Class notes for final
Class notes for final PSYCH 202 A
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AUDITION (Chap 7.2) Web Links for Auditory System http://www9.biostr.washington.edu:80/cgibin/DA/PageMaster? atlas:NeuroSyllabus+ffpathIndex/Syllabus^Chapters/SUBJECTS/Auditory+2 Receptors in the auditory system transduce vibratory energy (vibration of molecules in a medium). Sound is perceived. Three basic characteristics of sound: Frequency, Intensity, Velocity 1) Frequency: Cycles per second. 1 cycle/sec = 1 Hertz (Hz) Audible spectrum: 20 to 20,000 Hz. Spectrum varies for species (e.g., extends higher for dogs, bats), age. Frequency of stimulus is associated with pitch perception. (in vision, frequency of stimulus is associated with color perception) 2) Intensity: amount of energy in stimulus: loud or faint sounds. We can hear a broad range of intensities: from very faint sounds (rustling of leaves) to very loud ones: jet engine. 3) Velocity: depends on the medium in which waves travel. In air, sound travels at 750 miles/h (1250 Km/h) (sound barrier), Velocity is greater in denser media (wood, metal) Function: What? (Recognition, identification) Where? (location) Compare with visual system The Auditory System (Chapter 7.2) The Ear 1) Outer: Auditory canal and tympanic membrane (eardrum) 2) Middle: 3 ossicles: hammer (malleus), anvil (incus), stirrup (stapes). function: interface between air in outer ear and liquid in inner ear. 3) Inner ear: Oval and round windows. Cochlea, contains the Organ of Corti Organ of Corti: Tectorial membrane Hair cells (receptors) Basilar membrane Stirrup pushes oval window in, forcing round window out, creating liquid wave inside cochlea. Wave in cochlea induces vibrations in basilar membrane Hair cells on basilar membrane collide with tectorial membrane. Oval/Round Window Movie (watch in slide show mode) Transduction: Hairs in hair cells are bent, which opens ion channels on hair cells. Receptor potential in hair cell is created, and transmitter is released. Receptor potential produces action potentials in ganglion cells (spiral ganglion, in the cochlea) whose axons form the auditory nerve (8th pair). Recognition of sound (what?) Basilar membrane analyses the component frequencies of sound. The basilar membrane is tonotopically organized: Different regions of membrane vibrate with different frequencies (as a keyboard). Base (near windows) is thick and stiff and vibrates with HIGH frequencies. Apex (end of membrane) is thin and flexible and vibrates with LOW frequencies. Auditory pathway Spiral ganglion cells project to the cochlear nucleus, in the medulla (myelencephalon), from here to other nuclei, but eventually to the thalamus (medial geniculate nucleus), and from here to the auditory cortex temporal lobe Neurons in primary auditory cortex respond to pure tones, but neurons in secondary auditory cortex require more complex sounds. For instance, in monkeys, neurons in secondary auditory cortex respond better to monkey calls. This pathway is tonotopically organized (cells prefer specific frequencies). Sound Localization (where?): requires two ears. Auditory system can analyze differences in the intensity and in the time of sound arrival between the two ears. Comparison of time of arrival occurs in the Medial Superior Olives, in the medulla Comparison of intensity of sound between the two ears is done in the Lateral Superior Olives. The Medial and Lateral Superior Olives are in the medulla (myelencephalon) Deafness. Complete deafness is rare. Two kinds 1. Nerve deafness, or inner ear deafness: damage to cochlea or hair cells, or nerve Bilateral lesions of the primary auditory cortex in laboratory mammals produce no permament deficit in their ability to detect sounds. However, cortical lesions can disrupt the ability to localize brief sounds, and to recognize complex sounds. 2. Conductive deafness, or middle ear deafness. Patients hear their voices. DEMOS DEVELOPMENT OF THE NERVOUS SYSTEM (Chapter 9.1) Early phases of neural development Embryos consist of three layers: ectoderm, mesoderm and endoderm. Induction of neural plate (ectodermal tissue) by underlying mesoderm (week 3 after conception). Cells of the neural plate are referred to as embryonic stem cells (neural and glial stem cells): They have unlimited capacity for selfrenewal They have the ability to develop into different types of mature cells. The neural plate leads to the formation of the neural tube, from where forebrain, midbrain and hindbrain develop (by 40 days after conception). The inside of the neural tube will eventually become the cerebral ventricles and spinal canal. Growth and Development of Neuron Proliferation: cells lining the ventricles divide and form neurons and glial cells. Migration: Movement of cells from ventricular zone to final destination. Radial migration. From the ventricular zone to the surface of the neural tube. Tangential migration. Parallel to the wall of the neural tube Migration can occur by: Somal translocation (caterpillarlike movement), or Gliamediated migration (radial glial cells) Cortex develops “inside out”. This means that newborn cells migrate from ventricular zone to form cortical layer 6 first, and then 5, 4, 3 and 2 (layer one does not have neurons). Aggregation. Cells accumulate in certain areas forming nuclei (singular: nucleus). Differentiation Neurons take their adult morphology. Myelination. In humans, starts in spinal cord and progresses toward forebrain. Neural crest. Located dorsal to the neural tube Neural crest cells develop into the neurons and glial cells of the PNS. Axon Growth and Synapse Formation. How do axons make correct connections with appropriate targets? Growth cones and filopodia Three major mechanisms can guide the process of target finding and synapse formation: 1. Blueprint hypothesis. This hypothesis proposes that there are preformed pathways and tunnels. Pioneer growth cones, guidepost cells. Fasciculation Role of celladhesion