Drug Induced Plasticity.pdf

Drug Induced Plasticity Drug-induced changes - Some drug-induced changes do not last long: opening and closing ion channels Other changes might be long-lasting (forever?) Is there a common circuitry that mediates the e ects of the di erent drugs? We are going to focus on the mesocorticolimbic DA pa...

Drug Induced Plasticity Drug-induced changes - Some drug-induced changes do not last long: opening and closing ion channels Other changes might be long-lasting (forever?) Is there a common circuitry that mediates the e ects of the di erent drugs? We are going to focus on the mesocorticolimbic DA pathway since all the addictive drugs increase DA concentration in this pathway - The mesolimboc DA system, might also be a common pathway for “natural rewards” • Cross sensitization between sucrose and amphetamine • Similar abnormalities in striatum of obese and drug addicts Amphetamine > sugar - rats given amphetamine repeatedly and tested their response to sugar - Rats who were given amphetamine: showed sensitization to sucrose - Take more than rats who were given saline - Cross-sensitization: amphetamine to sugar Sugar > amphetamine ff ff - 4 conditions: - Unlimited access to food - unlimited access to food + unlimited access to sugar - Access to food + abstinence from food - access to food + Abstinence from food + access to sugar - Animals who went through complete abstinence but had free access to food and sugar = increased response to amphetamine (sensitized) - Cycles where people go through diets, where they lose weight and start consuming as much as they can once they’re done, is harmful - Makes you sensitized MANY BRAIN AREAS INTERACT WITH THE MESOCORTICOLIMBIC PATHWAY - important for stress responses, learning, emotions MOLECULAR CHANGES - chronic exposure to drug results in long-term changes in AMPA-R in the VTA - AMPA R: - 4 subunits that allow Na in but not Ca - NMDA’s Mg block is pop o and will allow Ca in 1. Drugs elevate DA in the VTA (somato-dendritic release),which stimulate D1 receptors on the terminals of glutamate neurons - DA is released by Glu pre-s - DAd1 is activated when DA is around which tells Glu R to release more Glu in the synapse 2. This increases the release of glutamate which acts on AMPA and NMDA receptors on VTA neurons (DAergic) 3. Activation of AMPA & NMDA receptors results in an in ux of Ca2+ through NMDA and Ltype channels. fl ff 4. Ca2+ acts to recruit “silent” AMPA receptors (AR) from intra- cellular pool to the surface. - leads to neuroadaptations: - More AMPA R through silent Rs inside the membrane that move to the surface 5. Next glutamate release following drug exposure results in even larger increase in DA release in the VTA, higher glutamate levels and increase Ca2+ in ux. - usually Glu R would have many subunits - But after many exposures and all the Ca that comes in do not have the GluA2, and allows Ca to come in 6. This process increases the number of GluR1 (now known as GluA1) AMPA subunits (early adaptations). 7. Accumulation of the GluA1 subunits leads to AMPA receptors constructed by these units only (homomeric-AR*), which are highly permeable to Ca2+. 8. This increased sensitivity to the e ects of glutamate leads to pathophysiological conditions associated with high intra-cellular concentration Ca2+. - homomeric (lacking A2) R allow more and more Ca to come in - Neurons look di erent: bloated and thinner axons 9. Levels of TH are also increased - because axons are thinner, the amount of TH (although increased in the soma) in the DA terminal is lower and less DA is released from those neurons - sensitization to DA because levels are down 10. Finally, impaired function and observable morphological changes in VTA neurons appear. ADAPTATIONS IN GLU-R IN THE VTA 1. Even a single drug intake can result in synaptic adaptations in the VTA that will last about 1 week - NMDA-R are changing - Exposure to drugs = GluN3: cannot be permeable to Ca anymore - Calcium now gets in through AMPA-R - Calcium doesn’t need NMDA depolarization anymore - More calcium can go in? - Depolarization can now occur randomly at Ca goes in because its positive 2. After prolonged abstinence from drug SA, GluA2-lacking AMPA-R replace the GluA2containing R on the membrane -> highly excitable synapse - decrease of AMPA-R on the membrane - Acute exposure: normal AMPA-R will be sucked in and become less responsive/ excitable - Repeated exposure: AMPA-R with A2-lacking replace normal AMPA R - Allow Ca to enter regardless of depolarization = highly excitable 3. As mentioned before, AMPA receptor become GluA2-lacking and are very permeable to Ca2+ fl ff ff 4. This drastically changes the way the synapse functions (e.g., no need for membrane depolarization to allow Ca into the post-synaptic cell MOLECULAR CHANGES: - Chronic exposure to drug results in long-term changes in AMPA (and NMDA) glutamate receptors in the NAc 1. Acutely, there is a decrease in AMPA receptors on the membrane surface (reduced AMPA-R/NMDA-R ratio) --> less excitation of the synapse - For the NMDA R to open, you need depolarization for Mg to pop out - Synapse learns/adapts to depolarize faster & allow more Calcium in: - More AMPA R = more Na in ux = faster depolarization = more Calcium - GluA2-lacking = allows calcium in regardless of NMDAR 2. After prolonged abstinence from chronic drug self- administration, GluA2-lacking AMPA receptors replace the GluA2-containing receptor on the membrane --> highly excitable synapse - Most input in NAc is glutamatergic - Initial exposure to drugs = reduction of AMPAR (less excitable) - Over time/chronic use, reverse e ects + GluA2-L replace GluA2-C (more excitable) - Changes continue to occur despite uses fi ff fl Summary - many molecular changes that are induced by chronic exposure to drugs - Some drug types induce opposite morphological adaptation - Some adaptations are drug-speci c (GABA-A-R, opiate-R), while some changes are common to all drugs (altered DA transmission, induced ΔFosB)