title: Cav1.2 L-type Ca²⁺ channels mediate cocaine-induced GluA1 trafficking in the nucleus accumbens, a long-term adaptation dependent on ventral tegmental area Ca(v)1.3 channels.
abstract: AMPA receptor (AMPAR) plasticity at glutamatergic synapses in the mesoaccumbal dopaminergic pathway has been implicated in persistent cocaine-induced behavioral responses; however, the precise mechanism underlying these changes remains unknown. Utilizing cocaine psychomotor sensitization, we have examined phosphorylation of GluA1 at key residues serine 845 (S845) and S831, as well as GluA1 cell surface levels in the nucleus accumbens (NAc) of cocaine-preexposed mice and the role of brain-specific Ca(v)1.2 and Ca(v)1.3 L-type Ca²⁺ channels (LTCCs), therein. We found higher basal levels of S845 phospho-GluA1 (P-GluA1) and cell surface GluA1 in the NAc following protracted withdrawal from cocaine exposure, changes that occur independently of LTCCs. In contrast, we found that a cocaine challenge that elicits expression of the cocaine-sensitized response increases S831 P-GluA1 that further increases surface GluA1 beyond the higher basal levels. Intra-NAc pharmacological manipulations indicate that the Ca(v)1.2-activated CaM kinase II (CaMKII) mediates cocaine-induced increase in S831 P-GluA1 and that both Ca(v)1.2-activated CaMKII and extracellular signal-regulated kinase 2 (ERK2) mediate the increase in GluA1 cell surface levels specific to the sensitized response. Experiments using adenoassociated viral vectors expressing Ca(v)1.3 and ERK2 siRNA further indicate that recruitment of the Ca(v)1.2 pathway in the NAc is dependent on ventral tegmental area Ca(v)1.3 LTCCs and ERK2. Together, these results identify candidate pathways that mediate cocaine-induced AMPAR plasticity in the NAc and provide a mechanism linking LTCCs and GluA1 plasticity to cocaine-induced persistent behavioral changes.
authors.affiliation: Graduate Program in Neuroscience, Department of Pediatrics, Division of Pediatric Neurology, and Department of Pharmacology, Weill Cornell Medical College, New York, New York 10065, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schierberl
authors.forename: Jin
authors.initials: J
authors.lastname: Hao
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tropea
authors.forename: Stephen
authors.initials: S
authors.lastname: Ra
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Giordano
authors.forename: Qinghao
authors.initials: Q
authors.lastname: Xu
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Garraway
authors.forename: Franz
authors.initials: F
authors.lastname: Hofmann
authors.forename: Sven
authors.initials: S
authors.lastname: Moosmang
authors.forename: Joerg
authors.initials: J
authors.lastname: Striessnig
authors.forename: Charles E
authors.initials: CE
authors.lastname: Inturrisi
authors.forename: Anjali M
authors.initials: AM
authors.lastname: Rajadhyaksha
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000502:physiology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D000229:Dependovirus / Q000235:genetics; D005822:Genetic Vectors; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000502:physiology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D018091:Receptors, AMPA / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*
chemical_list: D020746:Calcium Channels, L-Type; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003042:Cocaine; D008565:Membrane Proteins; D019950:Mitogen-Activated Protein Kinase 1; D034741:RNA, Small Interfering; D018091:Receptors, AMPA; C485995:Cacna1d protein, mouse; C419385:L-type calcium channel alpha(1C)