molecules (NCAMs) Evidence against blueprint hypothesis: Cells with altered locations (transplants) still find targets 2. Chemoaffinity hypothesis: connections are highly specific. Sperry’s eyerotation experiments (1943). After cutting optic nerves and rotating eyes 180 deg, the axons of retinal ganglion cells regenerated back to original target regions in the optic tectum (mesencephalon). Frogs whose eyes had been rotated, but without cutting the optic nerves, responded in the same way. How specific are the connections? If half of the retina was destroyed, remaining axons project in an orderly way on the entire tectum . If half of the tectum was destroyed, all of retinal axons accommodated in the remaining tectum and formed appropriate map. These observations support the Chemical Gradient Hypothesis 3. Finetuning of connections by spontaneous and experienceevoked neural activity Neural activity can lead to a strengthening of some synapses and a weakening of others. The Hebb postulate: Neurons that fire together wire together. Role of glutamate receptors. Respond to glutamate. NMDA receptors, are glutamate receptors that are also stimulated by NmethylDaspartate (NMDA) Detect correlated activity between presynaptic and postsynaptic cells. nonNMDA receptors. are glutamate receptors that do not respond to NMDA Role of spontaneous and evoked activity Critical or sensitive periods in development. Neuron Death and Synapse Rearrangement Regulation of cell numbers During normal development, many neurons die. It is believed that they fail to compete successfully for lifepreserving chemicals. Among these chemicals are the neurotrophins or trophic factors, such as Nerve growth factor (NGF), and brain derived neurotrophic factor (BDNF). Lack of trophic factors triggers Apoptosis, or active, programmed cell death (different from Necrosis, or passive cell death) Why does the CNS produce more neurons that it needs? To compensate for failure of some axons to find target. To compensate for target variability in size Synapse Rearrangement. Synapses that are "wrong" are likely to disappear The vulnerable developing brain Many factors can go wrong during development More than 200 genetic mutations associated with mental retardation The developing brain is more vulnerable than the mature brain to the effects of malnutrition, toxic chemical and infections. For instance, impaired function of the thyroid gland (endocrine gland) in infancy produces mental retardation that can be permanent. In the adult, thyroid impairment produces lethargy and other symptoms, but not mental retardation. Another example is early exposure to alcohol: fetal alcohol syndrome (mental retardation, motor problems, hyperactivity, decreased alertness, heart defects and facial abnormalities. Dendrites tend to be short, with few branches. (see Movie). Rett Syndrome: Anomaly of brain development with mental retardation affecting mainly girls older than 12 years. Associated with lack of dendritic development, perhaps due to deficit of neurotrophic factors Epilepsy NOTE: sections 9.2, 9.3, 9.4, 9.5 are not included. LEARNING, MEMORY, and AMNESIA (Chap 11) What is learning? The study of learning focuses on the changes in the nervous system that are induced by experiences, whereas the study of memory focuses on how these changes are maintained over time, and expressed (recalled). Learning is impossible without memory, and memory is impossible without learning: memory and learning are inseparable. The study of learning is difficult. It probably occurs in large areas of the brain, and trying to find the changes that occur during learning in a brain as complex as ours is a big challenge. Amnesic effects of bilateral medial temporal lobectomy Amnesia: condition characterized by the incapacity to remember Bilateral medial temporal lobectomy: removal of the medial portion of the temporal lobe in both sides of the brain Lobectomy: removal of a cerebral lobe Patient HM underwent bilateral medial temporal lobectomy to alleviate severe epilepsy (in 1953). The tissue removed on both sides included the hippocampus, amygdala and adjacent cortex (rhinal cortex). His epileptic condition improved, but he suffered devastating amnesic effects. He had some degree of retrograde amnesia (backwardacting). He could remember his childhood well but less well those episodes within the last two years before surgery. However, he suffered a severe anterograde (forwardacting) amnesia. Shortterm memory was within normal range (digit span of 6 digits). But he could not form new longterm memories. He could not consolidate new memories (process of transferring shortterm memories into longterm memories). Testing anterograde amnesia with objective tests: Digit span + 1 test. HM could remember about 6 digits; normal can remember about 15. Blocktapping memoryspan test. HM could follow 5 blocks, within the normal range. However, HM’ s memory for sensorimotor tasks was preserved: Mirror drawing test, and Rotarypursuit test. HM could improve by training, although he could not remember that he had practiced. He also improved in some nonsensorimotor tasks, such as the Incompletepicture test, but could not recall previously performing the task. He also learned a Pavlovian conditioning task. Eye blink response: pairing sound with air puff on the eye. Scientific Contributions of HM’s case. HM symptoms suggested that individual brain structures could be related to specific memory (mnemonic) processes. HM’s specific problem was a difficulty with memory consolidation. Also, he was the first patient to suggest that that there are two parallel memory systems: One for explicit memories (conscious memories), and One for implicit memories, memories that are expressed by improved test performance, but without conscious awareness. Tests to assess implicit memory are called Repetition priming tests. Examples are the incompletepicture test and test that involve memory for words. Amnesiacs can improve at recognizing