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Lecture 4

PSYC 318 - Week 4 Lecture notes

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PSYC 318
Wayne Sossin

PSYCH 318 Behavioral Neuroscience II Professor Marco Leyton Week 4, Class 1: Reward and Dopamine Reward: • Elicits approach o Draws the individuals interest towards the stimulus o Drives the individual to obtain the stimulus • Produces learning o Reinforcing, increasing probability that approach will be repeated • Positive value / pleasure / expectation of pleasure? Neurobiology of Reward • Used to seem a “silly” Idea • How would you map reward in the brain? Study: Discovery of brain stimulation reward – 1950s • Put animal in a box, every time animal went to a certain site, it got a “zap”: o “I applied a brief train of 60-cycle sine-wave electrical current whenever the animal entered one corner of the enclosure. The animal…came back quickly after a brief sortie which followed the second stimulation. By the time the third electrical stimulus had been applied the animal seemed indubitably to be coming back for more.” ▪ Extraordinary observation! ▪ First evidence for an area responsible for “reward” o “This particular rat,” Milner later wrote, “would advance, sniffing and searching, whenever the stimulation was turned on, and would stop or turn back when it was switched off.” Unfortunately, no proper histology was performed. We don’t know the precise location of the electrode. Dopamine Synthesis: Phenylalanine is an essential amino acid. • Used to create our own proteins • Sometimes used to create neurotransmitters. Phenylalanine hydroxylase adds Hydroxyl group to phenylalanine. • Obtain Tyrosine • Hydroxylation of phenylalanine to tyrosine occurs in the liver. • Hydroxyl group + Phenylalanine = Tyrosine TH catalyzes addition of hydroxyl group to meta position of tyrosine. • Produces dihydroxy-l-phenylalanine (L-DOPA). • Hydroxylation of tyrosine to L- DOPA, L-DOPA to DA occurs in cytosol • Considered the rate-limiting step in Dopamine synthesis. o Slowest of all processes o Controls amount of dopamine being made. L-DOPA is substrate for AAAD which rapidly decarboxylases L-DOPA producing DA. • Obtain Dopamine DA is then stored in vesicles. Vesicles maintain DA stores and mediate release by fusing with cell membrane: • Action Potential • Ca++ channels open • Ca++ influx promotes fusion of vesicle with cell membrane Note: Feedback Loop: • TH activity is dependent on the availability of 4H & 2 . • DA competes with BH fo4 TH binding site, and inhibits TH. Low DA increases TH. Dopamine Neuroanatomy Where is Dopamine Found? • Dopamine cells only make up ~1% of the brain. • Project to several areas. Most interested in areas with cell bodies in the upper brain stem: • Where the spinal cord enters the brain. VTA & Substantia Nigra are important. • VTA is particularly important. • Neurons from VTA project to several areas: o Nucleus Accumbens is of particular importance. Dopamine is involved in reward. • First behavior in which Dopamine was implicated in was the Initiation of Movement Study: Reserpine & L-DOPA • Reserpine was known to cause certain animals to “collapse”, “drop” o They would not move. • Giving the animals L-DOPA reversed this effect o Dopamine must be critical in the ability to initiate movement? o Initial assumption was this was due to norepinephrine. ▪ Dopamine was thought to be nearly a precursor Post-Mortem Bunny Brains • Certain areas showed an increase in dopamine, but there was very little change in norepinephrine. • Distributions of dopamine and norepinephrine were quite different. o Argument arose that Dopamine itself was responsible for the initiation of movement seen here ▪ Dopamine itself was a neurotransmitter ▪ Very hard argument to make, many people thought this impossible. • In addition to this, Sparks vs Soups debate was raging o Many thought chemical neurotransmission was impossible. Post-Mortem Tissue Dopamine • DOPA was established as a treatment for Parkinson’s disease. o Increased dopamine levels in subjects. Response to Sensory Stimuli • Response to stimuli was tested by poking a mouse with a stick, noises, smells, etc. Nigrostriatal DA Lesions • Creating lesions in one side of the Dopamine system caused the animal to ignore stimulation of the contralateral site. o Completely ignored the stimulus ▪ Sensory Neglect Dopamine and responses to rewards: • Bilateral dopamine Lesions disrupted feeding in test animals o Animals lost weight • Electrical cell stimulation of the brain o Amphetamines were known to increase stimulation ▪ Increase both dopamine and norepinephrine. ▪ To which neurotransmitter to we attribute this behavior? o Animals were stimulated ▪ Given D-Amphetamine & L-Amphetamine • Equally effective for Dopamine • D Isomer is ~10X more potent for