Alcohol drinking behavior and prefrontal cortex neuron loss during adolescence

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6.¿¿PROJECT¿SUMMARY/ABSTRACT¿¿ Adolescence¿in¿humans¿is¿a¿period¿of¿life¿when¿alcohol¿use¿is¿often¿initiated.¿¿Unfortunately,¿it¿is¿also¿a¿ time¿when¿some¿individuals¿develop¿longlasting¿patterns¿of¿alcohol¿abuse¿and¿alcoholism.¿¿Human¿and¿ animal¿studies¿have¿revealed¿that¿during¿adolescence,¿brain¿areas¿such¿as¿the¿prefrontal¿cortex¿(PFC)¿are¿ undergoing¿significant,¿yet¿normal,¿changes¿in¿synaptic¿connectivity.¿¿These¿changes¿in¿synaptic¿organization¿ have¿important¿implications¿in¿the¿adolescent¿and¿adult¿PFC.¿¿For¿example,¿in¿a¿recent¿report¿(Markam¿et¿al.,¿ 2007),¿we¿demonstrated¿region¿and¿sexspecific¿decreases¿in¿the¿number¿of¿neurons¿in¿the¿medial¿PFC¿(mPFC)¿ of¿adolescent¿compared¿to¿adult¿rats.¿¿It¿is¿possible¿that¿alcohol¿alters¿these¿normal¿patterns¿of¿adolescentto adult¿changes¿in¿mPFC¿and¿thereby¿produces¿a¿particularly¿susceptible¿nervous¿system.¿¿Furthermore,¿ pubertal¿hormones¿may¿interact¿with¿alcohol's¿effects¿in¿the¿mPFC,¿and¿this¿might¿contribute¿to¿sex¿ differences¿in¿drinking¿behavior.¿¿¿ In¿the¿research¿proposed¿here,¿we¿will¿use¿animal¿models¿to¿explore¿the¿effects¿of¿alcohol¿exposure¿during¿ adolescence¿on¿the¿mPFC¿and¿on¿the¿operant¿selfadministration¿of¿alcohol¿in¿adulthood.¿This¿will¿be¿ accomplished¿by:¿(1)¿examining¿whether¿alcohol¿exposure¿during¿adolescence¿alters¿decreases¿in¿neuron¿ number¿in¿the¿rat¿mPFC¿and¿if¿gonadal¿hormones¿contribute¿to¿alcohol's¿effects;¿and¿(2)¿investigate¿whether¿ alcohol¿exposure¿during¿adolescence¿alters¿alcohol¿drinking¿behavior¿in¿adulthood¿and¿if¿there¿is¿an¿influence¿ of¿sex¿and¿hormonal¿status.¿¿Rats¿will¿be¿divided¿into¿eight¿different¿groups¿(n¿=¿10/group)¿based¿on¿sex¿(male¿ or¿female),¿hormone¿status¿(intact¿or¿prepubertal¿gonadectomy),¿and¿adolescent¿exposure¿to¿alcohol¿(saline¿or¿ 3.0¿g/kg¿ethanol).¿¿As¿adults¿(PND¿90),¿rats¿will¿be¿either¿euthanized¿for¿brain¿removal¿and¿subsequent¿ stereological¿analysis¿of¿the¿number¿of¿neurons¿in¿the¿mPFC¿(Aim¿1)¿or¿they¿will¿begin¿training¿for¿operant¿ selfadministration¿of¿alcohol¿(Aim¿2).¿¿Ultimately,¿the¿information¿learned¿in¿these¿studies¿will¿help¿us¿ understand¿if¿alcoholinduced¿brain¿changes¿are¿a¿contributing¿factor¿to¿the¿high¿rates¿of¿alcoholism¿in¿ individuals¿who¿begin¿drinking¿at¿an¿early¿age.¿¿¿ 7.¿¿PROJECT¿NARRATIVE¿ ¿ The¿results¿of¿these¿experiments¿in¿animal¿models,¿which¿assess¿the¿effects¿of¿adolescent¿alcohol¿exposure¿on¿ medial¿prefrontal¿cortex¿neuron¿number,¿will¿also¿help¿clarify¿how¿exposure¿to¿alcohol¿early¿in¿life¿influences¿ alcohol¿drinking¿behavior¿in¿adulthood.¿¿Ultimately,¿the¿information¿learned¿in¿these¿studies¿will¿help¿us¿ understand¿if¿alcoholinduced¿brain¿changes¿are¿a¿contributing¿factor¿to¿the¿high¿rates¿of¿alcoholism¿in¿ individuals¿who¿begin¿drinking¿at¿an¿early¿age.¿¿Furthermore,¿the¿insight¿gained¿from¿these¿studies¿can¿be¿ used¿to¿develop¿more¿personalized,¿and¿thereby¿more¿effective,¿prevention¿and¿treatment¿strategies.¿ ¿ ¿