Lecture 6 - Drugs PDF

Introduction to Behavioral Neuroscience PSYC 211 Lecture 6 of 24 – Psychopharmacology (rest of chapter 4) Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  Snakes and Spiders The venom of hundreds of differ...

Introduction to Behavioral Neuroscience PSYC 211 Lecture 6 of 24 – Psychopharmacology (rest of chapter 4) Professor Jonathan Britt Questions? Concerns? Please write to [email protected]  Snakes and Spiders The venom of hundreds of different species (primarily spiders and snakes) contain substances that interfere with neurotransmitter signaling. Much of our knowledge of drugs and neurotransmitter signaling came from studying these compounds, many of which interfere with neurotransmitter signaling at the neuromuscular junction, which can cause paralysis (no movement) or spasms (excessive muscle contraction).  Acetylcholine Acetylcholine acts as a neuromodulator in the CNS (brain & spinal cord), often at axoaxonic synapses. Acetylcholine is also the primary neurotransmitter released by motor neurons at the neuromuscular junction. There, it activates excitatory ionotropic receptors on muscle cells, causing fast EPSPs and muscle contraction. Motor neurons generally release acetylcholine as their main neurotransmitter. Sensory neurons generally release glutamate as their main neurotransmitter.  THE BLACK WIDOW SPIDER The Black Widow Spider often eats her partner after mating (in lab settings). Her bite can kill a human baby. One of the toxins in her venom causes a massive release of acetylcholine in the neuromuscular junction, which causes muscle cramps, pain, and nausea.  NEUROTRANSMITTER RELEASE Black widow Poison produced by the black widow spider that spider venom triggers the release of acetylcholine from motor neurons. Botulinum toxin Produced by bacteria that grow in improperly (botox) canned food. It prevents acetylcholine release from motor neurons, causing muscle paralysis. CONVENTIONAL NEUROTRANSMITTER RELEASE Many natural toxins target the vesicle release machinery.  NEUROTRANSMITTER CLEARANCE Neostigmine Drug that inhibits acetylcholinesterase, which is the enzyme that breaks down acetylcholine in the synapse. Neostigmine causes acetylcholine to stay around longer in the synapse, causing prolonged muscle contraction. Myasthenia Gravis is an autoimmune disorder in which a person’s immune system attacks healthy acetylcholine receptors. People with this disorder become noticeably weaker and weaker over time (fatigability). We don’t yet have a good way to restore acetylcholine receptors, but drugs like neostigmine keep acetylcholine in the synapse for longer periods of time.  DRUG CATEGORIZATION A receptor agonist is a drug that directly or indirectly increases the activity of postsynaptic receptor proteins. A receptor antagonist is a drug that directly or indirectly decreases the activity of postsynaptic receptor proteins. Drugs can affect the activity of postsynaptic receptors directly or indirectly. Direct agonists/antagonists bind directly to postsynaptic receptors. Indirect agonists/antagonists affect the activity of postsynaptic receptors in an indirect manner (i.e., they do not directly bind to postsynaptic receptors).  DRUGS THAT CHANGED THE WORLD Direct dopamine receptor antagonists (dopamine receptor blockers) Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. It affects approximately 1% of the population. Symptoms may include delusions, hallucinations, incoherent speech, and behaviour that is inappropriate for the situation. Antipsychotics Class of drugs used to treat psychosis. (neuroleptics) They are mostly dirty drugs, which means they bind to more than type of receptor. However, the one action they all have in common is they directly block the dopamine D2 receptor, which is an inhibitory metabotropic receptor expressed by neurons all over the brain.  DRUGS THAT CHANGED THE WORLD Direct serotonin receptor agonists (serotonin receptor activators) Many drugs are used recreationally. People have long been fond of drugs that cause hallucinations. A wide variety of drugs cause hallucinations. The most popular ones directly activate serotonin 2A receptors, which are inhibitory metabotropic receptors expressed by neurons all over the brain. But not all serotonin 2A receptor agonists cause hallucinations. Researchers have explored why this is the case.  HALLUCINOGENS Here are 4 drugs that all directly activate the serotonin receptor 5HT-2A: mescaline psilocybin hallucinogens LSD lisuride not a hallucinogen When these drugs activate the 5HT-2A receptor, which is metabotropic, they launch an intracellular signaling cascade that starts with the g protein Gq/11. Serotonin activates this receptor in the same manner. However, hallucinogenic drugs also trigger the receptor to activate a different g protein: Gi/o. Hallucinations seem to result from 5HT-2A receptor activation of Gi/o proteins. We do not yet know why this signaling cascade causes hallucinations.  