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Chapter 8 psychopharmacology

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PSY 402
Tara M Burke

Chapter 8: Glutamate and GABA o Glutamate – An amino acid – Used throughout the body • Building proteins • Helps with energy metabolism – Also serve as NTs • excitatory • Glutamine can be converted to glutamate via the enzyme glutaminase Vesicular Glutamate Transporter • VGLUT1, VGLUT2, and VGLUT3 – Package glutamate into vesicles – Different parts of the brain use different VGLUTs • Not really known why v Reuptake • Excitatory amino acid transporter (EAAT1-EAAT5) – EAAT3 is main neuronal transporter – EAAT1 and EAAT2 are actually found on astrocytes – This relationship may occur because extracellular glutamate is dangerous • Spreading ischemia Cycling of Glutamate and Glutamine between Glutamatergic Neurons andAstrocytes • Astrocytes breakdown glutamate – Into glutamine – via the enzyme glutamine synthetase • Then the astrocytes release the glutamine so it can be picked up by neurons and converted back to glutamate • This complex system may help prevent the toxicity of extracellular glutamate • Glutamate is the workhorse transmitter for excitatory signaling in the nervous system • Glutamate is found throughout the brain, so there’s no specific pathways for this neurotransmitter • Involved in many behavioral and physiological functions, but perhaps the most important is synaptic plasticity – Changes in the strength of connections – Learning and memory Receptors • Ionotropic glutamate receptors: 3 subtypes 1)AMPA – Named for the drugAMPA(a selective agonist of this receptor) – Most fast excitatory responses to glutamate occur through this receptor 2) Kainate – Named for the drug Kainic acid (a selective agonist) 3) NMDA – Named for N-methyl-D-aspartate (NMDA; selective agonist) • The AMPAand Kainate receptors mediate the flow of Na+ – Excitatory post synaptic potentials • NMDAreceptors mediates Na+, but also Ca++ – CA++ works as a second messenger – Thus, NMDAreceptors can directly activate a second messenger system All Ionotropic Glutamate receptor channels conduct Na+ ions into the cell NMDAReceptors • NMDAreceptors require two different neurotransmitters to open the channel – 1) Glutamate – 2) Glycine or D-serine • Glycine (or D-serine) has its own binding site. – Thus glycine (or D-serine) is considered to be a co-agonist. • Usually the co-agonist binding site is occupied though, so the presence or absence of glutamate determines channel opening • There are two other binding sites on NMDAreceptors that affect their function – Both of these receptor locations are inside the channel • Magnesium receptor – Mg++ • Phencyclidine receptor – PCP Mg++ • When the cell membrane is at resting potential (-60 or -70 mv). – Mg++ binds to its location within the channel. – Thus, even if glutamate (and glycine or D-serine) bind to the receptor the ions cannot flow. 1) • However, if the membrane becomes somewhat depolarized the Mg++ will leave its binding site and exit the channel. – Now the channel will allow the flow of ions if glutamate and the co-agonist are present. NMDAReceptor (coincidence detector) • Thus, the NMDAchannel will open only if other receptors are active simultaneously – Two events must occur close together in time. • So channel will only open if 1) glutamate is released onto NMDAreceptor 2) the cell membrane is depolarized by a different excitatory receptor. PCP • This receptor recognizes – Phencyclidine (PCP) – Ketamine (Special K) – MK-801 (dizocilpine; a research drug) • Most of the behavioral effects of PCP and Ketamine are the result of antagonizing the NMDAreceptor NMDAReceptors and learning and memory • Classical conditioning is based on the close timing of two events – Bell à Food • The NMDAreceptor may be a biochemical mechanism that allows for these kinds of associations. – NMDAantagonism impairs learning and memory – The hippocampus has a high density of NMDAreceptors – NMDAreceptors are critically involved in synaptic plasticity • Long-term potentiation (LTP) LTP • LTP is a persistent (at least 1 hour) increase in synaptic strength. – Produced by a burst of activity from the presynaptic neuron LTPStudies • Get a slice from the rat hippocampus and keep alive in Petri dish. – It is common to stimulate CA3 region which synapses with cells in CA1 • 100 stimulations in 1 second – Tetanic stimulation (tetanus) – Measure response of CA1 neurons – You can produce similar effects in other parts of the pathway, however. Role of Glutamate Receptors in Long-Term Potentiation SynapticActivity at test pulse • Test pulse elicits release of a small amount glutamate from CA3 axons onto CA1 – Glutamate binds toAMPAreceptors and NMDAreceptors – Channel does not open because membrane not depolarized enough to dislodge Mg++ SynapticActivity During • More glutamate is released – Prolonged activation ofAMPA • Depolarization dissociates Mg++ • NMDAchannel opens – Na+ enters – More importantly Ca++ enters • Ca++ Works as a second messenger – Increases the sensitivity of receptors to glutamate – Inserts more AMPAreceptors into the membrane. – May also produce presynaptic changes that
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