The document discusses the neurobiology of drug addiction. It describes how drugs of abuse act on the brain's reward system and other neurocircuitry to produce rewarding and reinforcing effects that lead to compulsion and addiction. Key areas discussed include how drugs increase dopamine and activate opioid receptors in the nucleus accumbens and amygdala during the acute phase, and later recruit stress systems like CRF to drive compulsive use associated with withdrawal.

1. The neurobiology of drug addiction Dr. Syed Faheem Shams Student of MD (Part-II) Department of Psychiatry, BSMMU

3. Drug Addiction — Chronically relapsing disorder that is characterized by a compulsion to seek and take drug, loss of control in limiting intake, and emergence of a negative emotional state (e.g. dysphoria, anxiety, irritability) when access to the drug is prevented. Koob GF. The neurobiology of addiction, 2006

4. Stages of the Addiction Cycle

6. It is widely accepted that increased levels of dopamine in the nucleus accumbens are key in mediating the rewarding effects or positive reinforcement of drugs of misuse ( Koob & Le Moal , 2001 ). Evidence is still accruing to support this. Regarding Serotonin ⇒⇒⇒ Serotonin does not directly participate in motivation-reward, but exerts influence through its effects on the DA system. Application of 5-HT onto dopaminergic neurons from the VTA increased their firing rate in vitro attributed to action of 5-HT on 5-HT2 receptors. www.elsevier.com/locate/biochempharm Neurobiology of addiction An integrative review, 2008 BASICS

9. Anticipation In an elegant series of experiments, Schultz ( 2001 ) found that in primates trained to associate a cue with a pleasurable experience (food), increased dopaminergic activity was seen in response to the cue and not to the food . If the food was not then presented, dopaminergic function dropped. Reduced dopaminergic function is thought to be associated with negative affect (e.g. dysphoria). Thus, an individual with an addiction may see a ‘cue’ (e.g. a public house, mirror or needle) and if their drug of choice is not available may feel dysphoric, which is likely to increase the drive to obtain the drug.

10. Key Common Neuroanatomical Structures in Addiction Nucleus Accumbens and Central Nucleus of the Amygdala — Forebrain structures involved in the rewarding effects of drugs of abuse and drives the binge intoxication stage of addiction. Contains key reward neurotransmitters: dopamine and opioid peptides. Extended Amygdala — Composed of central nucleus of the amygdala, bed nucleus of the stria terminalis, and a transition zone in the medial part of the nucleus accumbens. Contains “brain stress” neurotransmitter, corticotropin releasing factor that is involved in the anti-reward effects of drug dependence. Medial Prefrontal Cortex — neurobiological substrate for “executive function” that is compromised in drug dependence and plays a key role in facilitating relapse. Contains major glutamatergic projection to nucleus accumbens and amygdala.

11. The Dopamine receptors

12. There are five types of receptors for dopamine in the human brain, identified as D1 to D5. They are not all equally involved in pleasure-seeking behavior. For instances, some studies have shown that D3 receptors appear to be more involved in the phenomenon of dependency . The functions of D1, D2 and D3 receptors primarily concern motivation and reward, while D4 and D5 receptors are more involved with behavioral inhibition. http://www.britishpainsociety.org/book_drug_misuse

14. Neurobiological Substrates for the Acute Reinforcing Effects of Drugs of Abuse Neurotransmitter Dopamine Opioid Peptides GABA Glutamate Site Ventral tegmental area, nucleus accumbens Nucleus accumbens, amygdala, ventral tegmental area Amygdala, bed nucleus of stria terminalis Nucleus accumbens

15. Converging Acute Actions of Drugs of Abuse on the Ventral Tegmental Area and Nucleus Accumbens From: Nestler EJ, Nat Neurosci , 2005, 8:1445-1449.

