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33 Cards in this Set
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Pavlovian conditioning
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Responses to cues that predicts events - there is not control over learning. 4. key elements of Pavlovian conditioning: 1. Unconditioned stimulus 2. Conditioned stimulus 3. Unconditioned response 4. Conditioned response 5 important points that allow for Pavlovian conditioning. 1.CS must reliably predict US 2. Delivery of CS and US are uncontrollable to the organism 3. CR is uncontrollable, usually autonomic response. If motor, then Pavlovian approach. 4. In humans, CR occurs without conscious knowledge 5. Long lasting, extinction can occur, but also reinstated quickly. Human conditioned preference: subjects are asked to conduct a memory task. If they are successful, they are given a food reward, and a distinct visual background is shown, a pleasant tone played. Failure results in no reward, another distinct visual background, and no tone. When shown an array of patterns, healthy humans prefer pattern similar to success pattern, even without conscious realization as to why. If asked, they will rationalize and make up a response. If the left or right amygdala is lesioned, then there is no preference Extinction: if after shock pairing, tone is played without shock, rats will no longer freeze. This is a form of new learning that suppresses the old response, rather than extinction. Regulated by the PFC. |
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Auditory fear conditioning |
Rat show an innate fear response by freezing up. If a auditory tone (CS) is associated with an electric shock (US), the amoutn of time spent frozen can be measured and quantified. If the amygdala is lesioned before association learning, then the learning will not occur. If lesioned after, then there is no recall - the tone alone will also not cause freezing. Neural circuit: Medial geniculate thalamus processes auditory information. It projects to the lateral amygdala, where pain sensation is simultaneously projected to. The LA signals the central amygdala to initiate autonomic, emotional, and freezing responses. The LA will change its firing patters when learning occurs such that the same pattern is seen when tone is heard and shock is delivered as is when the tone is delivered alone. If the LA is lesioned, then conditioned place preference for all types of rewards is abolished - the LA regulates Pavlovian conditioning if the stimuli is rewarding as well as harmful, known as appetitive conditioning. |
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Instrumental conditioning |
Association of an action with a consequence (reinforcement). The organism is able to control its own learning. Reinforcer: something that change the likelihood of a repeat response occurring. Instrumental conditioning is regulated by the striatum in the basal ganglia. It receives input from sensory/motor cortex and dopamine system, integrating them to decide on the appropriate movement for a task. The amygdala can input to the striatum to influence instrumental action. 2 phases in instrumental learning: 1. Early: goal directed - response is made to obtain a goal 2. Late: responses are automatic and habitual, mediated by the dorsal striatum. This frees up for other processes. Experiment: first, associate CS light with food reward, then insert 2 levers. One lever gives light, other gives nothing, neither gives food. Light becomes reinforcing, the animals work towards it and not the food. If amygdala is lesioned, rats show no preference towards the light lever, but will still show preference for a lever if it dispenses food. Thus, instrumental learning occurs, but no Pavlovian. Previous neural environmental cues associated with their reward controls behavior, but we are not consciously aware of their control. |
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Memory |
3 components: 2. Storage 3. Retrieval 3 main points to understand about the neural basis of memory: 1. There are multiple forms of memory 2. Different types of memory are regulated by distinct brain regions. 3. One type of memory is regulated by interactions between multiple brain regions. Memory taxonomy: declarative (explicit) or procedural (implicit). Declarative can be split into episodic (personal experience) or semantic (facts). Procedural can be skill learning or conditioning, regulated by the striatum and amygdala, respectively. Memory can be defined by how long it lasts: Short term memory: information held while the necessary physiological changes for long term potentiation are made. Has a capacity of 7 plus or minus 2 items. Neurons will fire in the same pattern as when the information was presented. Susceptible to distraction, requires active rehearsal to maintain, and information can be lost through displacement or decay, but it will either be lost or moved to other parts of memory. Long term memory: very stable, potentially unlimited capacity and retention time. Can be gained actively or passively. Consolidation is due to physiological changes Amnesia: certain types of brain injury or drugs can lead to long term memory processing impairments. Retrograde: loss of memory for events prior to injury Anterograde: inability to form new memories after injury |