norepinephrine. ▪ If the targeted neurotransmitter is norepinephrine, D-Amphetamine should have a much greater effect on the test animals. • Equally effective! ▪ Dopamine is involved in this effect! • Animals trained to self-administer amphetamine. o Once rate of administration was stable, challenged them with various doses of Pimozide ▪ Pimozide is a dopamine antagonist! o Pimozide disrupted the bar-pressing behavior in drastic ways. ▪ Low doses: bar-pressing went up and stabilized at a higher level ▪ Extremely high doses caused an initial spike followed by a drastic drop until low levels were reached. • Very important implications: o Added to the evidence that dopamine is important for reward behaviors o Important for drug self-administration behavior o Important for movement: no motor deficit, simply no desire to move. • Dopamine might be associated with pleasure o Low dose = More drug, Why? ▪ Diminish dopamine transition, diluted, I’ll take some more. ▪ Blocked dopamine completely, NO reward! Animal gives up. • Study: o Amphetamine produces particularly large effects in the Nuccleus Accumbens ▪ Increases Dopamine release in the NAcc ▪ Also increases dopamine in the Caud.N • More dorsal part of the striatum. o Seen across many drug classes! ▪ Cocaine ▪ Ethanol ▪ Nicotine ▪ THC ▪ Opiates o Further suggests dopamine is involved in reward-mediated behaviors such as drug use. Dopamine and Reward: ▪ Measuring Dopamine firing in Monkey brains in different conditions o Unexpected drop of grape juice ▪ Monkeys show spike in dopamine cell firing ▪ Conditioned response o Dopamine increases only after trigger o Drops at reward. ▪ Similar results seen in the rat. ▪ Is dopamine really related to pleasure? o Expectation of pleasure? o Thinking of pleasure? Measuring Dopamine release in NAcc • Animals are trained to self-administer cocaine • Animals debate getting cocaine (blip at -6) • Animals self-administer at 0 • Dopamine comes down as cocaine kicks in A causal relationship: • Inducing self-firing caused animals to go press the bar. Conclusions: Dopamine Cells Respond to Many Things • Natural rewards and their paired cues o Conditioned effects, unexpected rewards, etc. • Drug rewards and their paired cues • Highly salient non-reward cues Ex: Flash of light means cocaine, dopamine release. Play loud beep, also get dopamine release. o Potential rewards ▪ Generalization of stimulus? ▪ Boring in the box, possibility of reward? o Effect habituates • Aversive events Pinch a rat, dopamine response. Why? o Salience + reward stimulus generalization o A few DA cells respond to aversive cues ▪ Helps animal cope and seek out something better? What role is dopamine playing exactly? Study: The Taste Reactivity Test • Animal presented with a variety of taste stimuli o Different facial responses in result to different stimuli ▪ Pleasant: • Tongue Protrusion • Finger/Paw liking ▪ Unpleasant: • Gapes • Forearm flails • Head shakes o Disrupting the dopamine system has no effect on positive/negative facial expression. Test: • Higher amount of work needed to obtain a higher cocaine dose o Decreases in bar-pressing behavior when a dopamine antagonist is used o Also works for food. Summary 1) A wide range of rewards, reward related cues, and other salient stimuli induce striatal DA release with preferential effects occurring within the NAcc. o NAcc. may be called (Ventral striatum in primates) 2) These DA responses increase the ability of the rewards to grab and hold attention, initiating and sustaining approach, exploration & learning. 3) These DAergic effects seem not to be due to changes in the pleasurable effects. Studies in Humans Drug Effects Study: PET / [ C]Raclopride Studies • Labelled raclopride binds dopamine receptors o Can be detected with PET • Dopamine competes with tracer o More dopamine, tracer goes down. Methylphenidate • Used for ADHD treatment • Induced DA Response o Mainly seen in the Striatum. ▪ Striatum receives ~0% of the dopamine signals. o Less Raclopride, More Dopamine release. Effect mainly seen in the ventral part of the striatum. (N.Acc) Only statistically relevant effects are highlighted. Behavioral Significance of Drug-Induced DA Response • Would dopamine antagonists disrupt the pleasurable effects of amphetamine? o Pimozide had no effect on “pleasurable” rating of amphetamine. • Acute Phenylalanine/Tyrosine Depletion (APTD) method o Feeding subjects a shake deficient in Phenylalanine and Tyrosine causes Dopamine release to plummet, both in a resting state or in response to a drug challenge. Drug Euphoria: • Cocaine response study o No change in self-reported euphoria when dopamine is manipulated • Amphetamine study o Positive effect is not changed by dopamine manipulation • Same goes for Tobacco and Alcohol Effects seen: • Healthy participants doing