Neurotransmitters

1. Neurotransmitters • Neuropeptides • Opioid peptides • Enkephalins (ENK) • Endorphins (END) • Peptide Hormones • Oxytocin (Oxy) • Substance P • Cholecystokinin (CCK) • Vasopressin (ADH) • Neuropeptide Y (NPY) • Hypothalamic Releasing Hormones • GnRH • TRH • CRH • Amines • Quaternary amines • Acetylcholine (ACh) • Monoamines • Catelcholamines • Epinephrine (EPI) • Norepinephrine (NE) • Dopamine (DA) • Indoleamines • Serotonin (5-HT) • Melatonin • Amino acids • Gamma-aminobutyric acid (GABA) • Glutamate (GLU) • Glycine • Histamine (HIST)

2. Drugs can acts as Agonists Agonist binds and has same effect as endogenous neurotransmitter, channel opens Normal receptor at rest, channel is closed Neurotransmitter binds receptor and opens channel

3. Drugs can act as Antagonists Typical antagonist binds in place of endogenous neurotransmitter, prevents neurotransmitter action Non-competitive binding antagonist doesn’t interfere with neurotransmitter binding but still prevents neurotransmitter action

4. Presynaptic Drug Actions • 8. Blockade of NT • degradation • MAO inhibitors • Prozac • Chemical Weapons

5. Postsynaptic Drug Actions

6. Illegal Drug Use in the U.S. • Marijuana • Cocaine • Crack • Amphetamines • Heroin

7. #1 most widely used illegal drug in US • from cannabis sativa • mild hallucinogen • brain has cannabinoid receptors (CB1) • cerebral cortex • hippocampus • basal ganglia • cerebellum • endogenous NTs are: • Anandamide • 2-arachidonylglycerol (2-AG) • oleamide • THC is active ingredient • causes • memory loss • impaired tracking ability • lung damage • anxiety or paranoia • Amotivational syndrome • Gateway drug? Marijuana

8. Cocaine • #2 most popular illegal drug in US • from coca leave in South America • CNS stimulant • is addictive • blocks reuptake of DA, NE, and 5-HT • creates • stereotypic behaviors • nail biting/teeth grinding • pacing • an irregular heartbeat • arterial spasms • seizures • cardiac failure • has a synergistic effect with alcohol

9. Opiates • Opium, Heroin, and Morphine • CNS depressant • is very addictive • human brain has opiate receptors • limbic system • hypothalamus • locus coeruleus • periaqueductal gray • endogenous NT are • endorphins • enkephalins • dynorphins • causes • analgesia/pain suppression • down-regulation of receptors • can lead to death by overdose

10. Hallucinogens • LSD, Mushrooms • acts as a 5-HT2 agonist • causes • vivid images in the absence of input • geometric forms • meaningful images • separation from the body • similar effect as in • oxygen loss • sensory deprivation • can lead to “Bad Trips” • paranoia • depression • confusion

11. Ecstasy (MDMA) • MDMA : 3-4 methylenedioxymethamphetamine • is related to • Mescaline • MDA • methamphetamine. • it prompts nerve cells to release a flood of serotonin. • bring about the increased awareness of • emotion • intimacy • self-confidence • The ensuing chemical low tide could explain the depression users describe when they are coming down. • damages serotonin cells • damages dopamine cells

12. Ecstasy (MDMA) Earlier animal studies had shown that repeated ecstasy use damages the serotonin brain cells, which help to regulate mood and behavior. This image shows that serotonin axons are destroyed in a squirrel monkey after a single dose of MDMA.

13. Control Users Ecstasy (MDMA) BRAIN CHANGES appear prominently in positron emission tomography (PET) scans of Ecstasy users as well as people who abstain. Drug users (right), though, have far less serotonin activity, as is indicated by the dark areas, compared to the controls (left). New studies show that this difference may contribute to permanent brain damage. Serotonin Activity

14. Alcohol • CNS Depressant • is a great inhibitor • causes • slowing of brain activity that controls reason • slowing of reaction time • depression of respiration • increase in aggressiveness • increase in risk of digestive tract cancers • increase in heart disease • decrease in sex drive • memory loss • depression • cirrhosis of the liver • fetal alcohol syndrome • brain cell death

15. Models of Addiction Moral Model Disease Model Physical Dependence Model Reward Model

16. Intra-Cranial Self-Stimulation ICSS: Electrodes are placed in the Medial Forebrain Bundle (MFB)

17. Reward Pathway Ventral Tegmental Area (VTA) to Nucleus Accumbens via the Medial Forebrain Bundle and then to the Prefrontal Cortex

18. Drug Addiction Initially the CREB protein dominates leading to Tolerance and the feeling of discomfort with the absence of the drug But the CREB protein falls after a few days if drug use discontinues But Delta fosB stays elevated for weeks after the discontinued use of the drug leading to Drug Sensitivity

19. Drug Tolerance During drug use VTA cells are stimulated and release Dopamine triggering the reward circuit Dopamine binds the receptors of the Nucleus Accumbens and increases cAMP and Ca2+ ion concentrations cAMP and Ca2+activate the CREB protein CREB activates the Dynorphin gene to make the Dynorphin protein The Dynorphin protein is released back on the VTA where it inhibits Dopamine release depressing the reward circuit and causing the user to need more drug for the same high

20. Drug Sensitivity Neurobiology of Drug Addiction During drug use VTA cells are stimulated and release Dopamine triggering the reward circuit Dopamine stimulates the formation of Delta fosB Delta fosB inactivates the Dynorphingene and activates the CDK5 gene The CDK5 protein stimulates dendritic spine growth in the Nucleus Accumbens Nucleus Accumbens neuron Increasing Drug Sensitivity/Addiction

21. Drug Sensitivity/Addiction Nucleus Accumbens neurons in non-human animals: Non-Addictive Drugs Cocaine Greater density of Dendritic Spines Contributes to Drug Sensitivity (increased risk of drug relapse) Delta fosB may be the contributing factor of increased spine growth