word fragments if they see the complete words beforehand, even if they do not recall seeing the words. Two kinds of explicit memories: Semantic memories are explicit memories for general facts or information, for example, what one would learn in school, language, grammar and facts. Episodic memories are explicit memories for events and experiences in one’s life (seeing a particular movie). Patients with medial temporal lobe amnesia mainly have deficits in episodic memories. Why are there two parallel memory systems: one for explicit memories (conscious memories), and one for implicit memories? The conscious (explicit) system may have evolved to confer flexibility: ability to use implicit learning in different ways or contexts. Studies showed that although amnesic patients were able to learn an implicit task, they could not use this knowledge in a different context. Amnesia after Concussion: Evidence for Consolidation. Posttraumatic amnesia. Amnesia resulting from nonpenetrating blows to the head that cause concussion (temporary disturbance of consciousness) or coma (loss of consciousness). When patients regain conciousness, there is a period of confusion during which the patients have shortterm memory and appear reasonably lucid, but they fail to consolidate these memories into longterm memories. Also, they show a permanent retrograde amnesia for the events that led to the blow Gradients of Retrograde Amnesia and Memory Consolidation The fact that concussions disrupt recent memories suggests that the storage of older memories is protected by a process of consolidation. Consolidation has been studied with electroconvulsive shocks (ECS) to test the hypothesis that disrupting neural activity with the shocks would erase those memories that had not yet consolidated. The idea is that the length of the period of retrograde amnesia would correlate with the time needed for memory consolidation. Hebb postulated that prior to consolidation, memory is held in reverberating circuits that are susceptible to disruption of neural activity, such as that caused by ECS. Results from one experiment in rats suggested that consolidation took less than one hour Electric shocks applied later than one hour after the training did not erase what the rats had learned (the location of a water spout). However, experiments in humans that were treated with ECS for depression suggested that shocks could erase memories up to 3 years old. Thus, consolidation may be an ongoing process, which makes Hebb’s hypothesis unlikely. Reconsolidation Recent studies suggest that each time a memory is retrieved from longterm storage, it is again stored in shortterm memory, being therefore susceptible to posttraumatic amnesia. The Hippocampus and Consolidation There are some studies suggesting that the hippocampus may be involved in the consolidation process. It has been proposed that memories are temporarily stored in the hippocampus until they are transferred to a more stable cortical storage. Neuroanatomy of ObjectRecognition Memory Monkey Model of ObjectRecognition Amnesia: The Delayed NonmatchingtoSample Test Monkeys with bilateral medial temporal lobe lesions had deficits in the delayed nonmatchingtosample test These deficits were similar to those of HM’s (explicit, episodic memories). Monkeys could show shortterm memories, but had difficulty consolidating them into longterm memories In fact, humans with bilateral medial temporal lobe lesions behaved similarly in the delayed nonmatching to sample tests. One problem with monkeys is that lesions aimed at hippocampus also damaged the rhinal cortex (cortex adjacent to the hippocampus) Therefore, researchers could not be sure whether memory deficits in monkeys were due to lesion of the hippocampus or rhinal cortex. The Delayed NonmatchingtoSample Test for Rats However, the rat model presented the advantage that lesions could be restricted to the hippocampus The version of the delayed nonmatchingtosample task in rats is the Mumby box This box has 3 compartments. In one compartment, the rat is exposed to the sample object concealing the food. In the middle compartment, the rat is made to wait through the delay. In the third compartment, the rat was presented with the sample object that had to be rejected in favor of the new one that now conceals the food. Rats performed as well as monkeys with delays up to one minute. Neuroanatomical Basis of the ObjectRecognition Deficits Resulting from Medial Temporal Lobectomy The rodent model revealed that the hippocampus and amygdala were not involved in deficits of objectrecognition memory tested with delayed nonmatchingtosample tasks. Instead, these experiments found that the rhinal cortex was important for object recognition memory The hippocampus and memory for spatial location. The hippocampus does play a key role in memory for spatial location. Hippocampal Lesions Disrupt Spatial Memory Damage of the hippocampus result in severe deficits in spatial memory tested in mazes like the Morris water maze and the radial arm maze tests. In the radial arm maze, each day rats quickly learn the position of the arms with food (reference memory for the general principles and skills needed in the task) and refrain to visit an arm more than once during the day (working memory: ability to maintain relevant memories while a task is being performed). Both reference and working memories are deficient after lesion of the hippocampus. Hippocampal Place Cells When rats familiarize themselves with the environment, many cells in the hippocampus acquire a place field, that is, they fire when the rats is in a particular place in the environment. Comparative Studies of the Hippocampus and Spatial Memory Species of birds that remember where they store seeds have larger hippocampuses than birds that do not store seeds, supporting the idea that hippocampus is important for spatial memory in many, if not all, species. Experiment with humans in virtualreality towns (show activity in