Drug abuse, drug addiction OBJECTIVES Describe the major actions of drugs that are commonly abused and the likely mechanisms behind addiction. Understand the central role of dopamine in the central reward circuitry. Describe the major signs and symptoms of overdose with, and withdrawal from, CNS stimulants, opioid analgesics, and sedative-hypnotics, including ethanol. Describe the general principles of the management of overdose of commonly abused drugs.
Drug abuse, Drug addiction References . E.J. Nestler, Historical Review: Molecular and Cellular Mechanisms of Opiate and Cocaine Addiction, Trends Pharmacological Sciences 25, 210-218, 2004. Trainspotting (1996) director Danny Boyle, from the Novel by Irving Welsh (available at Video Difference, Quinpool)
Addiction, abuse, dependence • Conceptual separation of “dependence” and “addiction” • Older term of “physical dependence” now referred to as “dependence: • Older term of “psychological dependence” now referred to as “addiction”
Drug abuse Dependence • Psychological -compulsive drug seeking -Activation of reward system b) Physiological -withdrawal Tolerance • Metabolic -increased metabolism, excretion (pharmacokinetic) • Behavioural -learned behaviours • Functional -pharmacodynamic (receptors, etc) • Reverse tolerance!!!
CSF Microdialysis Dialysis tubing in blue Steel tubing in black
Reinforcement and addictive disorders: key concepts • Addiction is compulsive, out-of-control drug use, despite negative consequences. • Addictive drugs induce pleasurable states or relief from distress, thus motivating repetition.
The anatomy of addiction: key concepts • Addictive drugs act on brain reward circuitry. • Major component of brain reward circuitry is mesolimbic dopamine projection. • Dopamine acts to change expression of genes that regulate gene expression.
Addiction • The brain reward circuitry targeted by addictive drugs normally responds to natural reinforcers such as food, water, sex • Brain reward circuitry includes the dopamine neurons in ventral tegmental area and projections to nucleus accumbens and forebrain • Addiction involves neural plasticity, changes in expression of immediate-early genes (c-fos, c-jun) and expression of proteins for adenylyl cyclase, increased expression of CREB, activation of gene expression • Addiction may involve neurogenesis
Addiction • ACTIVATION OF STRIATAL µ AND OPIOID RECEPTORS IS REWARDING • ACTIVATION OF OPIOID RECEPTORS OPPOSES REWARD
The molecular neurobiology of addiction: key concepts • The long-term effects of addiction (craving) probably involve transcription factors like ∆FosB, and CREB. • These transcription factors in turn regulate expression of target genes that include proenkephalin, prodynorphin, c-fos, and numerous other genes.
Drugs of abuse: Key concepts Drugs exert addictive effects via specific receptors or neurotransmitters
Addiction -THC • THC produces cognitive deficits in heavy users. Whether these are irreversible remains controversial • THC probably doesn’t have long term effects on global intelligence • THC may be a causal factor (6.7x) in developing schizophrenia-like illness later (SE study) • THC may increase risk (X4) of developing schizophrenia-like symptoms in those who begin use before 15 (NZ study) • THC may precipitate age of onset of schizophrenia by 6.9 yrs (NL study) • THC in combination with certain alleles of COMT increases risk of schizophrenia by factor of 10.
ECSTASY (MDMA) Ecstasy is the name of a class of drugs that includes a large variety of derivatives of the amphetamine-related compound methylenedioxymethamphetamine (MDMA). Today, MDMA and its many derivatives are often produced in small quantities in ad hoc laboratories and distributed at parties or "raves" where it is taken orally. Preferential affinity for the serotonin transporter (SERT) and therefore most strongly increases the extracellular concentration of serotonin. Serotonin depletion may become permanent, which has triggered a debate on its neurotoxicity. Although direct proof from animal models for neurotoxicity remains weak, several studies report long-term cognitive impairment in heavy users of MDMA. In contrast, there is a wide consensus that MDMA has several acute toxic effects, in particular hyperthermia, which along with dehydration may be fatal. Other complications include serotonin syndrome and seizures. Following warnings about the dangers of MDMA, some users have attempted to compensate for hyperthermia by drinking excessive amounts of water, causing water intoxication involving severe hyponatremia, seizures, and even death. Withdrawal is marked by a mood "offset" characterized by depression lasting up to several weeks. There have also been reports of increased aggression during periods of abstinence in chronic MDMA users.Taken together, the evidence for irreversible damage to the brain, although not completely convincing, implies that even occasional recreational use of MDMA cannot be considered safe.
1) Which one of the following chemicals does not satisfy the criteria for a neurotransmitter role in the CNS? A) Acetylcholine B) Dopamine C) Glycine D) Nitric oxide E) Substance P 6) Which of the following statements is true? A) Lamotrigine combined with clozapine is useful in treating depression B) Lamotrigine combined with carbamazepine is useful in treating schizophrenia C) Carbamazepine is not useful in trigeminal neuralgia D) Valproic acid and carbamazepine are effective in bipolar disorder E) None of the above is true 11) Which of the following is correct? A) Knockout of 5-HT1A receptors blocks the antidepressant effect of haloperidol B) Preventing hippocampal neurogenesis blocks the antidepressant effects of fluoxetine C) Fluoxetine is selective for 5-HT1A receptors D) X-irradiation kills 5-HT neurons and causes depression E) None of the above is correect
Drugs of abuse (classes) Opioids Barbiturates and other sedative hypnotics -barbiturates -benzodiazepines Stimulants -caffeine -nicotine -cocaine -amphetamine -methamphetamine -MDMA (ecstasy) -Khat
Drugs of abuse (classes) Hallucinogens -LSD -mescaline -psilocybin -phencyclidine Marijauna Inhalants -Nitrous oxide -ether, cloroform, solvents -isobutyl nitrite
Drug therapies and Addiction • Antabuse • Campral • Naltrexone • Topiramate • NK1 antagonists
Drug therapies and Neurogenesis • Antabuse • Campral • Naltrexone • Topiramate • NK1 antagonists