Differences in Glutamate Receptor mRNA Expression in the Brains of Rats Bred for Nicotine Preference

Project no. 32691 · Status: Kapanmış (Yayın bekleniyor) · 2024

Summary

<p><strong>INTRODUCTION&nbsp;AND&nbsp;AIM:&nbsp;</strong>Tobacco&nbsp;addiction&nbsp;is&nbsp;one&nbsp;of&nbsp;the&nbsp;most&nbsp;common&nbsp;substance&nbsp;dependencies&nbsp;worldwide,&nbsp;and&nbsp;nicotine&nbsp;is&nbsp;the&nbsp;primary&nbsp;agent&nbsp;responsible&nbsp;for&nbsp;its&nbsp;reinforcing&nbsp;effects.&nbsp;The&nbsp;mesocorticolimbic&nbsp;system&nbsp;forms&nbsp;the&nbsp;neurobiological&nbsp;basis&nbsp;of&nbsp;nicotine&nbsp;addiction,&nbsp;mediating&nbsp;reward&nbsp;through&nbsp;dopaminergic&nbsp;projections&nbsp;from&nbsp;the&nbsp;ventral&nbsp;tegmental&nbsp;area&nbsp;(VTA)&nbsp;to&nbsp;the&nbsp;prefrontal&nbsp;cortex&nbsp;(PFC)&nbsp;and&nbsp;nucleus&nbsp;accumbens&nbsp;(NAc).&nbsp;Recent&nbsp;studies&nbsp;also&nbsp;highlight&nbsp;the&nbsp;importance&nbsp;of&nbsp;glutamatergic&nbsp;transmission&nbsp;in&nbsp;addiction-related&nbsp;plasticity.&nbsp;The&nbsp;hippocampus&nbsp;may&nbsp;further&nbsp;contribute&nbsp;to&nbsp;addictive&nbsp;behaviors&nbsp;via&nbsp;glutamate-dependent&nbsp;learning&nbsp;and&nbsp;memory&nbsp;processes.&nbsp;In&nbsp;the&nbsp;Physiology&nbsp;Department&nbsp;Laboratory&nbsp;at&nbsp;Ege&nbsp;University,&nbsp;a&nbsp;selectively&nbsp;bred&nbsp;Nicotine-Preferring&nbsp;Rat&nbsp;Line&nbsp;(NP&nbsp;line)&nbsp;has&nbsp;been&nbsp;developed&nbsp;to&nbsp;investigate&nbsp;heritable&nbsp;vulnerability&nbsp;to&nbsp;nicotine.&nbsp;In&nbsp;this&nbsp;study,&nbsp;we&nbsp;aimed&nbsp;to&nbsp;examine&nbsp;the&nbsp;effects&nbsp;of&nbsp;chronic&nbsp;nicotine&nbsp;exposure&nbsp;on&nbsp;the&nbsp;mRNA&nbsp;expression&nbsp;of&nbsp;the&nbsp;NMDA&nbsp;receptor&nbsp;subunits&nbsp;Grin1,&nbsp;Grin2a&nbsp;and&nbsp;Grin2b,&nbsp;and&nbsp;the&nbsp;metabotropic&nbsp;receptor&nbsp;Grm5&nbsp;(mGluR5)&nbsp;in&nbsp;the&nbsp;VTA,&nbsp;PFC,&nbsp;NAc&nbsp;and&nbsp;hippocampus&nbsp;of&nbsp;NP&nbsp;and&nbsp;control&nbsp;rats,&nbsp;to&nbsp;elucidate&nbsp;the&nbsp;contribution&nbsp;of&nbsp;genetic&nbsp;predisposition&nbsp;to&nbsp;nicotine&nbsp;addiction&nbsp;the&nbsp;role&nbsp;of&nbsp;glutamatergic&nbsp;function&nbsp;in&nbsp;this&nbsp;process.&nbsp;</p><p><strong>MATERIALS&nbsp;AND&nbsp;METHODS:&nbsp;</strong>Adult&nbsp;male&nbsp;rats&nbsp;from&nbsp;the&nbsp;NP&nbsp;line&nbsp;and&nbsp;Sprague–Dawley&nbsp;controls&nbsp;were&nbsp;used.&nbsp;Four&nbsp;groups&nbsp;were&nbsp;formed:&nbsp;water-treated&nbsp;control&nbsp;(WC),&nbsp;nicotine-treated&nbsp;control&nbsp;(NC),&nbsp;water-treated&nbsp;NP&nbsp;(WNP)&nbsp;and&nbsp;nicotine-treated&nbsp;NP&nbsp;(NNP).&nbsp;Nicotine&nbsp;was&nbsp;administered&nbsp;orally&nbsp;for&nbsp;five&nbsp;weeks&nbsp;using&nbsp;a&nbsp;two-bottle&nbsp;free-choice&nbsp;paradigm&nbsp;(10&nbsp;mg/L&nbsp;for&nbsp;two&nbsp;weeks,&nbsp;20&nbsp;mg/L&nbsp;for&nbsp;three&nbsp;weeks).&nbsp;After&nbsp;treatment,&nbsp;animals&nbsp;were&nbsp;decapitated&nbsp;and&nbsp;PFC,&nbsp;NAc,&nbsp;VTA&nbsp;and&nbsp;hippocampus&nbsp;were&nbsp;dissected.&nbsp;Grin1,&nbsp;Grin2a,&nbsp;Grin2b&nbsp;and&nbsp;Grm5&nbsp;mRNA&nbsp;levels&nbsp;were&nbsp;quantified&nbsp;by&nbsp;real-time&nbsp;PCR.