Deletion of the AMPAR-clustering protein Narp reduces cocaine-induced locomotion and increases its rewarding properties

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

Atlanta, GA, USA

Congreso; 36th Annual Meeting of Neurosciences; 2006

<!-- /* 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;} --> Narp (neuronal activity-regulated pentraxin) is an immediate early gene induced by synaptic activity. Narp is secreted and enriched at excitatory synapses, where it plays a role in aggregating AMPA receptors (AMPAR) by interacting with GluR1-GluR4 subunits. Previous studies have shown that AMPAR-mediated transmission in the NAcc is necessary for cocaine-induced behavioral plasticity. For instance, AMPAR antagonist injected into the NAcc blocks the expression of behavioral sensitization to cocaine. The present experiments were designed to determine whether Narp participates in cocaine-induced neuroadaptations. We examined locomotor responses to cocaine and cocaine place conditioning in Narp KO mice and their WT littermates. Four cocaine injections (0,10,20,30 mg/kg IP) were given once every other day during a biased place conditioning paradigm. During conditioning sessions locomotor activity was measured. In another experiment, mice were bilaterally implanted with cannulae into the NAcc, and after recovery from surgery, the distance traveled after AMPA or DA microinjection was measured. WT mice displayed cocaine place conditioning and locomotor sensitization at 10 and 30 mg/kg, while at 20 mg/kg showed a locomotor ceiling effect and no place conditioning. However, the Narp KO mice displayed locomotor sensitization only at the higher doses tested and place conditioning at all doses. Furthermore, the Narp KO locomotor response to acute and repeated cocaine was lower than the WT. AMPA and DA injections into NAcc allowed us to determine if the reduced locomotor response to cocaine was related to a dysfunctional AMPAR in the NAcc. After AMPA injection, only WT mice displayed an increase in locomotor activity. By contrast, both genotypes responded with an identical level of activation to intra-NAcc DA injections These behavioral data indicate that: 1) Narp is required for cocaine-induced locomotor activity; 2) the locomotor deficit in Narp KO mice results from decreased AMPAR signaling, and 3) the dysfunction in the AMPAR increases cocaine rewarding properties. Further studies will examine the dopamine and glutamate release in NAcc after acute and repeated cocaine treatment, as well as the baseline levels of both neurotransmitters.