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HM |
Removed hippocampus, amygdala, and temporal cortex. He had severe anterograde amnesia, and 3 years worth of retrograde amnesia. His short term memory was maintained, but there was no consolidation. Tasks that HM could not do: 1. Digit span + 1 test: have subject report back increasing number of digits until error is made. Normal people could do 15, HM can only go up to 8. 2. Matching to sample: after showing a pattern, an array of patterns is shown after a delay, and subject is asked to match the correct one. HM could remember after 40s delay, but only due to active rehearsal. If he is distracted, or if the patterns were switched so that it was hard to rehearse, impairment would occur. Tasks HM could do: 1. Mirror drawing task: asked to redraw an object seen in mirror 2. Rotary pursuit task: subjects keep pen on target on rotating disk. Both tasks have a learning curve, thus HM could improve despite not remembering that he has seen the task before - procedural long term memories could still be learned. HM was gradually able to form semantic memories, but will not recall learning them. HM supports the 2 stage model for memory formation, as short term memory is unaffected, and also supports that the hippocampus aids in consolidation, but memory is stored elsewhere. Not all learning or memory is associated with the memory |
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Hippocampus |
Radial arm maze: arts navigates an asterisks shaped maze using relative distance from 2 or more distinct visual cues to infer location and orient self. Hippocampal lesioned rats are unable to learn, make more errors, and keep re-entering previously visited arms. Morris water maze: pool is filled with opaque water, escape platform hidden below surface. Rats use visual cues to navigate: normal rats learn quickly, hippocampal lesioned rats do not. Humans with hippocampal damage show difficulty in remembering routes and navigating. Healthy humans show increased hippocampal activity when learning new routes. Taxi drivers show increased hippocampal activity when recalling taxi routes,but none if asked to project new routes. Thus, hippocampus is critical for learning about relationships between different stimuli. Hippocampal place cells: different neurons fire preferentially at different locations by using relative distance of environmental stimuli to decide when to fire. Sensory cortices project to and integrate at the hippocampus, where it is stored temporarily before being consolidated in the same region that sensed the stimulus. A retrieval group of neurons can activate neuronal groups in the hippocampus, which cascades to activate all neurons involved with that particular episode for recall. Over time, hippocampal involvement in recall of this memory is not necessary. |
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Emotion on memory |
Amygdala mediates emotional enhancement of memory consolidation using norepinephrine. NA-beta receptor antagonists will selectively reduce the effect of emotional events on increasing memory, despite subjects still reporting an emotional response. This mechanism may underlie PTSD associated memory modulation. If the amygdala is stimulated with drugs immediately after learning, rats will show increased memory |
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Short term memory consolidation |
Every memory encoded will change the neuronal structure in the brain - brain plasticity. Short term memory is carried out by groups of interconnected neurons known as cell assemblies. Activity driven by a sensory input can start a chain reaction that continues for some time, known as a reverberatory circuit, which can continue for some time. If activity in the cell assembly circuit is strong enough or rehearsed enough, then physiological long term alterations will occur at the synapse level, increasing EPSP and making memory more permanentL |
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Long term potentiation |