hippocampus using positron emission tomography, PET) and with taxi drivers (bigger hippocampuses measured with magnetic resonance imaging, MRI) also support this idea. Theories of Hippocampal Function The hippocampus may use sensory input to form an allocentric map of the environment (space represented by the relation between external landmarks). The hippocampus may be important for recognizing spatial arrangements of objects (such as furniture, pictures, etc., in a familiar room). Where are memories stored? In addition to the structures damaged in patients with medial temporal amnesia (hippocampus, amygdala and adjacent cortex (rhinal cortex)), other brain nuclei also play a role in memory. Some of these structures, such as the mediodorsal nucleus of the thalamus, and the basal forebrain (a midline area, rich in Ach, located just above the hypothalamus) (Fig. 11.17) appear to be damaged in patients suffering Korsakoff syndrome (often due to alcoholism, as we will see later in the course) and Alzheimer syndrome (a terminal condition including progressive amnesia and dementia). Other areas implicated in memory are The inferotemporal cortex stores memories of visual patterns. The amygdala plays a role in memory for the emotional significance of experiences. Rats with amigdala lesion fail to associate shocks with fear. The prefrontal cortex stores the temporal order of events, affecting jobs that require a series of responses, such as cooking. The cerebellum stores implicit sensorimotor tasks such as the eyeblink response. The striatum, part of the basal ganglia stores implicit sensorimotor tasks such as habit formation that develop incrementally after many trials. SYNAPTIC MECHANISMS OF LEARNING AND MEMORY (Chapter 11.8) In an attempt to study learning, research has focused on simpler systems that show some changes associated with learning, with the hope that these changes are similar to those that occur in more complex brains. Two main approaches. One approach studies the neural bases of learning in a sea snail (marine mollusk), called Aplysia (sea slug) The other approach focuses on a phenomenon that it is thought to be related to learning in brains like ours. The phenomenon is called longterm potentiation (LTP). We will concentrate on this approach. LTP as a model for learning . LTP in mammalian brains is the most widely studied neuroplastic phenomenon LTP: Enduring facilitation of synaptic transmission that occurs following activation of a synapse by intense highfrequency (100/sec) stimulation (for 14 sec) of the presynaptic neuron. It is longlasting: hours or weeks. Properties that implicate LTP in learning and memory 1) LTP shows cooperativity (spatial effect): Nearly simultaneous stimulation of two or more axons produces LTP, whereas stimulation of just one is less effective. If there are several inpus to a cell, only those that cooperate become facilitated, the others may actually weaken. 2) LTP shows associativity: Pairing a weak input with a strong input enhances later responses to the weak input. 3) LTP is the kind of synaptic facilitation that Hebb postulated in 1949 as the basis of learning and memory: Hebb's postulate for learning: The synaptic efficacy between A and B will increase when A fires B consistently. In order to account for associative learning and memory, synaptic facilitation must result from an interaction of simultaneous presynaptic and postsynaptic activity. In fact, LTP does not occur if the postsynaptic cell does not fire (only the presynaptic). Or when the postsynaptic cell fires alone. It is the cooccurrence that matters. Mechanisms of LTP. Receptors for Glutamate can be NMDA receptors, or nonNMDA receptors The hebbian nature of LTP results from the properties of the NMDA receptor Normally glutamate does not activate NMDA receptors because they are blocked by Mg+ + (magnesium). In order to repel the magnesium, it is necessary to depolarize the cell by activating nonNMDA receptors (e.g., AMPA receptors). Glutamate can now open NMDA receptors, which let Na+ and Ca++ in. Entry of Ca++ in postsynaptic cell induces cellular changes (Fig. 11.21). Temporarily activate genes and produce certain proteins. Proteins alter dendrites and potentiates synapse. NMDA receptors are necessary for inducing LTP, but not for maintaining it. It is now clear that effects of LTP are both presynaptic and postsynaptic LTP appears to increase the presynaptic release of glutamate LTP appears to promote the insertion of increased number of glutamate receptors in the postsynaptic membrane. Signal from postsynaptic to presynaptic cell: Changes in the postsynaptic cell may be transmitted to the presynaptic cell by the soluble gas Nitric Oxide (NO) (blocking the synthesis of NO blocks LTP), although other factors may also play a role. LTP and behavior LTP can occur during training in vivo. Blocking LTP interferes with learning. Mice with a mutation of a gene controlling NMDA receptors did not have LTP and could not learn a spatial task DRUGS AND ADDICTION (Chapter 15) In USA, over 60 million people are addicted to nicotine, alcohol, or both. About 5.5 million are addicted to illegal drugs, and several millions to prescription drugs. Psychoactive drugs: Drugs that influence behavior and subjective experience by acting on the nervous system. (Hormones and neurotransmitters can also act on the nervous system and produce changes in behavior.) We will refer to drugs that are administered and abused by humans. Basic Principles of Drug Action. Drug Administration and Absorption. The route of administration influences the rate at which, and the degree to which, the drug reaches its site of action. Oral ingestion: easy and safe, but unpredictable: rate depends on presence of foods, etc. Alcohol can be absorbed at the level of the stomach Injection. Used in medical practice because the effects can be large, rapid and predictable. Subcutaneous (SC), intramuscular (IM), or intravenous (IV). However, there is little