S6 Molecular neuropsychopharmacology the striatum, and genetic overexpression of deltaFosB increases the sensitivity to the rewarding effects of several addictive drugs. We have previously shown that naturally rewarding behavior, such as the rodent running wheel paradigm, is sufficient to induce deltaFosB expression in the nucleus accumbens [1]. Running behavior was especially evident in animals where deltaFosB was overexpressed in dynorphin producing medium spiny neurons (MSNs). All MSNs express high levels of the dopamine and cAMP-regulated phosphoprotein of 32kDa (DARPP-32). Dopamine D1 receptor-mediated activation of PKA is known to phosphorylate DARPP-32 at Thr34, thereby converting DARPP-32 into a potent inhibitor of protein phosphatase-1. DARPP-32 mediates synaptic plasticity and controls behavioral responses to a wide range of addictive substances [2]. Interestingly, deltaFosB expression to cocaine treatment was abolished in DARPP-32 knockout mice. In this study, we have investigated the role of DARPP-32 and FosB in wheel running. Methods: In situ hybridization was performed with S35-dATP labeled oligonucleotide probes against dynor- phin and enkephalin mRNA on coronal slices from control mice and running mice. Positive cells were counted on one slide per animal by an observer unaware of the experimental design. Wild-type, DARPP-32 knockout and FosB mutant mice were given access to running wheels for 4 weeks, and the revolutions performed were recorded for 24h per day by a computer. The levels of DARPP-32 was determined by western blotting of striatal tissue extracts from control and wheel running mice with a phospho- Thr34-DARPP-32 and DARPP-32 antibody, respectively. Results: We found that one week of wheel running resulted in increased levels of dynorphin mRNA in the medial part of the striatum. This increase was still present following 4 weeks of running. In contrast, running did not affect enkephalin expression. In addition, we found that running resulted in significantly reduced levels of phosphorylation of DARPP-32 at Thr34. In order to examine the physiological significance of DARPP-32 and FosB, we analyzed the effects of genetic inactivation of DARPP-32 and FosB, respectively, on running behavior. Our results showed that DARPP-32 knockout and FosB mutant mice performed significantly less revolutions/day compared with wild-type animals. Conclusions: Here, we demonstrate an important contribution of DARPP-32 and FosB for wheel running, a natural rewarding behavior. Thus, running was reduced in mice with genetic inactivation of DARPP-32 and FosB, respectively. We also show a running-dependent increase in striatal dynorphin expression and that running decreases phosphorylation of DARPP-32 at Thr34. We have previously demonstrated a critical involvement of deltaFosB in wheel running [1]. Thus, we hypothesize that wheel running depends on FosB and involves accumulation of deltaFosB in dynorphin positive MSNs. Dynorphin is known to reduce dopamine release in the striatum via activation of kappa-opioid receptors. Augmented dynorphin transmission would decrease dopamine release and decrease the basal levels of dopamine D1 receptor- dependent phosphorylation of DARPP-32 at Thr34. Reference(s) [1] Werme M, Messer C, Olson L, Gilden L, Thoren P, Nestler EJ, Brene, S, 2002, Delta FosB regulates wheel running. J Neurosci 22, 8133–8138. [2] Borgkvist A, Fisone G, 2007, Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons. Neurosci Biobehav Rev 31, 79−88. P.1.06 Impaired mitochondrial respiration due to dopamine inhibition of complex I activity: implication to schizophrenia H. Brenner Lavie 1 ° , E. Klein 1 , D. Ben-shachar 1 . 1 Rambam Medical Center and Technion, Dept. of Psychiatry, Haifa, Israel Over the past decade evidence has accumulated on the role of mitochondria in neuronal pathologies such as Parkinson’s disease as well as in several mental disorders including bipolar disease and schizophrenia. In these diseases, abnormal dopamine (DA) transmission is well documented. Notably, mitochondria are target organelles for DA by the virtue of the fact that MAO, the main metabolizing enzyme of DA, is located on their outer membrane. We have previously demonstrated that DA induced a reduction in ATP concentrations in a dose dependent manner and significantly dissipated mitochondrial membrane potential in SH-SY5Y neuronal cells. In disrupted mitochondria DA reversibly inhibited complex I activity, with no effect on complexes II, IV and V of the respiratory system [1,2]. We further demonstrated that intact mitochondria can accumulate DA in a saturated manner, with an apparent Km = 122.1±28.6nM and Vmax = 1.41±0.15pmol/mg protein/min, thereby enabling the interaction between DA and complex I [3]. In order to further investigate the relevance of DA- complex I interaction to the dysfunction of mitochondria, we studied the effect of DA on mitochondrial respiration in intact viable cells. Mitochondrial respiration was determined polarographically using a thermostatically controlled (37ºC) Clark oxygen electrode (Strathkelvin 782 Oxygen System). The formation of intracellular ROS