The Science of Drug Action Pharmacology: study of the actions of drugs and their effects on living organisms. Neuropharmacology: study of drug-induced changes in nervous system cell functioning. Psychopharmacology: emphasizes drug-induced changes in mood, thinking, and behavior. Neuropsychopharmacology: identifies chemical substances that act on the nervous system to alter behavior. Bioavailability: amount of drug in the blood that is free to bind at target sites. Pharmacokinetic Effect: component of drug action: the dynamic factors that contribute to bioavailability. Placebo Effect: Where belief in a drug may produce real physiological effects despite the lack of chemical activity. 1

Pharmacokinetic Factors Drug Administration Absorption and Distribution Binding Inactivation Excretion

Drugs can acts as Agonists: Drug Actions Drugs can acts as Agonists: Endogenous Exogenous Drugs can acts as Antagonists: Competitive Noncompetitive

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

Postsynaptic Drug Actions

Illegal Drug Use in the U.S.

Marijuana #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?

Drug Schedules US DEA (1989) I: Marijuana II: PCP, Morphine III: Steroids, Speed IV: Valium

Medicinal Marijuana Multiple Sclerosis Treatment: Cancer Treatment: Pain Shaking Spasms Spasticity Fatigue Sleep Quality Mobility Well Being Cancer Treatment: MMP-2: enzyme that promotes spread of cancer

Trends in ER Drug Mentions Cocaine Heroin/Morphine Marijuana Meth/Speed

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

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

Opioid Epidemic

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

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

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.

Ecstasy (MDMA) Control Users 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

(yellow is more; green is less) Ecstasy (MDMA) In the new work, Johns Hopkins University researchers working with squirrel monkeys and baboons found that two or three sequential doses of the drug—the amount typically taken by young adults at all-night "raves"—killed dopamine neurons, which are involved in controlling movement, emotional and cognitive responses and the ability to feel pleasure. Indeed, some 60 to 80 percent of the dopaminergic nerve endings in a region of the brain known as the striatum were destroyed after just one multi-dose regimen. Control MDMA Dopamine Neurons (yellow is more; green is less)

MDMA Induced Cortical Brain Damage Induced Cortical Thinning (Kish et al 2010): Parietal Cortex Occipital Cortex Temporal Cortex Frontal Cortex Cingulate Cortex MDMA Induced Cortical Brain Damage Induced Grey Matter Reduction (Daumann et al 2011): Cingulate Cortex Serotonin Transporter Deficiency (Kish et al 2010): Visual Cortex

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

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

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

Microdialysis Data Dopamine levels in Nucleus Accumbens following self-administration of cocaine in rats

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

Drug Rush PET scans of Human Cocaine Addicts: Brain area activation during the Drug Rush: Nucleus Accumbens Amygdala Sublenticular Extended Amygdala VTA

Drug Craving PET scans of Human Cocaine Addicts: Nucleus Accumbens and the Amygdala Brain area activation during Drug Craving: Craving becomes stronger as the drug wears off

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

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

Neurobiology of Drug Addiction 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 Dynorphin gene and activates the CDK5 gene The CDK5 protein stimulates dendritic spine growth in the Nucleus Accumbens Nucleus Accumbens neuron Increasing Drug Sensitivity/Addiction

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