opportunity to counteract overdoses, impurities in the drug and allergic reactions. There is also damage to veins. Inhalation. Through the capillaries in the lungs. Some anesthetics, tobacco and marijuana. It is difficult to precisely regulate the dose of drugs, and there can be damage to airways and lungs after chronic use. Absorption through the mucous membrane, for instance in the mouth, nose (cocaine) or rectum. Drug Penetration of the Central Nervous System Drugs eventually reach the blood stream, and from here, to the brain. Blood brain barrier protects the brain from many blood borne substances. Mechanism of Drug Action (see FIGURE) Drugs can act through many mechanisms, and often these are not very wellunderstood. For instance: By binding to some receptors, By influencing the synthesis, transport, release, or deactivation of neurotransmitters. Although some drugs are specific, most drugs influence brain activity in more than one way. Drug Metabolism and Elimination Why does the effect of a drug stop? Drug metabolism: The drug can be metabolized, that is, it is transformed by the effect of enzymes synthetized in the liver. Some drugs can be eliminated through the urine, feces, sweat, breath, and mother's milk. Drug Tolerance. Decreased sensitivity to a drug that develops as a result of exposure to it. There is a shift in the doseresponse curve. More drug is needed to produce the same effect. Development of tolerance is not necessarily specific to the drug that induces it, or to all of its effects. 1. Tolerance to one drug may cause tolerance to other drugs that have similar mechanisms of action (cross tolerance). 2. There can be tolerance to some effects of one drug but not to other effects of the same drug. Sometimes, sensitivity to other effects of the same drug increases, a phenomenon called drug sensitization. This can be dangerous. 3. Tolerance can be Metabolic or Functional. Metabolic Tolerance occurs when the amount of drug reaching the sites of action decreases. Functional Tolerance occurs when there is a reduction in the reactivity of the sites of action to the drug. Tolerance to psychoactive drugs is mainly Functional. For instance, there can be a reduction in the receptors to the drug, or less binding of the drug to cell receptors, or less effect on the cells. Drug Withdrawal Effects and Physical dependence. Withdrawal syndrome: Set of clinical symptoms that develop when there is a sudden drop in the blood levels of certain drugs. They can be quite serious in some cases. The symptoms are often the opposite to the initial effects of the drug. For example, if the drug is an anticonvulsant (it prevents convulsions), withdrawal of the drug may cause convulsions. Individuals who suffer withdrawal syndromes when they stop taking a drug are said to be physically dependent on that drug. It is thought that withdrawal effects are produced by the same neural changes in the nervous system that offset the drug's effects and produce tolerance. ADDICTION: WHAT IS IT? Not all habitual drug users are addicts. Addicts are those that are incapable of stopping the use of a certain drug despite the adverse effects that the drug habit has on the person's health and social life, and despite the addict's repeated efforts to stop the use of drugs. Addiction is not merely caused by physical dependence (withdrawal symptoms) because even when the withdrawal symptoms end, the addict will often take the drug again. Role of Learning in Drug Tolerance and Drug Withdrawal. Contingent Drug Tolerance occurs when tolerance develops only to drugs whose effects are actually experienced. Example: tolerance develops when alcohol is injected so that it prevents subsequent convulsions, but not when convulsions occur before the alcohol administration (alcohol would not have a chance to act as anticonvulsant). Conditioned Drug Tolerance: tolerance effects are maximally expressed only when a drug is administered in the habitual conditions. There is less tolerance in novel conditions. For instance, tolerance that develops in one environment may not be present in a novel environment. Danger of overdosing in a motel for somebody that developed tolerance at home. Siegel proposes that each incidence of drug administration is a Pavlovian conditioning trial. The constant environmental stimuli that predict when the drug will be administered (e.g., a certain room) are the conditional stimuli, and the drug effects are the unconditional stimuli. The conditional stimuli (predict drug use) would elicit conditioned compensatory responses, which would oppose the effects of the unconditional stimuli (the drug effects). This opposition would cause situationally specific drug tolerance . Conditioned Withdrawal Effects are the effects that are elicited by the drug environment or by other drugassociated cues. For instance, a drug user is in the room that is used for drug administration, but no drug is available. The effects would be opposite to those produced by the drug. BIOPSYCHOLOGICAL THEORIES OF ADDICTION Are addicts driven by internal need? Or, are they driven by anticipated pleasure? PhysicalDependence and PositiveIncentive Perspectives of Addiction. PhysicalDependence Theory of Addiction. Initially it was thought that drug addiction was related to physical dependence. Addicts would be driven by their withdrawal symptoms to selfadminister the drug. Addicts would be trapped in a vicious circle of drug taking and withdrawal symptoms. Treatment: gradual withdrawing drugs in hospital environment. Unfortunately, after being detoxified, most addicts go back to drugs. Detoxified addicts are addicts who have no drugs in their bodies and no longer experience withdrawal symptoms. Relapse of detoxified addicts is no surprising because: some drugs like cocaine and amphetamines do not cause severe withdrawal symptoms some addicts go through cycles of binges and detoxification because of working schedules, lack of money, jail time, etc. PositiveIncentive