Synaptic strength is measured by changes in EPSP evoked by an input. Synaptic strength can be modlated by by: 1. amount of transmitter release 2. number of receptors 3. sensitivity of receptors LTP can be measured by stimulating presynaptic neurons at a low frequency, thus establishing a baseline of EPSP that is induced. When then stimulated at a high frequency (tetanus), then EPSPs reach threshold and APs are fired. Returning to the basal low frequency shows that EPSPs are now stronger - the input is now potentiated, leading to a higher probability of firing an AP. LTP can only occur when there is simultaneous activity in both the presynaptic and postsynaptic neurons. It requires that a high frequency of inputs are applied. If the same number of inputs are spread out over a long period of time, there will not be any LTP. LTP can occur in all brain regions that have glutamate receptors, as well as in vitro 1. amygdala 2. straitum 3. cortex 4. thalamus 5. cerebellum 2 phases to LTP: phase 1 involves immediate changes - increased receptor count and glutamate release, and it can be blocked by NMDA antagonists. Phase 2 involves physiological changes from protein synthesis, which can change the shape/size/number of dendrites, and it can be blocked by protein synthesis blockers.Both phases are blocked by Ca2+ blockers. Blocking LTP with drugs will only disrupt learning during the learning phase, and will be ineffective afterwards. But if protein synthesis blockers are given after learning, then disruption will still occur. If NMDA receptors are blocked in the hypothalamus, learning is disrupted. Amygdala disrupts fear conditioning. Striatum distrupts instrumental learning. |
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Biochemical basis for LTP |
Glutamate receptors are ionotropic and in 2 families: AMPA and NMDA. Both are ligand gated Na+ channels, but NMDA is also a Ca2+ channel. In the hyperpolarized basal state of the postsynaptic neuron, NMDA is blocked by Mg2+, but AMPA can be induced to open. Mg2+ is released when the cell is depolarized sufficiently due to high frequency stimulation, setting up a voltage dependent Mg2+ block. Ca2+ is now allowed to enter the cell, which ultilizes the CaM pathway to activate different kinases. CaMK is one such kinase, which transports pre-existing cytoplasmic AMPA receptors to the cell surface and expresses it, allowing for more Na+ to enter. Ca2+ also activates both PKC and tyrosine kinase, which phosphorylates CREB. CREB will form a retrograde messenger in the form of NO, causing increased glutamate release, and it will also promote transcription of genes to alter the neuron. In mice, knocking out CREB or CaM will show disrupted learning and LTP. |
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Prefrontal cortex |
Coordinates activity between the different memory systems. Humans have the largest PFC size relative to their brain, but as a result it develops late compared to other animals. The medial and orbital regions of the PFC regulates emotions, while the dorsolateral PFC regulates planning and working memory. In rats, the medial PFC is functionally analogous to the dorsolateral PFC in humans. Working memory is defined as the short term manipulation and retrieval of information - information is encoded in one form, but it is manipulated to guide behavior in another form. For example, memorizing a string of digits is considered short term memory, but repeating it backwards would be working memory. Delayed response task: animals acquire information and must hold it over a delayed amount of time before using it to guide a response for a reward. Multiple trials are given in rapid succession with short inter-trial intervals, and each trial presents unique information that distinguishes it from previous trials. Thus, animals must quickly adjust to new trial's information to get the reward. If the dorsolateral/medial PFC is lesioned, there is impairment, even with the shortest delay between information presentation and behavior. High neural activity is seen during the delay period while animals hold the information in their working memory, with lower activity during both stimulus and recall. Thus, neuronal activity during the delay phase is positively correlated with accuracy of recall. Wisconsin card sorting task tests behavioral flexibility. Subjects are first asked to sort cards based on a stimulus dimension (e.g. number), but the rule isn't told to them. Instead, they figure out the rule when the researcher says correct or incorrect based on trial and error. Part way through the trail, the rule is switched without telling the subject, now they have to sort based on a different dimension (e.g. color) and they have to realize and adapt to the new rule. Damaged dorsolateral PFC subjects are able to learn the new rule, but cannot adapt to the second and switch strategies - they display perseveration. Rats are trained to turn in a specific direction via striatal training, with a visual stimulus placed randomly in either direction during the training. Afterwards, the reward is now placed where the visual stimulus is presented, and the rat must learn to respond to the visual cue instead and undo their striatal training. If the medial PFC is inactivated during the shift in the rule, then rats will not be able to adapt. However, inactivation during striatal training will show no impairment. responsible for temporal organization of behavior, damaged patients are able to keep track of items, but not the order. Tower of London: assess planning of movement sequences, PFC lesioned patients are unable to complete, or take much more moves to reach a position in as few moves as possible. Dinner party problem: given a number of errands to run and questions to answer. Specifically told to not enter shops unnecessarily and finish tasks asap, but despite remembering and understanding rules, PFC damage patients were unable to comply. PFC damage is a deficit in integrating memory to form a plan of action, rather than a memory deficit. |
