Lecture_9b_Drug_Action_Syn...pdf

Fundamentals of Neuroscience: Lecture 9b Drug Action and Synapses Drug Effects at the Synapse ? Agonists are drugs that increase the effectiveness of a given neurotransmitter ? Antagonists are drugs that decrease the effectiveness of a given neurotransmitter ? E.g., dopamine agonists increase the activity of dopamine synapses The Acetylcholine Synapse Botulin Toxin ? Prevents the release of acetylcholine by blocking the interaction between the synaptic vesicles (the structures within which acetylcholine is stored) and the cell membrane that leads to acetylcholine release and transmission of the impulse. ? The toxin acts as an enzyme, a protease, that breaks down the protein complex that the vesicle binds to. ? This catalytic action means that it may take only one or two molecules to completely inactivate a nerve ending. Botox ? A very dilute solution of botulin toxin is injected near specific facial muscles in order to paralyze them ? Ostensibly this is good because it smoothes out wrinkles ? Because so little is needed, this dose is not dangerous to the patient ? It does wear off, however Nicotine ? Nicotine stimulates ACh receptors in skeletal muscle the same way ACh itself does ? Smokers experience increased muscle tension and changes in sensitivity to muscle tension Nicotine vs. Curare ? Both nicotine and curare interact with ACh receptors. Yet one is an agonist and one is an antagonist. What gives? ? Nicotine is similar enough to ACh that it stimulates the receptor in the same way (like a key in a lock) ? Curare, on the other hand, just occupies that space. ACh can?t compete for the space and thus can?t stimulate muscles (like tape over the keyhole) ACh (Ant)agonists and Alzheimer?s ? Note that many of the drugs we just talked about don?t promote Alzheimer?s Disease, or help prevent it. Most of these cannot pass the blood-brain barrier. Sedatives and Antianxiety Drugs ? Both barbiturates and benzodiazepines act on GABAA receptors ? GABA is typically an inhibitory neurotransmitter, so, as you would guess, these drugs slow down neurotransmission ? Benzodiazepines seem to be a bit safer, in that the line between normal action and overdose is quite wide Benzodiazepines vs. Barbiturates Alcohol and barbiturates seem to directly stimulate the GABAA receptor, while benzos seem to enhance normal communication. This could be the reason for the differing toxicity curves. Anticonvulsants ? Def: treat epileptic seizures ? Inc. Barbiturates and Benzodiazepines ? Also Valproic Acid (Depakote) ? May inhibit GABA inactivation ? Blocks voltage-gated sodium channels ? Blocks t-type calcium channels (imporant in certain types of seizures) ? Also Phenytoin (Dilantin) ? stabilizes inactive state of sodium channel ? Also Carbamazepine (Tegretol) -- stabilizes inactive state of sodium channel Schizophrenia: The Dopamine Hypothesis Antidepressants Narcotic Analgesics ? Opioid peptides (such as endorphins, or enkephalins) and their receptors are located at key points in the pain modulatory system ? Codeine also suppress the ?cough center? in the medulla ? One type of opiate in the brain is considered rewarding: lab animals will self-administer opiates ? Note: ?Opioid? = endogenous; ?opiate? = drug Narcotic Analgesics ? Codeine, morphine, and heroin are agonists that directly bind to the receptor ? Naloxone is structurally similar to morphine, but blocks the receptor instead of stimulating and is thus an antagonist Stimulants 4 types: ? Behavioral stimulants ? Convulsants ? General stimulants ? Psychedelic drugs Behavioral Stimulants ? Examples are cocaine and amphetamine ? These drugs block the dopamine transporter, which is involved in reuptake of dopamine ? Thus DA is left in the synaptic cleft for a longer period of time ? Thus these are DA agonists ? They seem to get people up and moving Convulsants ? Strychnine is generally used as a poison to remove pests. ? It attacks the nervous system by antagonizing the action of glycine, an amino acid responsible for transmitting inhibitory nerve impulses which control muscle contraction. ? As a result the skeletal muscles become hyperexcitable and contract simultaneously without the normal restraints; this is a convulsion or seizure. Convulsions prevent respiration, causing the animal to suffocate and die. General Stimulants ? Caffeine increases cAMP activity in the nervous system in general ? Caffeine blocks adenosine receptors, but it also reduces enzymes that break down cAMP ? Seriously, caffeine has been said to enhance short-term physical stamina and short-term memory, probably due to its effects on energy availability and arousal (adenosine receptors may be involved in sleep?!?!) Typical Caffeine Content in Foods & Drinks Item Caffeine Content (mg) NoDoz, 1 tablet 200 Excedrin, 2 tablets 130 Coffee, brewed, 8 oz 135 Snapple Iced Tea, 16 oz 42 Diet Coke, 12 oz 46.5 Coke Classic, 12 oz 34.5 Hershey Bar 10 From the website http://www.cspinet.org/new/cafchart.htm Psychedelics ? Defined as drugs that alter sensory perception and cognitive processes (they produce hallucinations) ? The funny thing is, none of these act on DA action, even though schizophrenia, a disease characterized by hallucinations, is thought to be generated at least in part by DA agonist action ? Please note that THC (the drug found in marijuana) is characterized as a psychedelic Glutamate hypothesis of Schizophrenia ? Phencyclidine (PCP): dissociative anesthetic ? ? Auditory hallucinations ? Depersonalization ? Delusions ? Noncompetitive NMDA antagonist (blocks Ca2+ channel) http://www.psy-world.com/slides.htm http://www.psy-world.com/slides.htm Glutamate hypothesis of Schizophrenia ? 2 weeks PCP in monkeys ? schiz.-like symptoms ? Ketamine (NMDA antag)? similar effects ? So, why not give glutamate agonists to treat schizophrenia????? http://www.psy-world.com/slides.htm Tetrahydrocannibinal (THC) ? Acts on metabotropic receptors that may affect Ca2+ and K+ channels ? The natural ligands for these receptors seem to be lipids, making them quite unique among neurotransmitters ? One natural ligand is anandamide, which appears to inhibit memory! Why do we need this function? ? A mutation of one of its receptors abolishes the reinforcing effects of morphine, but not of cocaine, amphetamine, or nicotine Tetrahydrocannibinal (THC) The wonders of THC: ? Produces analgesia and sedation ? Stimulates appetite ? Reduces nausea ? Relieves asthma attacks ? Decreases pressure within the eyes in patients with glaucoma ? Reduces the symptoms of certain motor disorders Barbara Malt Mind and Brain: Lecture 12