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1 Drugs of Abuse Yacoub Irshaid MD, PhD, ABCP Department of Pharmacology

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  • Drugs of AbuseYacoub Irshaid MD, PhD, ABCPDepartment of Pharmacology

  • Drugs of AbuseDrugs are abused when they are used in ways that are not medically approved, because they cause strong feelings of euphoria or alter perception.Repetitive exposure induces widespread adaptive changes in the brain. As a consequence drug use may become compulsive the hallmark of addiction.

  • Drugs of AbuseThe older term "physical dependence" is now denoted dependence, while "psychological dependence" is more simply called addiction.Once the abused drug is no longer available, signs of withdrawal become apparent, which defines dependence.

  • Drugs of AbuseDependence is not always a correlate of drug abuse it can also occur with many classes of nonpsychoactive drugs such as sympathomimetic vasoconstrictors and bronchodilators, and organic nitrate vasodilators.

  • Drugs of AbuseAddiction, on the other hand, consists of compulsive, relapsing drug use (after a successful withdrawal) despite negative consequences.

  • Drugs of AbuseAs a general rule, all addictive drugs activate the mesolimbic dopamine system increase in dopamine (?). Mesolimbic dopamine codes for the difference between expected and actual reward, and thus, constitutes a strong learning signal.

  • Major connections of the mesolimbic dopamine system in the brain. Schematic diagram of brain sections illustrating that the dopamine projections originate in the ventral tegmental area and target the nucleus accumbens, prefrontal cortex, amygdala, and hippocampus. The dashed lines on the sagittal section indicate where the horizontal and coronal sections were made.

  • Drugs of AbuseAddictive drugs can be distinguished into 3 classes:A first group binds to Gio-coupled receptors which inhibit neurons through postsynaptic hyperpolarization and presynaptic regulation of transmitter release. The action of these drugs is preferential on GABA neurons that act as local inhibitory interneurons.

  • Drugs of Abuse2. A second group interacts with ionotropic receptors or ion channels, and have combined effects on dopamine neurons and GABA neurons, eventually leading to enhanced release of dopamine.

  • Drugs of Abuse3. A third group targets monoamine transporters, which block reuptake of or stimulate nonvesicular release of dopamine, causing an accumulation of extracellular dopamine in target structures.

  • Neuropharmacologic classification of addictive drugs by primary target (see text and Table 32-1). DA, dopamine; GABA, -aminobutyric acid; GHB, -hydroxybutyric acid; GPCRs, G protein-coupled receptors; THC, 9-tetrahydrocannabinol.

  • Drugs of AbuseAntidepressants that block serotonin and norepinephrine uptake, but not dopamine uptake, do not cause addiction even after prolonged use.

  • AddictionIs a disease of maladaptive learning.It is characterized by a high motivation to obtain and use a drug despite negative consequences. With time, drug use becomes compulsive ("wanting without liking") ( ).Addicted individuals are at high risk of relapsing.

  • AddictionRelapse is typically triggered by one of the following three conditions:A. Re-exposure to the drug of abuse.B. Stress.C. A context that recalls prior drug use.((

  • AddictionLarge individual differences exist in vulnerability to addiction. Whereas one person may become addict" after a few doses, others may be able to use a drug occasionally during their entire lives without ever having difficulty in stopping. Even when dependence is induced with chronic exposure, only a fraction of dependent users will go on to become addicted.

  • AddictionHeritability of addiction, as determined by comparing monozygotic with dizygotic twins, is relatively modest for cannabinoids but very high for cocaine.

  • Nonaddictive Drugs of AbuseSome drugs of abuse do not lead to addiction.This occurs with substances that alter perception without causing sensations of reward and euphoria, such as the hallucinogens and the dissociative anesthetics.These agents primarily target cortical and thalamic circuits unlike addictive drugs which primarily target the mesolimbic dopamine system.

  • CannabinoidsEndogenous cannabinoids that act as neurotransmitters include 2-arachidonyl glycerol (2-AG) and anandamide, both of which bind to CB1 receptors.These very lipid-soluble compounds are released at the postsynaptic somatodendritic membrane, and diffuse through the extracellular space to bind at presynaptic CB1 receptors, where they inhibit the release of either glutamate or GABA.

  • Disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA) through drugs that act via Gio-coupled receptors. Top: Opioids target -opioid receptors (MORs) that in the VTA are located exclusively on -aminobutyric acid (GABA) neurons. MORs are expressed on the presynaptic terminal of these cells and the somatodendritic compartment of the postsynaptic cells. Each compartment has distinct effectors (insets). G protein- -mediated inhibition of voltage-gated calcium channels (VGCC) is the major mechanism in the presynaptic terminal. Conversely, in dendrites MORs activate K channels. Middle: 9-tetrahydrocannabinol (THC) and other cannabinoids mainly act through presynaptic inhibition. Bottom: Gama-hydroxybutyric acid (GHB) targets GABAB receptors, which are located on both cell types. However, GABA neurons are more sensitive to GHB than are DA neurons, leading to disinhibition at concentrations typically obtained with recreational use. CB1R, cannabinoid receptors.

  • CannabinoidsBecause of such backward signaling, endocannabinoids are called retrograde messengers.In the hippocampus, release of endocannabinoids from pyramidal neurons selectively affects inhibitory transmission, and may contribute to the induction of synaptic plasticity during learning and memory formation.

  • CannabinoidsExogenous cannabinoids (in marijuana), comprise several pharmacologically active substances including 9-tetrahydrocannabinol (THC), a powerful psychoactive substance. THC causes disinhibition of dopamine neurons, mainly by presynaptic inhibition of GABA neurons in the ventral tegmental area (VTA).

  • CannabinoidsThe half-life of THC is about 4 hours.The onset of effects of THC after smoking marijuana occurs within minutes and reaches a maximum after 12 hours.The most prominent effects are euphoria and relaxation.Users also report feelings of well-being, grandiosity, and altered perception of passage of time.

  • CannabinoidsDose-dependent perceptual changes (visual distortions), drowsiness, diminished coordination, and memory impairment may occur. Cannabinoids can also create a dysphoric state and in rare cases, following the use of very high doses, may result in visual hallucinations, depersonalization, and frank psychotic episodes.

  • CannabinoidsAdditional effects of THC include: increased appetite, attenuation of nausea, decreased intraocular pressure, and relief of chronic pain, have led to the use of cannabinoids in medical therapeutics.Chronic exposure to marijuana leads to dependence, which is revealed by a distinctive, but mild and short-lived, withdrawal syndrome that includes:

  • CannabinoidsRestlessness, irritability, mild agitation, insomnia, nausea, and cramping. Synthetic agents include 9-THC analogs dronabinol and nabilone.

  • LSD, Mescaline, and PsilocybinThey are commonly called hallucinogens because of their ability to alter consciousness such that the individual senses things that are not present.They induce, often in an unpredictable way, perceptual symptoms, including shape and color distortion. Psychosis-like manifestations (depersonalization, hallucinations, distorted time

  • LSD, Mescaline, and Psilocybinperception) have led some to classify these drugs as psychotomimetics.They also produce somatic symptoms (dizziness, nausea, paresthesias, and blurred vision).Some users have reported intense reexperiencing of perceptual effects (flashbacks) up to several years after the last drug exposure.

  • LSD, Mescaline, and PsilocybinThey induce neither dependence nor addiction. However repetitive exposure still leads to rapid tolerance. These drugs also fail to stimulate dopamine release, further supporting the idea that only drugs that activate the mesolimbic dopamine system are addictive.

  • LSD, Mescaline, and PsilocybinInstead, hallucinogens increase glutamate release in the cortex, presumably by enhancing excitatory afferent input from the thalamus.The molecular target of hallucinogens is the 5-HT2A receptor. This receptor couples to G proteins of the Gq type and generates inositol trisphosphate (IP3), leading to a release of intracellular calcium.

  • NicotineIts addiction exceeds all other forms of addiction, touching more than 50% of all adults in some countries.Nicotine withdrawal is mild, and involves irritability and sleeplessness. However, nicotine is among the most addictive drugs and relapse after attempted cessation is very common.Treatment for nicotine addiction includes:Substitution of nicotine.The antidepressant bupropion.Both combined with behavioral therapies.

  • Alcohol (Ethanol)The pharmacology of alcohol is complex and no single receptor mediates all of its effects.On the contrary, alcohol alters the function of several receptors and cellular functions, including GABAA receptors, Kir3/GIRK channels (G protein regulated inward rectifying potassium channels ), adenosine reuptake (through the equilibrative nucleoside transporter, ENT1), glycine receptor, NMDA receptor, and 5-HT3 receptor. They are all, with the exception of ENT1, either ionotropic receptors or io

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