BIASED AGONISM Biased agonism is when a ligand causes a metabotropic receptor to preferentially activate one type of intracellular g protein, whereas another ligand at the same receptor might preferentially activate a different g protein. Sasha Shulgin: Godfather of Molly Sasha Shulgin: Godfather of Molly  DRUG COMPLEXITY How can there be dozens (or hundreds) of different drugs that increase serotonin 2A receptor activity yet produce different behavioural effects? How many ways are there to increase serotonin 2A receptor activity?  COMPETITIVE BINDING Direct agonists/antagonists can be classified as competitive or non-competitive.  A competitive agonist acts similarly to the endogenous neurotransmitter. It activates the receptor by binding where the neurotransmitter normally binds. Direct receptor agonists can be full agonists or partial agonists.  A competitive antagonist attaches to the same binding where the neurotransmitter normally binds, but it doesn’t activate the receptor. Competitive antagonists are full Competitive binding antagonists. The competition for a binding site between an endogenous neurotransmitter and an exogenous drug will depend on their relative concentrations and their affinity for the binding site. Affinity refers to the probability and tightness of ligand-receptor binding.  NON-COMPETITIVE BINDING When a drug binds to a receptor at a site that does not interfere with the binding site of the normal ligand it is called non-competitive binding. It is possible for a neurotransmitter to bind on one site of a receptor while a drug binds on another. A non-competitive agonist fully or partially activates the receptor. A non-competitive antagonist fully blocks receptor activation. It doesn’t compete for the neurotransmitter binding site. It “wins” without competing by binding to an alternative site. Allosteric modulators: Non-competitive drugs that only influence receptor activity when the neurotransmitter is also bound to the receptor. Non-competitive binding  Negative allosteric modulators reduce the effect of the primary ligand.  Positive allosteric modulators amplify the effect of the primary ligand. PRINCIPLES OF PSYCHOPHARMACOLOGY: There are many drugs that influence the activity of postsynaptic receptors without directly binding to them. Let’s consider the classical neurotransmitters and the different ways that drugs can influence the activity of their postsynaptic receptors.  NEUROTRANSMITTER SYNTHESIS Parkinson’s disease is a neurological disorder that is characterized by tremors, rigidity of limbs, poor balance, and difficulty initiating movements. It is caused by the degeneration (death) of dopamine neurons in the midbrain. The amino acid L-Dopa is used as a drug to treat Parkinson’s disease because it increases dopamine production in the brain and thus acts as an indirect dopamine receptor agonist.  PRINCIPLES OF PSYCHOPHARMACOLOGY: There are many ways to influence receptor activity besides directly binding to receptor proteins Conventional neurotransmitters are made in axon terminals, where an enzyme converts a precursor molecule (typically an amino acid) into a neurotransmitter. In some cases, the precursor molecule can be given as a drug, since it can increase the amount of neurotransmitter that is made and released. In such cases, the precursor molecule is an indirect receptor agonist. Enzymes synthesize neurotransmitter from precursor molecules. Some antagonists work by blocking these enzymes, thus reducing production of the neurotransmitter so there is less in each synaptic vesicle. Once made, neurotransmitters are packaged into synaptic vesicles. Some antagonists work by blocking the transporter proteins that package neurotransmitter into vesicles. When this occurs, the synaptic vesicles can remain empty, so nothing is released when they fuse with the presynaptic membrane. Remember that a single protein (the vesicular monoamine transporter) packages all the monoamines into synaptic vesicles. So, this protein is expressed by every neuron that releases a monoamine neurotransmitter (i.e., serotonin, dopamine, and norepinephrine). AGO = agonist ANT = antagonist NT = neurotransmitter  PRINCIPLES OF PSYCHOPHARMACOLOGY: Many proteins in the axon terminal regulate neurotransmitter release (i.e., vesicle fusion with the presynaptic membrane) Some antagonists work by blocking the vesicular release machinery, so no neurotransmitter is ever released (e.g., botox). Some agonists work by activating the vesicular release machinery, causing neurotransmitter release (e.g., black widow spider venom). The clearance of neurotransmitters from the synapse is controlled by reuptake transporter proteins and enzymatic deactivation Some agonists block the enzymatic deactivation of neurotransmitter in the synaptic cleft (e.g., neostigmine). Some agonists block neurotransmitter reuptake transporters. Some agonists can even reverse the direction of reuptake transporters, so they push neurotransmitter into the synapse as soon as it is made (without being packaged into a synaptic vesicle).  NEUROTRANSMITTER REUPTAKE Methylphenidate, Drugs that block catecholamine reuptake transporters, Cocaine meaning they block the reuptake of dopamine & norepinephrine. Adderall, Drugs that reverse catecholamine reuptake transporters, Crystal meth causing dopamine and norepinephrine to flow out of the axon terminal before being packaged into a vesicle (i.e., action potential-independent, non-vesicular release). Ecstasy (MDMA) has a similar effect on all the monoamine reuptake transporters (i.e., causes them to run backwards).  