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Contextual fear conditioning |
Mediated by the hippocampus. Give CS tone+UCS shock in a unique context. In a separate context, tone will cause freezing in normal rats, but hippocampal lesioned rats will also freeze the tone since association is due to the amygdala. If rat is put back into context A, it will still freeze even without the tone due to hippocampal contextual learning. This will not occur if the hippocampus is lesioned. If both the hippocampus and amygdala are lesioned, freezing will not be seen due to neither tone nor context. |
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What memory system for what |
Hippocampus: declarative and spatial/relational memory Striatum/caudate nucleus/basal ganglia: procedural memory/habit forming/instrumental conditioning Amygdala: Pavlovian conditioning, both appetitive and aversive Triple dissociation of memory systems: 1. Using the spatial radial arm maze, rats are trained not to return to the same arm after reward is depleted. Impairment only if hippocampus is lesioned. 2. Giving a conditioned place preference test and training rats to return to the same arm as where food is given. Impairment only when the amygdala is lesioned. 3. Using a locally cued radial arm maze but with a light beam instead of spatial cues to show location of food. Impairment only when the striatum is lesioned. Given the choice of memory system for finding food, early training termination (3 days) defaults hippocampal memory - they will seek a new place to eat food. Later than that uses the striatum - returning to the same place for food. Both systems can learn independently but in parallel with each other, with hippocampal learning being more rapid. If one system is suppressed, the other will dominate. The same is seen with amygdala and the hippocampus - amygdala dominates after a long time of training |
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Schizophrenia |
A family of disorders characterized by distinct symptoms, either positive, hallucinations, delusions/paranoia, and psychosis, or negative, lack of insight, cognitive deficits, blunted emotional responses. One of three core symptoms are necessary for diagnosis: hallucinations, delusions, or disorganized speech. Cognitive functioning is the #1 predictor for prognosis, though severity of psychotic symptoms are not related to severity of cognitive deficits. 7 primary domains of cognition are affected, many of which are PFC regulated 1 speed of processing 2. working memory 3. visual learning/memory 4. social cognition 5. attention 6. reasoning/problem solving 7. verbal learning/memory Schizophrenics showed minimal increase in PFC when performing Wisconsin card sort task relative to their identical twins. There is a genetic link to schizophrenia, but it is not the only cause. Alterations during development are also major contributors, including poor nutrition, physical/immune stressors during pregnancy, premature birth, and early developmental insults leading to brain abnormalities in adulthood. Onset is triggered post puberty by stressors, but sensitivity to stressors is genetically determined. Schizophrenia causes 1. enlarged lateral ventricles due to smaller hippocampal neurons 2. haphazard organization of hippocampal neurons, originating from development 3. reduced number of dendrites in PFC pyramidal neurons, causing hypofrontality (reduced PFC function characteristic of negative symptoms). Also reduces GABAergic interneurons in the PFC and hippocampus, normally acting as information filters. |
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Dopamine hypothesis |
1950s: chlorpromazine found to be an antipsychotic, causes Parkinson's like symptoms in normal patients. Parkinson's=DA deprivation 1960s: amphetamines cause increased DA release, and induce psychotic symptoms, chlorpromazine and other antipsychotics block dopamine receptors 1970s: DA receptor subtypes discovered. Antipsychotic potentcy of a drug is correlated with affinity for D2 receptors. Concluded that schizophrenia is caused by unusually high DA levels on D2 receptors. Most of dopamine is produced in small nuclei in the brainthe VTA and NAc. Evidence: 1. All effective psychosis drugs block D2 receptors to some degree. 2. Schizophrenic brains do not show an increase in D2 receptors, but it may be seen due to chronic antipsychotic medication upregulating receptor production. 3. No increased DA production, no difference in DA metabolites in CSF. Thus, schizophrenics must be due to increased DA release in the NAc, confirmed with fMRI. DA release is hypersensitive in schizophrenics when given low doses of amphetamines, and amount of DA release is correlated with positive symptoms. Points against DA hypothesis: 1. antipsychotics block receptors immediately, but treatment takes 2 weeks to reach effect 2. not all schizophrenic patients respond to DA antagonist drugs 3. DA blockers alleviate psychosis, but negative symptoms unaffected. Doapine does not block D2 receptors, and has higher affinity for other receptors 4. Drugs that increase DA release can improve negative symptoms |