a go-no go task o Learn that if you press for certain numbers, you gain money. o Other numbers cause you to lose money • Decreasing Dopamine: o Subjects use the ability to preferentially respond to reward cues. ▪ Press more, but press “wrong” buttons. Alcohol Self-Administration: • Would women choose more/less in low dopamine? o Less dopamine, less alcohol consumption. • Not observed for regular cocaine users or tobacco-dependent individuals. o However, if subjects had to work for their drug reward, consumption did decrease. ▪ Seen in cocaine and tobacco users. ▪ In tobacco users, effects are observed across different stages of addiction. • Subjects work for money: o Low dopamine state, subjects work for less money. Summary (humans) 1) A wide range of drugs induce striatal DA release with preferential effects occurring within ventral limbic regions (NAcc) plus posterior putamen. 2) These DA responses enhance the salience of reward and reward-related cues, and the ability to sustain preferential responding for them. 3) The DAergic effects on reward-related behaviors are not due to changes in pleasurable effects. 4) In patients with substance use disorders, lowering DA might decrease their motivation to initiate a highcost bout of drug use but have little effect on the use of easily available drug. PSYCH 318 Behavioral Neuroscience II Doctor Salah El Mestikawy Week 4, Class 2: Neurotransmission Exam: Only basic/simple questions Dr. Salah El Mestikawy researches normal and pathological glutamatergic systems Neurons and Neurotransmission: Brain Cells • Central Nervous System contains: o Blood system cells, o Glial cells, o Neurons 9 • In the human brain, we find 500 10 (500 billions) cells o 10-20% neurons o 80-90% glial cells • Matter: o « grey » matter: neurons + astrocyte o « white » matter: oligodendrocytes + astrocytes • Each neuron makes hundreds of synaptic contacts 12 o Up to (10 ) synapses! • In rat or mice CNS, we find about 10 (100 millions) neurons Neurons are not the major cell type in the brain: • They are one of 5 • Neurons count for 2~% of the brain cells • The rest are Glial cells and blood cell system. o Blood System: Aside from neurons, we have two important systems: • Neurovascular system o Blood system cells o Important for all brain functions ▪ Horizontal section of a rodent brain: • Blood vessels cover the surface of the brain; brain is irrigated by blood vessels. o The brain uses a lot of glucose, but doesn’t make it ▪ Glucose must be brought to the brain by the blood cells • Glial cells: o Oligodendrocytes ▪ Make white matter and accelerate transmissions o Astrocytes: ▪ Clear outer space, contain homeostasis, may do glio-transmission. ▪ Glio-transmission is important for regulating transmission, especially in the glutamatergic system. ▪ Glial cells wrap the tripartite synapse. Many types of staining may be used to visualize neurons: • Gogli Method o Silver impregnation o Silver chromate crystallization, from a nucleation center. ▪ Only 1-10% of neurons are stained by this technique ▪ Allows you to visualize the whole neuron • Cresyl Violet (Nlssl) • Toludin Blue • Hematoxyline-eosin (HE) Neurons are very complex: • Asymmetrical cells. • Diversity of forms • Composed of a Dendritic field, Soma and Axon o Very asymmetric Asymmetry is essential because neurons are specialized in communication. • Neurons communicate with: o Themselves o Other neurons o The entire body o The outer world Neurons: • 2 major compartments: o Somatodendritic compartment: ▪ Cell body + dendritic field. ▪ To receive information. o Axon: ▪ Made to communicate/send information. Transmission may be very long: • Ex: A single neuron stretching from the spine to the tip of a finger o ~1m long. o Electric signaling permits rapid transmission • At the terminals there is a gap between neuron and post-synaptic target. o Chemical neurotransmission is used in this location: Synapse ▪ How neurons talk to each other. ▪ A lot of diversity/complexity is introduced thanks to these chemical neurotransmitters. ▪ These synapses are the target of a lot of drugs. Either therapeutic of abused substances. Nerve endings: • Can have different types of terminals: o Leek (one button) o Perl collar (several buttons) • Dendritic button: o “A dendritic button (or spine) is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon.” o Particular structure with a lot of little organelles called vesicles. • Mitochondria: o Provides energy to fuel transmission. • In brain,~80-90% of synapses are between axons & dendritic spines: o Axo-spinus contact. Synapse: • Wrapped by astrocytes to contain it in space. • Symmetrical contacts/synapses: o Inhibitory. o GABAergic, GABA or glycine o Most contacts are symmetrical • Asymmetrical contacts/syn
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