Deletion of neuronal Pentraxins produces differential effects on AMPA-induced locomotion and cocaine neuroadaptations

ALEJANDRA M. PACCHIONI,; PATRICIA STEINNER,; JOSEPH VALLONE ,; PAUL F. WORLEY ,; PETER W. KALIVAS.

San Diego, CA, USA

Congreso; 37th Annual Meeting of Neurosciences; 2007

Society for Neuroscience

<!-- /* Font Definitions */ @font-face {font-family:"Cambria Math"; panose-1:2 4 5 3 5 4 6 3 2 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-1610611985 1107304683 0 0 159 0;} @font-face {font-family:Times; panose-1:2 2 6 3 5 4 5 2 3 4; mso-font-charset:0; mso-generic-font-family:roman; mso-font-pitch:variable; mso-font-signature:-536859921 -1073711039 9 0 511 0;} /* Style Definitions */ p.MsoNormal, li.MsoNormal, div.MsoNormal {mso-style-unhide:no; mso-style-qformat:yes; mso-style-parent:""; margin:0in; margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; mso-bidi-font-size:10.0pt; font-family:"Times","serif"; mso-fareast-font-family:Times; mso-bidi-font-family:"Times New Roman";} .MsoChpDefault {mso-style-type:export-only; mso-default-props:yes; font-size:10.0pt; mso-ansi-font-size:10.0pt; mso-bidi-font-size:10.0pt; mso-ascii-font-family:Times; mso-fareast-font-family:Times; mso-hansi-font-family:Times;} @page Section1 {size:8.5in 11.0in; margin:1.0in 1.0in 1.0in 1.0in; mso-header-margin:.5in; mso-footer-margin:.5in; mso-paper-source:0;} div.Section1 {page:Section1;} --> Neuronal Pentraxins (NPs) are extracellular matrix proteins that are enriched in excitatory synapses, and play a role in aggregating AMPA receptors (AMPAR) by interacting with GluR subunits. Three different NPs have been described: Narp, NP1 and NPR. Narp is an immediate early gene stimulated by synaptic activity, while NP1 and NPR are constitutively expressed. NPR has a transmembrane domain which undergoes cleavage regulated by the stimulation of Group I metabotropic glutamate receptors (mGluR group I). When NPR is released from the membrane it is able to co-cluster  Narp-NP1-AMPAR and induce AMPAR endocytosis. Previous studies have shown that AMPAR-mediated transmission in the nucleus accumbens (NAcc) is necessary for cocaine-induced behavioral plasticity. The present experiments were designed to determine whether the NPs are differentially involved in mediating AMPAR clustering and endocytosis as it relates to cocaine-induced behavioral neuroadaptations. We examined cocaine reinforcing properties and locomotor response to AMPA injections into NAcc in NP1 KO, NPR KO mice and their WT mice. We used a place conditioning paradigm (4 Cocaine and 4 Saline), after which all mice were bilaterally implanted with cannulae into the NAcc. Three weeks after cocaine treatment AMPA induced locomotion was measured. NP1 and NPR deletions produced different effects on cocaine induced place conditioning and AMPA induced-locomotion compared to their WT. While NP1 KO mice displayed a higher cocaine place conditioning and lower locomotor response to AMPA injected into NAcc; NPR deletion showed the same response as WT. Considering pentraxin’s mechanism of action described above, NP1 deletion could be associated with a deficit in clustering AMPAR while NPR deletion could be associated with a deficit in mGluR group I induced endocytosis. These behavioral data suggest that each gene deletion has different consequences for cocaine-induced neuroadaptations. Furthermore, we previously showed that Narp deletion (also related to a deficit in clustering AMPAR) increases cocaine place conditioning and decreases AMPA induced locomotion. Further studies will examine: 1) the same behavioral responses in a triple NPs KO mice and 2) the molecular differences that underlie those differential effects.