Mechanism of habituation, dependence and withdrawal


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Mechanism of habituation, dependence and withdrawal

  1. 1. Mechanism of habituation, Dependence and withdrawal Dr. S. Parasuraman M.Pharm., Ph.D., Senior Lecturer, Faculty of Pharmacy, AIMST University, Bedong 08100, Malaysia.
  2. 2. • Short-term receptor desensitization, probably involves phosphorylation of the µ and δ receptors by protein kinase C (PKC). • Long-term tolerance has been associated with increases in adenylyl cyclase activity - a counter- regulation to the decrease in cyclic AMP levels. • Chronic treatment with µ-receptor opioids causes superactivation of adenylyl cyclase and this can be prevented by pretreatment with pertussis toxin. Mechanism of habituation (opioids)
  3. 3. Adenylate cyclase induced cAMP formation Alterations in cAMP affects many cellular functions through the increased activity of various cAMP- dependent protein kinases, which leads to increases in various cellular activity and inducing drug dependence.
  4. 4. • Genetic factors contribute up to 60% of an individual's susceptibility to most forms of drug abuse • Glutamatergic transmission plays a major role in short-term habituation. • Mutation in one or more genes (EAT-1, GLR-1, GLR-2, NMR-1, NMR-2) altered patterns of habituation and glutamatergic transmission (AMPA, NMDA) plays a critical role in habituation. • eat-4 and dop-1 are the gene product of bab-1 and plays an antagonistic role to the molecular mechanism of glutamatergic and dopamine signaling that is hypothesize to short-term habituation. Habituation-mechanism (Genetic factors)
  5. 5. • Genetic polymorphisms across several neurotransmitter systems have been linked to the development of drug addiction. • In humans the DAT gene (DAT1) has a variable number of tandem repeats (VNTR) in the 3´-untranslated region known to influence gene expression. • Mutation in DAT1, may have role in alcohol and nicotine addiction. Habituation-mechanism (Genetic factors)
  6. 6. • Habituation: – Sensory neurons are stimulated →fire action potentials – EPSP (excitatory postsynaptic potential) generated in motor neurons  motor neurons fire – If stimulus is repeated, the synaptic transmission between sensory neurons and motor neurons, as well as between interneurons and motor neurons, is reduced. Habituation-mechanism
  7. 7. • Drug dependence describes the state when drug-taking becomes compulsive, taking precedence over other needs. • Withdrawal syndrome or abstinence syndrome describes the adverse effects, both physical and psychological, of stopping a drug. • The common feature of dependence caused by various types of psychoactive drug is that all produce a rewarding effect (positive reinforcement). Coupled with the direct rewarding effect of the drug, usually process habituation, or adaptation. • Habituation results, cessation of the drug leads to aversive effect and negative reinforcement. Dependence and withdrawal-mechanism
  8. 8. • The physical withdrawal syndrome associated with physical dependence is an important manifestation of habituation. • The intensity and nature of physical withdrawal symptoms varies from one class of drug to another, being particularly marked with opioid. • In addition to the positive and negative reinforcement associated with drug administration and withdrawal, conditioning plays a significant part in sustaining drug dependence. Dependence and withdrawal-mechanism
  9. 9. Dependence and withdrawal-mechanism
  10. 10. Dependence and withdrawal-mechanism
  11. 11. • Substances of abuse lead to an increase in dopamine in the mesocorticolimbic system. • The common reward pathway is important because (i) single medication works for various classes of substances of abuse in addiction treatment; (ii) give a better understanding about addiction experience similar psycho-social devastation in spite of the variety of drug of choice. • Human brain has a complex system of ‘reward’ which help to access the medication on pleasurable behavior. The common reward pathway
  12. 12. The common reward pathway Individuals have conventional motivation items (A) Motivation items achieved such as endowed individuals feels good i.e., reward process. Part of this process depend on opioid and opiate signaling. If chemical messengers are taken exogenously [cocaine, alcohol, opiates, amphetamine] (B) normal motivational stimuli are lost and results can be achieved by bypassing these processes. More artificial reward process activity leading to higher doses and eventual dependence, which may resulting with permanent CNS changes.
  13. 13. The common reward pathway ventral tegmental area- VTA
  14. 14. • Chronic use of addictive substances can change the behavior of a key part of the brain’s reward circuit by activating dopamine-producing nerve cells (neurons) of the ventral tegmental area (VTA) to dopamine-sensitive cells in the nucleus accumbens. • The nucleus accumbens and VTA with other regions that can help to make drug users highly sensitive to reminders of past highs, vulnerable to relapses when stressed, and unable to control their urges to seek drugs. • Dopaminergic pathway is responsible for the positive reward but not for the negative withdrawal effects. The common reward pathway
  15. 15. • Other mediators, particularly 5-hydroxytryptamine (5- HT), glutamate and gamma-aminobutyric acid (GABA), influence the mesolimbic dopamine pathway, and possibly other reward pathways. • Increases of 5-HT activity (5-HT agonists or uptake blockers) reduce drug-seeking behaviour. • 5-HT-uptake inhibitors (e.g. zimeldine) or 5-HT agonists (e.g. buspirone) reduce slightly the alcohol consumption in alcoholic patients, and NMDA glutamate receptor antagonist also used for the treatment of alcoholism. The common reward pathway
  16. 16. Withdrawal mechanism
  17. 17. • CREB-mediated up-regulation of dynorphin - withdrawal from dependence • Supersensitization of adenylyl cyclase (AC), increase of cAMP concentration in medium spiny neurons of the accumbens, which activates dynorphin and increase the release of GABA, activating the k-opioid receptor located on dopamine neurons of the ventral tegmental area (VTA). • Dynorphin decreases dopamine release by binding to KORs on dopamine nerve terminals, which leads to drug tolerance and withdrawal symptoms. Withdrawal mechanism
  18. 18. Substance Possible mechanism of action Main Effect Other Cocaine Blocks DA uptake Inc Dopamine Directly increase doperminergic transmission in the NAc LSD Inc Serotonin Heroin Activates Mu & delta receptors Inc Dopamine through disinhibition in the VTA of dopamine neurons and direct effects on DA terminals Amphetamines Inc Dopamine & blocks DA uptake Inc Dopamine Nicotine Acetylcholine Inc Dopamine Alcohol GABA & Substance P Inc GABA Increased MDP activity Marijuana Activates Endocannabinoid receptors Inc Dopamine in MDP MDMA Inc Serotonin and block 5- HT uptake Inc Serotonin Inc Dopamine
  19. 19. Thank you
  20. 20. Common reward pathway Mechanism of habituation, dependence and withdrawal Drug abuse Short-term phosphorylation of the µ and δ receptors Long-term  increases in adenylyl cyclase activity Chronic treatment  superactivation of adenylyl cyclase Drug Dependence Positive reinforcement Habituation/ adaptation Negative reinforcement Glutamatergic transmission Mutation  DAT1 ,EAT-1, GLR-1, GLR-2, NMR-1, NMR-2, Alcohol/ nicotine/ drug addiction Brain Neural circuits ventral tegmental area (VTA) stimulated  ↑ cyclic AMP, ↑intracellular Calcium , ↑Dopamine Withdrawal ↓cyclic AMP, ↓interacellular Calcium, ↓Dopamine