4/28/15 – Lecture 26 – Neuropharmacology and addiction – classes of drugs and the reward system of the brain- Goal – to identify several common drugs, their uses and mechanisms, and how drugs affect key brain pathways- 7 main sites of drug actiono NT Synthesis – in cell body, axon, or terminalo NT Storage – transport into vesicleso NT Release – how many vesicles fuse per Action Potentialo Receptor Interactiono Inactivationo Reuptakeo Degradation- Classification of Drugs – drugs can be classified by their chemical structure, receptor affinity, neurotransmitter system effect, or behavior effecto 7 classes of drugs based on their behavioral effects Anti-Anxiety Agents and Sedatives (AGONIST = INCREASE Synaptic Transmission)- Characteristicso At low doses, they reduce anxietyo At medium doses, they sedateo At high doses, they anesthetize  Anti-Anxiety – benzodiazepines (valium) Sedatives – alcohol or barbiturateso Anti-Anxiety agents differ from sedatives primarily in their dose range and mechanism of action Anti-anxiety – move you from being too aroused to a good arousal level Sedatives – move you from being aroused to not aroused- Mechanisms of Actiono Antianxiety drugs – enhance binding of GABA to Cl- channel/receptoro Sedatives – open GABA Cl- channel (acts like GABA rather than enhancing it) Both increase flow of Cl- into postsynaptic neurons and hyperpolarize the neuron (less likely to fire Action Potential) Both globally decrease neuronal firing in CNS, which decreases arousal Main effects of overdose include drowsiness, decreased arousal, coma, and even death Antipsychotic Agents (ANTAGONIST)- Characteristics (not too addictive because it inhibits pleasure/dopamine)o Reduce motor activity, wild moods, and disconnected thoughts in schizophrenicso Ex – chlorpromazine, haloperidol, clozapineo A major side effect of long term use is dyskinesia (diminished movement and increased involuntary movements)- Mechanisms of Actiono Mechanism is not completely known, but one action is to block the D2dopamine receptoro Dopamine can’t bind to and activate D2 receptor, which means decreased action potential formation in postsynaptic cello Decreased dopamine signaling in the nigrostriatal pathway may reduce manic motor behaviors but may also cause dyskinesia side effectso Decreased dopamine signaling in the mesolimbic pathway of the brainmay improve mood regulationo Decreased dopamine signaling in the mesocortical pathway may improve cognitive functioning Antidepressants (AGONIST)- Characteristicso Important in treating clinical depressiono A major defect in depression is reduced levels of monoamine neurotransmitters (serotonin, dopamine, norepinephrine)o Monoamines play many roles in the brain but have major influences on mood and arousal and increase BDNF levels Ex – fluoxetine (Prozac), sertraline (Zoloft) The 3rd most widely used prescription drugs in the US, (1 in 10 people use them) Side effects – increased anxiety, suicide, sexual dysfunction, headaches, and nausea- Mechanism of Actiono MAO Inhibitors – inhibit breakdown of serotonin, dopamine, and norepinephrineo SSRI’s – blocks the reuptake of serotonin Increased serotonin (and other monoamines) in synaptic cleft Greater serotonin binding to its postsynaptic receptor Greater postsynaptic action potential firing Greater serotonin (and dopamine and norepinephrine) action improves mood and increases arousal Mood Stabilizers- Characteristicso Important in treating bipolar disorder (manic depressive illness)o Ex – lithium and valproic acid (VPA)o The depressive actions can lead to the manic episodes and vise versa- Mechanism of Actiono Mechanism is not knowno Both lithium and VPA inhibit a number of intracellular signaling molecules regulating cell growth and survival such as GSK, ERK, and IP3o Lithium may protect against glutamate toxicityo Mood stabilizers may therefore increase neuronal survival and health, particularly in the hippocampus, which regulates emotional responseso VPA also inhibits GABA degradation, increasing GABA signaling and therefore decreasing arousal Opioid Analgesics (AGONIST)- Characteristicso Important as narcotics and pain relieverso Other main effect is producing feelings of euphoria or intense calm pleasureo Ex – opium, codeine, morphine, oxycontin, Vicodin, and heroin- Mechanism of Actiono Opioids act as agonists for endogenous opioids or endorphinso Opioids bind to the mu endorphin receptors and inhibit neurotransmitter releaseo By inhibiting release of neurotransmitters involved in pain like Substance P, opioids act as PAIN KILLERSo In the mesolimbic pathway, opioid binding causes decreased release of GABAo Decreased GABA release results in greater dopamine release by mesolimbic neurons, increasing feelings of pleasure and reward or euphoria Psychomotor Stimulants- Characteristicso Increase motor behavior and alertness and elevate moodo EX General stimulants – caffeine and nicotineo EX Behavioral stimulants – amphetamines (meth), cocaine, and ecstasy- Mechanism of Actiono Nicotine – acts as an acetylcholine AGONIST, increasing stimulation of muscles and arousal in the brain Also stimulates dopaminergic neurons to release dopamine bybinding to acetylcholine receptors in dopaminergic neurons and activating themo Amphetamines and Cocaine – inhibit reuptake of dopamine More dopamine binds to its receptor on the postsynaptic neuron Greater postsynaptic stimulation of neurons in the reward center of the brain Psychedelics and Hallucinogens- Characteristicso Alter sensory perception and cognitive processes, induce hallucinationso There are many types, but the most common one is THC (a psychoactive component of marijuana) Main side effects of THC – memory problems and hallucinations THC also prevents nausea, improves appetite, and decreases pain- Mechanism of Actiono The THC binds to endogenous cannabinoid receptors CB1 and CB2 on presynaptic neuron and closes the voltage gated Ca2+ channelo Closing of Ca2+ channel decreases influx of Ca2+ into presynaptic cell, which results in less neurotransmitter release By inhibiting neuronal firing in the basal ganglia and cerebellum, THC decreases motor behavior By inhibiting neuronal firing/ LTP in the hippocampus, THC decreases memory By inhibiting neuronal firing of pain sensory neurons, THC inhibits pain sensations By