16. Neurochemical Changes Associated with the Drug Use, Dependence and Relapse

17. Common Molecular Changes Associated with Dependence Dopamine D-2 receptor binding - decreased in human imaging studies in dependent subjects. CREB ( cyclic adenosine monophosphate response element binding protein) transcription factor - decreased in nucleus accumbens and extended amygdala during the development of dependence. Delta-FosB transcription factor -changed during protracted abstinence to drugs of abuse. Koob GF. The neurobiology of addiction, 2006

18. Neuro circuitry of Addiction Reward Circuit - nucleus accumbens and extended amygdala (bed nucleus of the stria terminalis and central nucleus of the amygdala) “ Craving” Circuit - dorsal prefrontal cortex, basolateral amygdala “ Compulsivity” Circuit - ventral striatum, ventral pallidum,medial thalamic- orbitofrontal cortical loop Koob GF. The neurobiology of addiction, 2006

19. Key Common Neurocircuitry Elements in Drug Seeking Behavior of Addiction

20. Role of Corticotropin-releasing Factor in Dependence Drug CRF antagonist effects on withdrawal-induced anxiety-like responses Withdrawal-induced changes in extracellular CRF in CeA CRF antagonist effects on dependence-induced increases in self-administration Cocaine Opioids Ethanol Nicotine  9-THC ↓ ↓ ↓ ↓ ↓ ↑ ↑ ↑ ↑ ↑ ↓ ↓ ↓ ↓ ↓ CeA = central nucleus of the amygdala. Koob GF. The neurobiology of addiction, 2006

21. What Role Does Stress Play In Initiating Drug Use? STRESS DRUG USE (Self-Medication ) CRF Anxiety CRF Anxiety

22. What Happens When A Person Stops Taking A Drug?

23. RELAPSE Prolonged DRUG USE Abstinence CRF Anxiety

24. Extracellular CRF Levels in the Central Amygdala During Ethanol Withdrawal

25. CNS Depressants Alcohol [beer, wine, liquor, spirits, etc.] Opiates Morphine Heroin Methadone Opium Codeine Benzodiazepines Barbiturates General Anesthetics Sedative Antihistamines Volatile Substances [solvents, glues, thinners, strippers, aerosols, paints, gasoline, etc.] Gamma hydroxybutyrate (GHB)

26. CNS Stimulants Major Stimulants----- Cocaine [coke, snow, crack, freebase] Amphetamines [meth, speed, ice, crystal, cat, dexies] Minor Stimulants---- Nicotine [tobacco, certain products to help people quit smoking] Caffeine [coffee, tea, cocoa, chocolate, cola drinks, etc. ]

30. OPIOIDS Opiates act on— the reward circuit the amygdala the locus coeruleus the cauadate nucleus the periaqueductal grey matter. Opiates also affect the thalamus, which would explain their analgesic effect.

31. The mechanism of action of heroin at the mu (m) opiate receptors

32. Heroin modifies the action of dopamine in the nucleus accumbens and the ventral tegemental area of the brain. Once crossing the blood-brain barrier, heroin is converted to morphine, which acts as a powerful agonist at the mu opioid receptors subtype Inhibits the release of GABA from the nerve terminal Reduction of the inhibitory effect of GABA on dopaminergic neurones. The increased activation of dopaminergic neurones and the release of dopamine Continued activation of the dopaminergic reward pathway leads to the feelings of euphoria and the ‘high’ associated with heroin use .

41. www.niaaa.nih.gov , neurochemical changes in alcohol withdrawl, vol-22(1),1998,

44. Slide : Positron emission tomography (PET) scan of a person on cocaine

46. M/A of cannabis Slide : THC binding to THC receptors in the nucleus accumbens: increased dopamine release

47. M/A of cannabis (cont.) Slide: Increased cAMP produced in post-synaptic cell

64. Reward System in Addiction treated controls More Less Ability to Experience Rewards Is Damaged

65. Their Brains… Get Rewired by Drug Use

66. That was then . . . THANK YOU ALL Use the Science