Theories of Addiction. Failure of physicaldependence theories have focused attention on positiveincentive theories. According to positiveincentive theories, the users of drug seek the pleasureproducing effects of drugs. e.g., one addict would need $25 to get rid of withdrawal symptoms, yet he would use all his money for drugs: “I like drugs better than anything else, including sex”. Some pleasurable effects could be indirect, like disinhibition: e.g., effect of alcohol in single bars. It has been proposed that the positiveincentive value of addictive drugs increases with use. tolerance develops for aversive effects rather than pleasurable effects drug sensitizes their positive incentive value, leading to increased motivation to use drug. The positiveincentive value may appear out of proportion with the pleasure actually derived from it: addicts are miserable, in ruins, and the drug effects are not that great anymore, but they still crave the drug. Most evidence suggests that the positiveincentive value of addictive drugs is the primary factor in addiction. Causes of Relapse. Relapse is common, and the following reasons contribute to this: 1. Stress. For instance, cigarette and alcohol consumption increased after Sept 11th. 2. Priming. Trying the formerly abused drug brings full blown addiction. 3. Exposure to environmental cues associated with previous drug use. Intracranial SelfStimulation and the Pleasure Centers of the Brain. Reward circuits in the brain. Pioneer research by James Olds and Peter Milner in 1954 showed that rats preferred corners at which shock were delivered in certain brain regions. Intracranial selfstimulation. Animals including humans press lever to deliver electric pulses to selfstimulate pleasure centers (FIG. 15.6). Olds and Milner proposed that the brain sites mediating selfstimulation are the same that normally mediate the effects of natural rewards, including food, water and sex. These pleasure centers are now believed to mediate the experience of pleasure mediated by drugs, raising the possibility that these centers play a major role in addiction. Fundamental Characteristics of Intracranial Selfstimulation. Most early studies used lateral hypothalamic and septal stimulation because rats can be induced to press a lever thousands of times per hour, stopping only after they are exhausted. However, many other structures have been identified. At first, some puzzling observations suggested that lever pressing after lateral hypothalamic and septal stimulation was different than pressing for natural rewards (food, water, sex, etc.): The instant that electrical pulses were stopped, rats stopped pressing the lever immediately, not gradually , showing a rapid rate of extinction (if bills were delivered by pressing a lever, one would not stop immediately after a few failures). After stopping stimulating, rats would not immediately start after being returned to the cage; the operator had to get them started again (priming). However, further research has revealed that pleasure centers mediating selfstimulation are related to natural reward circuits: 1. Brain stimulation through electrodes that mediate selfstimulation often leads to natural motivated behaviors if the appropriate objects are present: food, water, etc. 2. Increasing natural motivation by, for example, food or water deprivation ofen increases the rate of electrical selfstimulation. 3. Confounding experimental factors were addressed. For instance, rats that pressed a lever for intracranial selfstimulation were not deprived, while those that pressed a lever for natural rewards (food pellets, water drops) were deprived. When experimental confounds were removed, the major differences between lever pressing for food or water and lever pressing for self stimulation disappeared. For instance, non deprived rats, which had chocolate delivered to their mouths by a lever learned to press just like when electrical stimulation was used (fast onset, rapid extinction, and showed a priming effect). THE MESOTELENCEPHALIC DOPAMINE SYSTEM AND INTRACRANIAL SELF STIMULATION The mesotelencephalic dopamine system is a system of dopaminergic neurons that projects from the mesencephalon (midbrain) into various regions of the telencephalon. These neurons are in the substantia nigra and ventral tegmental area (midbrain), and project to a variety of telencephalic sites including the striatum (basal ganglia), portions of the frontal cortex, limbic cortex, the olfactory tubercle, the amygdala, the septum and the nucleus accumbens. The mesotelencephalic dopamine system consists of the Nigrostriatal Pathway and the Mesocorticolimbic Pathway. The substantia nigra projects mainly to the dorsal striatum. This projection is called the Nigrostriatal Pathway. Degeneration of this pathway is associated with Parkinson's Disease, a motor disorder. The projection from the ventral tegmental area to various cortical and limbic sites is called the Mesocorticolimbic Pathway. The projection from neurons in the ventral tegmental area to the nucleus accumbens has been most often implicated in the rewarding effects of brain stimulation, natural rewards, and addictive drugs. Evidence that the mesocorticolimbic dopamine system plays an important role in intracranial selfstimulation. 1) Mapping studies: Many sites at which selfstimulation occurs are part of the mesocorticolimbic dopamine system. Other sites that do not contain a lot of dopamine project directly to nuclei of the dopamine system. 2) Cerebral dialysis studies: samples of extracellular fluids are collected for about 15 min and analyzed chemically. Selfstimulation is associated with an increase in dopamine release (Fig. 15.8). 3) Dopamine agonist and antagonist studies have revealed that agonists tend to increase intracraneal selfstimulation, while dopamine antagonists tend to decrease selfstimulation. 