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Dopamine in the brain |
DA highlights novel stimuli, causing increased neural activity, serving as a signal for determination of importance/relevancy. Hyperactive DA system may tag normally irrelevant stimuli as important, leading to aberrant salience attribution, which may contribute to delusions. Antipsychotic medications may reduce aberrant salience by decreasing DA activity. DA is also heavily involved in motor functions, as long term treatment with antipsychotics can cause movement side effects - extra pyramidal cells. 1/3rd of treatment patients develop tardive dyskinesia: abnormal facial movement that may continue after treatment termination. The most selective drugs for DA cause the worst side effects. Thus, antipsychotics can treat positive symptoms, but leave negative symptoms untreated. |
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Glutamate hypothesis |
Abuse of phencyclidine (PCP) or ketamine can cause spychotic ymptoms and cognitive deficits resembling schizophrenia by blocking NMDA receptors. This may be caused by decreased glutamate transmission, as PFC and hippocampal neurons use glutamate as a transmitter. Degeneration of these neurons can cause schizophrenia. In rats, increased PCP causes decreased DA release in PFC and cognitive deficits in PFC dependent tasks that persist for weeks after drug treatment has stopped. |
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Integrated hypothesis |
Schizophrenia is a combination of too much DA in the striatum and too little in the PFC, as well as too little GABA in the PFC/hippocampus. Decreased DA/glutamate in the PFC causes negative symptoms, and reduced GABA in the PFC leads to impaired focus. Meawhile, increased DA in NAc leads to positive symptoms Schizophrenics display abnormal fear learning, a high comorbidity with anxiety. Inappropriate discriminative fear conditioning: decreased fear to CS when presented with shock, but increased fear to CS if presented alone, without learning. This is due to increased PFC activity. If PFC GABA transmission is decreased, the decreased fear to CS+ and increased fear to CS- in rats. Humans show similar effects with skin conductance, thus dysfunctional GABA in PFC may lead to positive symptoms. |
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Depression |
Major unipolar depression is a common mood disorder, leading to absence of happiness, guilt, anergia, anhedonia, difficulty in concentration. It typically lasts 6-8 months, and occurs in episodes alternately with normal emotional states, while increasing in frequency and severity throughout life. Genetic link involved with depression, may be related with 5-HT related genes. Depression may come in multiple forms, all due to different pathophysiology. It's viewed as a stress related disorder, with it being linked with alterations in the HPA axis and high cortisol levels. When depression occurs, cortisol production cannot be suppressed by dexamethasone. Cushing's syndrome=increased glucocorticoid levels, patients are prone to depression. Diathesis-stress model of depression, an individual has a predisposition for depression, and a stressor triggers an episode. There is increased bloodflow to the amygdala and ventromedial PFC in depression, which may be caused by disrupted regulation of amygdala by PFC on emotional processing. Alternations of brain activation normalize with antidepressant treatment. Dysfunctional PFC may be the underlying mechanism leading to negative appraisal of events |
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Monoamine hypothesis |
Depression is the result of abnormal reductions in brain monoamines (5-HT, NA, and DA). 1950: resperine is a drug reducing monoamine levels, inducing depression. It works by transmitter vesicles, preventing transmitter from entering. 1960: monoamine oxidase inhibitors block metabolism of monoamines to increase levels in the brain, alleviates depression. It blocks monoanimase enzymes. First tricyclic antidepressants are made: imipramine, blockins monoamine uptake. 1980s: fluoxetine (prozac), an SSRI, is foudn to be effective in treating depression. Issues: 1. antidepressants increase monoamine levels quickly, but reduction of symptoms lag behind 2. Not all depressed patients respond to drugs that increase monoamine levels. There can be large placebo effects, and SSRIs are not more effective tha tricyclics. 3. SSRIs are correlated with increased risk of suicide in children and adolescents. 4. In animal models, decreased 5-HT do not cause depressive traits. |
