21Particular modulator transmitters should not be regarded as purely excitatory or inhibitory.Their exact action depends on context.On the same cell, they can be either excitatory or inhibitorydepending on the state of the cell.
22Arvid Carlsson Paul Greengard Eric Kandel The Nobel prize in 2000 went to three neuroscientistsfor working out the role of biogenic amines/monoaminesin the nervous system:Arvid CarlssonPaul GreengardEric Kandel
23Arvid Carlsson (dopamine/l-dopa therapy) The Nobel Prize in 2000 went to three neuroscientistsfor working out the role of biogenic amines/monoaminesin the nervous system:Arvid Carlsson (dopamine/l-dopa therapy)Paul Greengard (role of phosphorylation)Eric Kandel (serotonin in learning & memory)
24Carlsson, A (2001). A paradigm shift in brain research. Science, vol. 294, p**Greengard, P (2001). The neurobiology of slow synaptic transmission.Science, vol. 294, p**Kandel, ER (2001). The molecular biology of memory storage: adialogue between genes and synapses.Science, vol. 294, p
27Reuptake of NE MAO Inhibitors Monoamine oxidase, located on outer membraneof mitochondria; deaminates catecholamines free innerve terminal that are not protected by vesiclesAntidepressantSelective inhibitor,reboxetineStimulantCocaine blocks the NETReuptake of NE
28NE potentiation of responses to GABA Purkinje cells
42See:Chapter 63. Cellular mechanisms of learning.Page 1247.“Principles of Neuroscience” Kandel ER et al4th edition, 2000, McGraw-HillSee also, Chapter 13, Figure in Kandel et alOrChpater 50. Learning and memory: basic mechanisms.Page 1275Fundamental Neuroscience, second edition,Squire LR et al, 2003, Academic Press
43Humans Serotonin - a chemical manifestation of personality High level of serotonin: compulsivesobsessive-compulsive disorderse.g. compulsive hand-washingLow levels of serotonin: depression, suicide.Listening to Prozac, P.D. Kramer, 1993
50Dopamine pathways do many things: Control flow of blood through the brainMotor control (nigrostriatal) systemBehavioural controlDopamine is the brain’s motivational chemical. It works onglutamate synapses to modulate their excitability.A shortage of brain dopamine causes an indecisivepersonality, unable to initiate even the body’s ownmovement. Parkinson’s disease. Time stops.L-DOPA therapy. ‘Awakenings’ film. (Oliver Sachs)Excess dopamine, more arousal. Attention defecitdisorder. May cause schizophrenia.Dopamine’s action is essential for drug addiction.
51L-DOPA rescues Parkinsonian rabbits Rabbits treated withreserpineThe same rabbits15 minutes aftertreatment withL-DOPACarlsson, 1960See Science, vol 294, p1002, 2 November 2001
52DARP-32Dopamine and cAMP-regulated phosphoproteinMolecular weight, 32 kDaDARP-32 is a molecular integrator
69D4 dopamine receptorThe larger the number of repeats, the moreineffective is the dopamine D4 receptorin signalling
70The larger the number of loop 3 repeats, the more ineffective the dopamine D4 receptor in signalling“Long” D4DR genes imply low responsiveness to dopamine“short” D4DR gene imply high responsivenessThe ideaPeople with “long” D4DR genes have low responsiveness todopamine, so they need to take a more adventurous approach tolife to get the same dopamine “buzz” that short-gened people getfrom simple things.Obviously, this is just one possible factor of many.Don’t oversimplify!
71Neuromodulators Slow synaptic transmission Alan Summerfield