NEUROTRANSMITTER REUPTAKE Methylphenidate, Drugs that block catecholamine reuptake transporters, Cocaine meaning they block the reuptake of dopamine & norepinephrine. Adderall, Drugs that reverse catecholamine reuptake transporters, Crystal meth causing dopamine and norepinephrine to flow out of the axon terminal before being packaged into a vesicle (i.e., action potential-independent, non-vesicular release). Ecstasy (MDMA) has a similar effect on all the monoamine reuptake transporters (i.e., causing them to run backwards).  DRUG CATEGORIZATION Drugs are exogenous chemicals that at low doses significantly alter the function of certain cells. Drugs can be categorized in different ways: according to their effects on postsynaptic receptor activity according to their behavioural effects (e.g., upper, stimulant, downer, depressant) according to their physiological effects (e.g., action potential blocker) according to their actions on specific proteins (e.g., serotonin reuptake blocker) Principles of Psychopharmacology Entry of Drugs Into the Brain What are the similarities & differences between  Heroin o very easily crosses the blood-brain barrier (because an enzyme in the blood makes it very lipid/fat soluble)  Morphine o less easily crosses the blood-brain barrier (it is less lipid soluble than heroin)  Imodium Anti-Diarrheal o does not cross the blood-brain barrier. They are all very strong opiates (opioids) that cause constipation. There are 3 main types of opioid receptors (µ, δ, κ) – all inhibitory metabotropic receptors found throughout the body and brain. They normally get activated by endogenous opioid peptides that function as hormones in the body and as neuropeptides in the CNS.  Effects of Repeated Administration Tolerance is when a drug effect gets smaller with repeated administration. The body becomes used to the drug and actively counteracts its effects.  E.g., heroin users take larger and larger amounts of heroin to keep feeling the same euphoric effect. After tolerance develops, in the absence of the drug the user will suffer withdrawal symptoms, which are opposite the effects of the drug (e.g., euphoria vs dysphoria; constipation vs diarrhea).  E.g., barbiturates are GABA receptor agonists. They used to be popular because of their sedative (calming) effects, but they also reduce breathing and heart rate. Tolerance develops to the calming effects more quickly than to the depressive effects on breathing and heart rate. Thus, when larger doses of barbiturates are taken to achieve a desired sedative effect, there is the risk of dangerous reductions in breathing and heart rate. Sensitization occurs when a drug effect becomes larger with repeated use.  E.g., rodents sensitize to the effects of cocaine and amphetamine GENERAL INFO ABOUT BRAIN ANATOMY Before discussing general brain anatomy (next class), I want to introduce some definitions briefly mention brain development briefly mention cerebrospinal fluid  ANATOMICAL DIRECTIONS or superior or superior Ventral or inferior or inferior Neuraxis – imaginary line that runs along the length of the CNS Anterior – in front Superior Posterior – behind or rostral Superior – above Inferior – below Anterior or Posterior or Rostral – towards the beak Caudal – towards the tail Dorsal – towards the back Ventral – towards the belly Note that the 4 terms above rotate when we refer to human spinal cord. Lateral – away from the midline Inferior Medial – toward the midline or caudal “Geography” of the brain Coronal cut (also known as a frontal section) Medial (toward midline) Coronal Lateral (away from midline) Sagittal cut A mid-sagittal cut means the exact middle (between the eyes) Horizontal cut Medial Lateral (toward (away from midline) midline)  More useful terms Contralateral - structures on the opposite side of the body (e.g., the motor cortex controls movements of the contralateral hand.) Ipsilateral - structures on the same side of body (e.g., taste information is processed ipsilaterally, which means that taste receptors on the left side of your tongue are processed by your left cerebral hemisphere. Taste and smell are the only sensory systems that do not have contralateral organization.) Superficial – located close to the surface, close to the exterior of the animal Deep - located far away from the surface, deep in the interior of the animal Proximal – nearby Distal – far away Brain nuclei - in the brain, the word nuclei means a collection of neurons that are clustered together that all work together to serve some function. (E.g., there are many different brain nuclei in the hindbrain. One controls breathing, another controls vomiting, etc.) BRAIN DEVELOPMENT  BRAIN DEVELOPMENT A hollow, enclosed neural tube forms during the first month of human development in the womb. The first cells in this tube are neural progenitor cells. Up until the 8th week of development, these cells only undergo symmetrical cell division: each neural progenitor cell becomes two neural progenitor cells. Asymmetrical cell division starts around the 8th week of development. Over the next 3 months, when a neural progenitor cell divides, one of the daughter cells migrates away from the center of the neural tube. The next time that cell divides, it will produce either two neurons or two glia cells. By the end of the fifth month, there are 85 billion neurons in the human brain, the most we ever have. Many of these neurons die before birth, seemingly because they can’t find a place in the network.  