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Alternative treatments for depression |
1. Electroconvulsive shock therapy (ECT): used in extreme cases, mechanism poorly understood. 2. Trans-cranial magnetic stimulation (TMS): magnets alter cortical activity 3 Deep-brain stimulation (DBS): electrode surgically implanted in the brain. High frequency stimulation thought to overwhelm and inactivate brain region. Inserted into the ventral/subcortical PFC. 4. IV-ketamine: non-competitive NMDA antagonist that normally cause psychosis. Sub-anesthetic doses induce rapid reduction of depression after psychotic episode. 5. Cognitive-behavioral therapy: takes time, but just as effective as drugs. |
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Animal models of depression |
Experimental manipulations that cause depressed behavior similar to humans. e.g. learned helplessness: animal is exposed to repeated, inescapable stressful stimulus. After repeated exposure, more sensitive animals will not try to escape given the opportunity. These tend to have neurochemical alterations in the brain, such as decreased 5-HT function. Acute antidepressant treatment can reduce behavioral despair. Depression is induced by chronic stress given unpredictably, but social defeat and cortisol treatment can also induce depression. Forced tail suspension/swim: models despair. Immobility reflects passive coping strategy. Sucrose preference: models anhedonia. DEpressed models have decreased preference for sucrose over water, but chronic antidepressant reverses this effect. This does not translate into human depressed patients, but it can be used to screen for novel antidepressant treatments. |
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Olds and Milner |
Wanted to study how stimulation of reticular formation could affect learning. In a test to see if stimulation was aversive, one rat found it pleasurable, while others did not. Olds had accidentally inserted the electrode into the septum, causing reward behavior when stimulated. Give the opportunity, rats will stimulate self until exhaustion, ignoring physiological needs until near death. This serves as a better reward (than food) in instrumental learning. Multiple brain regions support self stimulation, but it is not ubiquitous. Stimulation of some sites cause aversion, though all self stimulation brain regions connect to the mesolimbic DA system. Self stimulation will increase DA release in the limbic system, especially in the NAc. DA agonists will reduce self stimulation. Natural rewards will increase NAc DA release. Systemic DA agonist administration establishes conditioned place preference. Animals will work to have DA agonists directly infused to the NAc. 2 components of rewards, liking and wanting. DA is more involved in the preparatory/approach behaviors rather than liking - it does not act as the reward, rather, endorphins play a main role in pleasurable aspect of rewards. |
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Tolerance, withdrawal, and sensitization |
Tolerance: decreased sensitivity to drug effect after repeated use, split into 2 different types. 1. Metabolic (pharmacokinetic): body increases efficiency at drug metabolism, decreased amount of drug at action site. 2. Functional (pharmacodynamic): occurs at drug action site, e.g. decreased number of drug receptors. Withdrawal: rebound action to eliminate drug from system in a direction oppposite to drug action. It's the body's attempt to maintain homeostasis developed from tolerance. The body engages in compensatory action to counter drug action, and the changes linger after drug elimination to cause withdrawal. Additional drug taking can alleviate withdrawal. It is the requisite to classify people as physically dependent, and the strength of the symptoms correlate with longer/greater exposure to the drug. Sensitization: repeated exposure can increase sensitivity to some effects. Amphetamine exposure can increase locomotor respones due to increased DA release. Drugs with high addictive potential produce DA sensitization on top of mesolimbic activation. Tolerance/withdrawal can be affected by Pavlovian conditioning, associating the dug effect with the context it was taken in Conditioned tolerance is maximal when drug is administered in a similar environment to where drug effects were experienced previously. This can be shown in rats with alcohol and measuring its hypothermia levels. In a different context, rats required less alcohol to reach hypothermia. Conditioned withdrawal is elicited by drug environment. In an experiment, 2 groups of rats were given morphine, and 1 was not. Of the 2 groups, the group that stayed in the same environment as where the drug was administered had the most withdrawal symptoms. Exposure to drug related cues can induce conditioned compensatory response. 3 main factors to qualify for addiction: 1. common sense, drug appears to be addictive 2. will animals self administer the drug? 3. physical dependence/withdrawal symptoms |