4) Lesion studies: lesions of the mesocorticolimbic dopamine system disrupt self stimulation. One side was used as control. Lesions in one side reduced self stimulation to electrical pulses in that side but not to stimulation of the other side. Neural Mechanisms of Motivation and Addiction Brain mechanisms did not evolve to mediate addiction. The idea that the mesocorticolimbic pathway is involved in drug addiction is supported by: 1. Evidence that the pleasurable effects of drugs, rather than the alleviation of withdrawal symptoms, are the major factors in addiction. 2. Evidence that the mesocorticolimbic pathway plays an important role in intracranial selfstimulation. 3. Evidence that the mesocorticolimbic pathway is involved in the effects of natural rewards (food, water, sex, etc). Current research aims at understanding how addictive drugs use the natural reward systems resulting in addiction. Two Key Methods for Measuring DrugProduced Reinforcement. Two behavioral paradigms have been used in experimental animals. 1. Drug selfadministration. Rat presses lever to selfinject drug through implanted cannulas. Cannulas can be intravenous or they can deliver drug directly into brain structures. The rat's drugtaking habits mimic in many ways the drug taking of human addicts. 2. Conditioned place preferences. In a box made of two different, but equalsized compartments, rats repeatedly receive drug in only one of the compartments. When rats are drugfree, their preference to either of the two compartments is measured. Rats prefer the compartment associated with the drug administration. Early Evidence of the Involvement of Dopamine in Drug Addiction Experiments in the 1970's suggest that dopamine signals something related to reward value or pleasure: Dopamine antagonists blocked the selfadministration of, or conditioned preference for, several different addictive drugs. Dopamine antagonists also reduced the reinforcing effect of food. The Nucleus Accumbens and Drug Addiction. Evidence suggesting a role of the nucleus accumbens in addiction: 1) Animals selfadminister microinjections of addictive drugs (e.g., cocaine, amphetamine and morphine) directly into the nucleus accumbens. 2) Microinjections of addictive drugs into the nucleus accumbens produced a conditioned place preference for the compartment in which they were administered. 3) Lesions to either the nucleus accumbens or the ventral tegmental area blocked the self administration of drugs into general circulation or the development of drugassociated conditioned place preferences. 4) Both the selfadministration of addictive drugs and the experience of natural reinforcers were found to be associated with elevated levels of extracellular dopamine in the nucleus accumbens. Support for the Involvement of Dopamine in Addiction: Evidence from Imaging Human Brains. Imaging techniques for measuring dopamine suggest that dopamine is involved in human reward and in addiction. It was observed that cocaine exerts an agonist effect on dopamine. Cocaine blocks the reuptake of dopamine by dopamine transporters that are located in the presynaptic terminal. This leads to an increase of dopamine in the synaptic cleft. The intensity of the "highs" experienced by the addicts was correlated with the degree to which radioactively labeled cocaine bound to the dopamine transporters. Binding to more than 50% of dopamine transporters was required to experience a high. In nonaddicts, increased levels of dopamine in the nucleus accumbens caused by IV injections of amphetamine are associated with an increase in their experience of euphoria. Dopamine, Nucleus Accumbens, and Addiction: Current View. It is not clear how the release of dopamine in the nucleus accumbens relates to the experience of reward. Studies of the activity of dopaminergic neurons in the ventral tegmental area (which projects to the n. accumbens) have shown that these neurons responded to rewards only when the rewards were presented unpredictably, as in the early stages of a conditioning experiments. On the other hand, if a reward was expected, as in the late stages of a conditioning experiment, the reward itself did not increase the activity of dopaminergic neurons, but the conditional stimulus that predicted the reward did. Thus, it appears that dopamine is involved in the expectation of reward, rather than the reward itself. In addition to the nucleus accumbens, other nuclei of the mesotelencephalic dopamine system are thought to be involved in reward. In fact, lesions of the n. accumbens have failed to block the relapse in opiate addicts, confirming that other structures play a role in addiction. In addition of dopamine, other neurotransmitters may also be involved in reward. This idea is supported by the observation that mice lacking dopamine are capable of being rewarded by sweet solutions. What can be done for addicts? Perhaps one possibility will be to develop selective dopamine antagonists that reduce the positiveincentive value of drugs in addicts without reducing the positiveincentive value of natural motivated behaviors. HUNGER, EATING and HEALTH (Chap. 12) Biology of ingestive behavior How is eating regulated? Hunger and satiety. Eating disorders are prevalent, indicating that the mechanisms that regulate eating behavior are complex and not well understood. By one estimate, over half of the adult U.S. population meets the current criteria of clinical obesity. Digestion and energy flow. Digestion is the gastrointestinal process of breaking down food and drink and absorbing them into the body. Digestive system and steps in Digestion 1. Chewing mixes food with saliva, and initiates digestion (action of enzymes in saliva). 2. Swallowing passes food through esophagus. 3. Stomach acts as a reservoir. HCl (hydrochloric acid) breaks up food into small particles and Pepsin (digestive enzyme), secreted by stomach, breaks down protein into amino acids (aa). 4. Stomach empties content into duodenum, where most of the absorption takes place. Here, digestive enzymes from liver (gall bladder) and pancreas act on proteins and sugars. The products can be absorbed into the blood stream and transported to the liver. 