BRAIN DEVELOPMENT Neurogenesis Production of new neurons. - Neural progenitor cells produce neurons and glia after they undergo asymmetrical cell division. Human neurogenesis largely stops five months after conception when neural progenitor cells undergo apoptosis. - There may be a little neurogenesis in some adult mammals, but whether this occurs in humans is controversial. Apoptosis A process of programmed cell death that occurs in multicellular organisms. - Apoptosis is a highly regulated and controlled form of cell suicide that ensures a dying cell does not cause problems for its neighbors. - Human neural progenitor cells undergo apoptosis around the fifth month of development in the womb.  THE NERVOUS SYSTEM HAS TWO PARTS Central nervous system (CNS) Everything in the brain AND spinal cord Peripheral nervous system (PNS) Any part of the nervous system outside the brain and spinal cord Sensory neurons and motor neurons typically span both regions. Parts of these cells are in the CNS and parts are in the PNS.  THE DISTINCTION BETWEEN THE CNS AND PNS IS REAL In the central nervous system, myelin is created by Oligodendrocytes. In the peripheral nervous system, myelin is created by Schwann cells. If a blue dye is injected into an animal's bloodstream, all tissues except the brain and spinal cord will be tinted blue Blood–brain barrier Semipermeable barrier between the blood and the brain  EXTRACELLULAR FLUID IN THE BODY & BRAIN There are small holes in the blood vessels that course around your body. The liquid part of blood (blood plasma) continually leaks out of these holes. This liquid forms the extracellular fluid of your body (also called interstitial fluid). Extracellular fluid flows around cells providing nutrients and collecting waste. The extracellular fluid of the body is collected into lymph vessels, which carries it to lymph nodes & lymph organs. These structures make up the lymphatic system, a part of the immune system that detects and destroys invading organisms and foreign particles. Liquid in the lymphatic system (lymph) is returned to the blood supply to start the process again. Blood  Extracellular fluid  Lymph  Blood The CNS (brain and spinal cord) does not participate in the lymphatic system of the body because there are no holes in the blood capillaries that pass through the brain and spinal cord. This property of the CNS is known as the blood brain barrier. Rather than letting blood plasma directly leak out of the circulatory system, the brain makes its own extracellular solution by actively picking out exactly what it needs from the blood. The liquid it makes (from scratch) is called cerebrospinal fluid (CSF).  The Meninges of the CNS The central nervous system is wrapped by 3 protective layers of tissue called meninges (whereas the peripheral nervous system is only surrounded by regular connective tissue). Moreover, the CNS is encased in bone (skull and vertebrae), whereas the PNS is not. The 3 types of meninges that surround the CNS: a) The outer layer is dura mater. It is thick, tough, unstretchable tissue. b) The middle layer is the arachnoid membrane. Its web-like extensions (arachnoid trabeculae) create a soft, spongy layer that is filled with cerebrospinal fluid (the extracellular fluid of the CNS). c) The third layer is pia mater. This layer sits closest to the brain and is a bit like Saran-Wrap. Large blood vessels course through the subarachnoid space (arachnoid trabeculae). Smaller blood vessels (capillaries) branch off and dive into the brain to provide nutrients and oxygen. Meninges in the Human Brain  THE VENTRICLES OF THE BRAIN The brain floats in cerebrospinal fluid (CSF). CSF is made from blood by tissue called choroid plexus, which are in each of the brain’s four ventricles (i.e., the interconnected hollow spaces at the center of the brain). The two large lateral ventricles sit underneath the cerebrum (cerebral cortex). The third ventricle lies between the two thalamic nuclei at the center of the brain. The cerebral aqueduct is a long, tube-like structure that connects the third and fourth ventricle. The fourth ventricle is in the hindbrain, between the pons and cerebellum. The central canal of the spinal cord connects to the fourth ventricle. CSF is made continuously and is fully exchanged about 4 times per day. It circulates around and into the brain providing nutrients and removing waste. CSF exits the CNS by passing through holes in the dura mater, where it is absorbed into the blood supply. The Ventricular System of the Brain CSF flows over immune system cells in the dura mater before returning to the blood supply central canal of the spinal cord