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Hallucinogens |
Low addictive potential. Different types work on different receptor systems. LSD works on 5-HT system to activate 5-HT 2A receptors. It normally acts as a filter in the visual system, but LSD interferes with it to cause hallucinations. Ecstasy/MDMA are amphetamine type drug which promotes monoamine release. They interfere with body temperature regulation, and OD is due to dehydration. It may led to damaged 5-HT systems. Most MDMA contains other hallucinogens to act on multiple sensory systems. |
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Marijuana |
Low addictive potential. The active ingredient is THC from cannabis, acting as a hallucinogen. Anandamide receptors throughout the brain, transmitter acts as a retrograde messenger. Lower doses cause increased sense of well being, altered sensory perceptions, and increased food cravings, while higher doses cause sensory disturbances, emotional intensification, and impaired motocognitive speech. It has a half life of 30 hours. Acute use affects cognitive functions and psychomotor performance, but interferes with all aspects of memory processing. Smoking may result in lung damage, decreased T levels in men, decreased immune response, but no potential to OD. It causes decreased activation in the PFC and amygdala, linked with schizophrenia. Medicinal effects include anti-nausea, analgesia, appetite stimulant, and antidepressant. |
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Alcohol
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High addictive potential with biphasic action. 1. Lower doses cause disinhibition, euphoria, and relaxation. This is due to it preferentially suppression of small GABA inhibitory interneurons, which disinhibits cortex. These interneurosn are smaller, and thus larger fractions of total receptors are affected per alcohol molecule relative to larger pyramidal neurons. 2. Higher doses cause slurred speech, disrupted motor coordination, sedation, and death. Alcohol disrupts neural firing by being a positive modulator for GABA receptors, acting as benzodiazepines. Reducing function of NMDA glutamate receptors, blocking Ca2+ channels, and disrupting second messenger systems. Alcohol increases DA release for addictive potential. Hangovers are due to increased levels of acetylaldehyde, dehydration, and electrolyte imbalance, and decreased opioid activity. Alcoholics have severe withdrawal (DTs), causing hallucinations, delusions, confusion, hypothermia, convulsion/seizure, unstable BP, etc. Dangers of alcohol: acute toxicity. 0.45 blood alcohol levels to reach lethal levels, though unconsciousness or vomiting occurs before then. Korsakoff's syndrome: severe anterograde amnesia linked to degeneration of medial thalamus caused by a vitamin B1 deficiency. Liver cirrhosis, most common cause of death in alcoholics Increased risk of cancer FAS. 2 types of alcoholics: type 1: 75% of population, onset after age 25, psychological dependence coupled with fear/guilt of addiction. Environment plays a role. type 2: male exclusive, onset before age 25, infrequent guilt, high degree of alcohol-related fighting. aggressiveness, and thrill seeking coupled with low harm avoidance. Genetic link to alcoholism, increased tolerance due to higher levels of ethanol metabolizing enzymes. Variations in the GABA-A recetpor, 5-HT transporter, and opioid receptors can also cause alcoholism. |
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Nicotine |
Highest addictive potential. It acts as an agonist to nicotinic ACh receptors residing on DA neurons to increase neural activity. Tolerance builds to aversive effects, while sensitization to rewarding effects. Smoking removes withdrawal symptoms, causing positive feelings and associations. Smoke from tobacco causes hazardous effects. Inhalation of tobacco smoke causes rapid, pulsatile increase in brain nicotine/DA levels. This pulsatile release pattern causes addictive properties, rendering therapies such as the nicotine patch not as effective. Sensory/temporal stimuli associated with smoking reinforce addiction due to Pavlovian conditioning - experienced smokes would prefer cigarettes without nicotine to IV nicotine. It improves cognition and attention while reducing the risk of Parkinson's. |
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Opiates |
High addictive potential. It acts on endogenous opioid receptors with peptide transmitters. Fentanyl>heroin>morphine>methadone>codeine. Enkephalin, dynorphin, and endorphins are endogenous opioid peptides that inhibit neural activity, mediating analgesia, emotions and sensory/motor functions. In NAc, they mediate pleasurable effects of natural rewards. Opioid receptors on GABA in VTA are inhibiting, causing disinhibition of DA neurons. IV opiates causes intense abdominal orgasmic pleasure, evolving to serene, drowsy euphoria. Main risk of opiates is OD causing respiratory arrest, or infection from needle sharing. Minor side effects include constipation, pupil constriction, menstrual irregularity, and decreased libido. Long term cognitive deficits with chronic heroin use. Withdrawal: 6-12 hours after last dose, increases restlessness, flu-like symptoms, fitful sleep. Opioid depresses CNS function, therefore withdrawal causes hyperactivity. Symptoms are the worst at 2-3 days, disappearing after 7. |