&nbsp;Data&nbsp;were&nbsp;analyzed&nbsp;using&nbsp;ANOVA&nbsp;followed&nbsp;by&nbsp;Tukey&nbsp;post&nbsp;hoc&nbsp;tests.&nbsp;</p><p><strong>RESULTS:&nbsp;</strong>NP&nbsp;rats&nbsp;consumed&nbsp;and&nbsp;preferred&nbsp;significantly&nbsp;more&nbsp;nicotine&nbsp;than&nbsp;controls&nbsp;throughout&nbsp;the&nbsp;study&nbsp;(preference:&nbsp;p=0.031;&nbsp;intake:&nbsp;p&lt;0.001),&nbsp;with&nbsp;the&nbsp;final&nbsp;two&nbsp;weeks&nbsp;showing&nbsp;the&nbsp;largest&nbsp;differences&nbsp;(both&nbsp;p&lt;0.001).&nbsp;Significant&nbsp;line&nbsp;×&nbsp;treatment&nbsp;interactions&nbsp;were&nbsp;found&nbsp;in&nbsp;the&nbsp;PFC&nbsp;for&nbsp;Grin1&nbsp;(p=0.007),&nbsp;Grin2b&nbsp;(p=0.006)&nbsp;and&nbsp;Grm5&nbsp;(p=0.009);&nbsp;in&nbsp;the&nbsp;hippocampus&nbsp;for&nbsp;Grin2b&nbsp;(p=0.002);&nbsp;and&nbsp;in&nbsp;the&nbsp;NAc&nbsp;for&nbsp;Grm5&nbsp;(p=0.014).&nbsp;Nicotine&nbsp;increased&nbsp;gene&nbsp;expression&nbsp;in&nbsp;controls&nbsp;but&nbsp;decreased&nbsp;it&nbsp;in&nbsp;NP&nbsp;rats.&nbsp;In&nbsp;NNP&nbsp;animals,&nbsp;PFC&nbsp;Grin2b&nbsp;expression&nbsp;was&nbsp;significantly&nbsp;lower&nbsp;than&nbsp;in&nbsp;NC&nbsp;(p=0.015)&nbsp;and&nbsp;WNP&nbsp;(p=0.018).&nbsp;NAc&nbsp;Grm5&nbsp;levels&nbsp;were&nbsp;also&nbsp;reduced&nbsp;in&nbsp;NNP&nbsp;rats&nbsp;compared&nbsp;with&nbsp;NC&nbsp;(p=0.037)&nbsp;and&nbsp;WNP&nbsp;(p=0.036).&nbsp;</p><p><strong>CONCLUSION:&nbsp;</strong>Glutamatergic&nbsp;receptor&nbsp;gene&nbsp;expression&nbsp;differed&nbsp;markedly&nbsp;between&nbsp;NP&nbsp;and&nbsp;control&nbsp;rats.&nbsp;Chronic&nbsp;nicotine&nbsp;produced&nbsp;increases&nbsp;in&nbsp;PFC&nbsp;Grin1,&nbsp;Grin2b&nbsp;and&nbsp;Grm5,&nbsp;NAc&nbsp;Grm5&nbsp;and&nbsp;hippocampal&nbsp;Grin2b&nbsp;in&nbsp;controls,&nbsp;whereas&nbsp;NP&nbsp;rats&nbsp;showed&nbsp;decreases.&nbsp;These&nbsp;findings&nbsp;suggest&nbsp;that&nbsp;genetic&nbsp;susceptibility&nbsp;in&nbsp;the&nbsp;NP&nbsp;line&nbsp;may&nbsp;alter&nbsp;the&nbsp;direction&nbsp;of&nbsp;glutamatergic&nbsp;neuroadaptations&nbsp;emerging&nbsp;during&nbsp;chronic&nbsp;nicotine&nbsp;exposure.&nbsp;The&nbsp;selective&nbsp;reduction&nbsp;of&nbsp;PFC&nbsp;GluN2B&nbsp;in&nbsp;NNP&nbsp;rats&nbsp;indicates&nbsp;a&nbsp;shift&nbsp;toward&nbsp;higher-threshold,&nbsp;less&nbsp;flexible&nbsp;prefrontal&nbsp;plasticity,&nbsp;consistent&nbsp;with&nbsp;reduced&nbsp;behavioral&nbsp;flexibility,&nbsp;perseveration&nbsp;and&nbsp;increased&nbsp;nicotine&nbsp;intake.&nbsp;The&nbsp;decrease&nbsp;in&nbsp;NAc&nbsp;Grm5&nbsp;limited&nbsp;to&nbsp;NNP&nbsp;rats&nbsp;appears&nbsp;to&nbsp;reflect&nbsp;a&nbsp;homeostatic&nbsp;down-regulation&nbsp;response&nbsp;to&nbsp;chronic&nbsp;nicotine.&nbsp;Its&nbsp;similarity&nbsp;to&nbsp;reduced&nbsp;mGluR5&nbsp;binding&nbsp;reported&nbsp;in&nbsp;human&nbsp;imaging&nbsp;studies&nbsp;suggests&nbsp;that&nbsp;this&nbsp;adaptation&nbsp;may&nbsp;represent&nbsp;a&nbsp;glutamatergic&nbsp;signature&nbsp;associated&nbsp;with&nbsp;genetic&nbsp;vulnerability&nbsp;to&nbsp;nicotine&nbsp;addiction.&nbsp;(Supported&nbsp;by&nbsp;BAP&nbsp;TS-TUT-2024-32691;&nbsp;Ethics:&nbsp;HADYEK-2024-036)&nbsp;</p>

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