexus, 2024; DOI: 10.1093/pnasnexus/pgae453 Dopaminergic and nondopaminergic components contribute to opioid reinforcement Dopaminergic mesolimbic pathway: originates in the VTA of the midbrain and projects to limbic areas, including the NAc Opioid drugs inhibit inhibitory GABAergic cells, increasing mesolimbic cell firing and DA release in the NAc The mesolimbic DA system may mediate aversive effects of opioids, as well as their reinforcing properties FIGURE 11.18 Model of the effects of opioids on mesolimbic dopaminergic cells  Long-term opioid use produces tolerance, sensitisation, and dependence Withdrawal or abstinence syndrome When the drug is no longer present, cell function returns to normal but also overshoots basal levels Opioids in general depress CNS function; opioid withdrawal is rebound hyperactivity Cross-dependence: administering any other opioid drug will stop or reduce withdrawal symptoms  The opioid epidemic The most significant factor: misleading and aggressive marketing of OxyContin to doctors and patients by the maker, Perdue Pharma OxyContin became a popular street drug, and abuse and overdoses spread around the country Heroin and counterfeit pills are now being adulterated with illicitly manufactured fentanyl, 50 times more potent than heroin Several brain areas contribute to the opioid abstinence syndrome Animal models are used to determine which areas of the brain are involved in withdrawal signs Locus coeruleus (LC) and periaqueductal grey (PAG) are particularly sensitive to opioid antagonists in terms of precipitating withdrawal Nucleus accumbens (NAc) is important in reinforcement; may be important in aversive stimulus effects or motivational aspects of withdrawal Neurobiological adaptation and rebound constitute tolerance and withdrawal Classic hypothesis of opioid tolerance and dependence (1943): nervous system adapts to a drug; tolerance develops; when drug is withdrawn, adaptation causes rebound effects Opioids acutely inhibit adenylyl cyclase and cAMP production but cAMP returns to normal (tolerance) During withdrawal, cAMP levels increase dramatically Environmental cues have a role in tolerance, drug abuse, and relapse Environmental cues can be classically conditioned to drug taking After repeated administration in the same environment, animals show physiological signs of anticipation in that environment Euphoria may be associated with camaraderie of the drug-using subculture, drug acquisition activities and drug injection rituals, which become secondary reinforcers and act as triggers that promote drug taking o i.e., neural and neurotransmitter activity related to environment is superimposed on drug activation A drug addict may find that tolerance is lowered in a new environment, which may contribute to overdosing  Treatment programs for opioid use disorder Treatment requires understanding the multiple contributors to the problem Most drug treatment programs utilise a biopsychosocial model as the basis for therapy, take into account the multidimensional nature of chronic drug use: o Physiological effects of the drug o Psychological status and history of drug use o Environmental factors that act as cues Detoxification is the first step in the therapeutic process Can be assisted by long-acting opioids, e.g., methadone – reduces symptoms to a comfortable level Clonidine: (α2-adrenergic agonist), acts on noradrenergic autoreceptors to reduce NE activity in the locus coeruleus Treatment goals and programs rely on pharmacological support and counseling Methadone maintenance program: most common and effective treatment for heroin addiction Methadone has cross-dependence with heroin – prevents severe withdrawal symptoms; reduces euphoric effect of heroin Programs require daily supervised oral administration; reduces use of the needle and its ritual; reduces risk of unsterile needles Treatment goals and programs rely on pharmacological support and counseling Buprenorphine (Buprenex): opioid partial agonist used in the same way as methadone Compared with psychological treatments alone or managed tapering off of opiate use, long-term maintenance with opioid agonists produces better treatment outcomes Treatment goals and programs rely on pharmacological support and counseling Narcotic antagonists such as Naltrexone (Trexan) and Nalmefene (Revex) are used in some programs for alcohol and opioid abuse o Reduce cravings and euphoria Vaccines would produce antibodies to bind to the drug and prevent entry to the brain; no clinical trials yet Medication-assisted treatment: a combination of detoxification, pharmacological support, and group or individual counseling