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Psychostimulant |
Cocaine and amphetamine: high addictive potential. Psychoactive effects include increased self confidence, alertness, energy, friendliness and talkative. Physiological effects include motor activation, decreased appetite and need for sleep, increased arousal and cardiovascular tone. Addicts abuse in sprees, only stopping when money runs out or toxicity develops. Withdrawal: fatigue, increased appetite, depression, anhedonia, anxiety, and irritability. Physical symptoms not as apparent, amphetamine withdrawal>cocaine. Normally, DA is released but quickly reuptaked by DA transporter on the pre-synaptic neuron. Cocaine blocks DA transporter, amphetamine reverses its direction. Both work on monoamine systems, reinforcing effects mediated by actions on DA. Psychostimulant toxicity: brain damage as a result of strokes, vasoconstriction due to increased NA release, or DA toxicity, causing deficits in cognition due to PFC damage. |
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Models of drug addiction |
Physical dependence: Addicts take drugs to negate withdrawal. Problems associated with this model: 1. addicts still relapse when withdrawal symptoms has passed 2. some drugs do not have severe withdrawal symptoms 3. detoxified addicts still remain addicted. 4. treatments to curb withdrawal symptoms are not 100% effective. Reward mode: Addicts take drugs for pleasurable feelings. Problems associated: 1. addicts continue drug seeking even when tolerance has built up. 2. some drugs are less euphoric but just as addictive. Incentive-sensitization hypothesis: cues associated with drug taking take over behavior. Addictive drugs increase mesolimbic DA levels, increased associative learning and approach behaviors. Drug induced increased DA tell brain that important event is occurring, associating cues from the environment to drug taking due to increased attention and awareness. Cues associated with drug increase DA release, triggerring drug taking behavior. Prolonged drug use leads to hyperDA state, amplifying drug-related cues effect. Drugs are initially taken for pleasure, but tolerance develops to hedonic effects. DA system is sensitized, associates cues with drug taking. Drug taking cues activate neural networks, triggers CR, which is CR. Associative memories between drug effects and cues increase by hyperdopaminergic state. |
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DA role in addiction |
decreasing DA transmission reduces/abolishes self administration for most drugs. Blocking DA receptors also disrupts conditioned place preference for drugs. Respones to drugs associated with increased DA release in NAc. Increase DA release correlated with natural rewards and associated cues, released during learning. Drugs activate brain's natural reward learning pathways to a pathological degree. Depletion of catecholamines/blockade of DA receptors do not alter subjective ratings of drugs. In primates, DA neuron firing in respoesn to reward when given unexpectedly as well as to conditioned cues. If reward is not given when cue is, DA neurons shut off. Repeated use of drugs induces sensitization of DA release, enhanced DA release to reward cues with long lasting effects. Repeated use leads to a hyperDA state, increased DA release in response to drug associated cues. Given striatal learning levels, rats press levers much more frequently if on amphetamine. Even when drug free, rats sensitized to amphetamine will respond more to CS. In hyperDA state, cues exert a more powerful influence on behavior. |
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Brain and addiction |
Key aspect of addiction is the relapse of drug taking after abstinence. It is triggered by the taste of drug, cues associated with drug taking, or stress. In animals, it is modeled with a reinstatement paradigm. 1. train rat to administer drug, link with cue 2. take rat through extinction, lever presses and cue no longer deliver drug 3. on test day, cue drug primer, or stress is given, but no drug. Relapse response lever is once again pressed due to incerased DA in NAc, causing increased cravings. Reinstatement is mediated by distributed networks: PFC, amygdala, and NAc Amygdala and PFC interprets cue, NAc releases DA. Lesions/decreased DA in any of these regions with disrupt reinstatement. Repeated drug exposure sensitizes these regions, human addicts show the same activate areas when craving drugs. Amount of activation correlated with amount of reported craving. |