5. Bile, produced by the liver and stored in the gall bladder, emulsifies fat (droplets), which then passes into the lymphatic system. 6. The large intestine absorbs most of the remaining water and electrolytes, and what is left exits the system through the anus. As a consequence of digestion, energy is delivered to the body in three main forms : 1) Lipids (fats) 2) Amino acids (aa), the breakdown products of proteins 3) glucose, the breakdown product of carbohydrates (starches and sugars) Energy is stored as: fats in adipose tissue (85%) Why so much? fats store twice as much energy as glycogen, and holds less water. A person would weigh 600 lb if energy were stored as glycogen (which is readily converted to glucose)! proteins in muscle (14.5%) glycogen in muscle and liver (.5%) Phases of energy metabolism: Cephalic: Preparatory phase, from seeing and smelling food to the beginning of absoption into the bloodstream. Absorptive: Food absorbed meets immediate energy needs. Fasting: Energy in stores is used, leading to weight loss. The flow of energy during these three phases is regulated by two hormones produced by the pancreas: insulin and glucagon. During the cephalic and absorptive phases, insulin is high, and glucagon is low. High levels of insulin promote: the use of glucose by body cells. the conversion of glucose into fats and glycogen, and aa into proteins. the storage of fats, glycogen and proteins During the fasting phase, glucagon is high and insulin is low. Because insulin is low, glucose cannot be easily utilized by the body. But most brain cells do not need insulin to use glucose. Thus, glucose is reserved for the brain. Low levels of insulin also promote gluconeogenesis: conversion of proteins to glucose. High levels of glucagon promote: the release of free fatty acids from adipose tissue to be used for energy. free fatty acids are also converted to ketones, which are used by muscles. Theories of Hunger and Eating: Set Points versus Positive Incentives. SetPoint Assumption Motivation to eat (hunger) would come from an energy deficit. There would be an energy set point that is maintained at a relatively constant level When the energy levels fall below the set point, hunger would develop, leading to eating behavior. Eating brings the level back to set point, and the person feels satiated (no longer hungry). Thermostat metaphor. Setpoint systems are feedback systems. They maintain homeostasis: a constant internal environment. GLUCOSTATIC and LIPOSTATIC SET POINT OF HUNGER AND EATING. In the 1940s and 1950s, it was proposed that food components would go from the gut to the brain through the blood stream and provide information (feed back) about energy supply: it would produce satiety if supply is large, and hunger if energy supply is small. Which component of food would provide the feedback? Several possibilities: the three sources of energy: 1. lipids (fats) 2. amino acids (aa) breakdown products of proteins 3. glucose, a simple breakdown product of complex carbohydrates (starches and sugars). GLUCOSTATIC THEORY It was proposed that there is a glucostat and a set point for glucose level in blood. Glucose would interact with glucoreceptors. The primary stimulus for hunger is a decrease in the level of blood glucose below its set point. The primary stimulus for satiety is an increase in the level of blood glucose above its set point. Later it was proposed that it was not the level of bloodglucose which was regulated but the level of glucose utilizatio . This explain cases of hyperphagia (overeating) associated with high levels of bloodglucose, as in patients with diabetes mellitus. In these patients, the pancreas does not produce enough insulin, which is needed for glucose to enter most cells in the body and be utilized. Where is the glucostat? Injections of gold thioglucose (neurotoxin) produced damage localized in the Ventromedial Hypothalamus (VMH). Treated mice overate and became very fat. This suggests that the VMH is the Satiety Center It was observed that weight gain had a dynamic phase and a static phase, in which the new body weight was defended. Further research suggested that the Lateral Hypothalamus (LH) is the Feeding Center Lesions of the LH caused aphagia (cessation of eating) and adipsia (cessation of drinking). Stimulation of the LH caused eating behavior. However, these notions have been challenged by more recent research (see below). LIPOSTATIC THEORY Proposes that there is a set point for body fat so that the level of body fat is maintained at a relatively constant level. This theory provides an explanation why shortterm diets do not work: the body regains its "normal" amount of fat after the diet is over. The lipostatic system would provide longterm regulation, whereas the glucostatic system would produce shortterm regulation. The DualCenter SetPoint model A theory of eating behavior based on the satiety center (VMH), the hunger center (LH), and the glucose and body fat set points was very popular in the 1940s and 1950s. Problems with Set Point Theories of Hunger and Eating. Setpoint theories are rigid and not sufficient to explain all aspects of eating behavior. For instance: Early ancestors needed to eat a lot to store energy as fat. Eating behavior is not always motivated by energy deficit. Other factors influence eating behavior, such as taste, learning and social factors. Alternative theories have added significant flexibility. PositiveIncentive perspective . The positiveincentive theory states that eating behavior is driven not so much by energy deficits, but by the anticipated pleasure of eating a particular food. Several factors influence the positiveincentive value of eating, including the flavor of the food, and other conditions at the time of the meal (social factors, etc.). In rats, the addition of saccharin, a sw
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