Resumo

Objective: Ethanol addiction has enormous individual and social importance and the responses related to this phenomenon mainly involve plasticity processes at the mesocorticolimbic system. Here we investigated the role of the cellular prion protein (PrPC) in ethanol induced addictive phenotypes, the dopaminergic (DA) content and DA receptors density. Material and Methods: Wild-type (Prnp+/+) and PrPC-null female mice (Prnp0/0) were submitted to: climbing behavior, spontaneous locomotor activity (SLA), rapid tolerance (RT), conditioned place preference (CPP) and oral self-administration. DA content was evaluated by HPLC in the olfactory bulb (OB), prefrontal cortex (PFC), striatum (STR) and hippocampus (HIP). STR D1-receptor density was measured by autoradiography method. Ethanol pharmacokinetic was controlled by blood ethanol concentration and hepatic histology. C57BL/6 mice were evaluated in ethanol induced-SLA and in ethanol oral self-administration after i.c.v. treatment with anti-prion protein antibody. Results: The absence of PrPC significantly increased the climbing behavior (climbing behavior (s): Prnp+/+:86,0+15,4 and Prnp0/0: 183,4+7,1), which was blocked when Prnp0/0 mice were treated (i.p.) with SCH-23390 (D1-antagonist) [climbing behavior (s): 12,0+2,2] or sulpiride (D2-antagonist) [climbing behavior (s): 69,5+19,6]. Alterations of DA levels (but not of norepinephrine and serotonin) were observed in the OB [DA levels (ng/g): Prnp+/+: 64,7+6,0; Prnp0/0: 36,4+17,5] and PFC [DA levels: Prnp+/+: 658,9+229,7; Prnp0/0: 233,4+102,1] of Prnp0/0 mice, but not in the STR and HIP, when compared to wild-type mice. Prnp0/0 mice also showed increased SLA [distance travelled (m): Prnp+/++ethanol: 35,7+3,2 Prnp0/0+ethanol: 50,0+4,4] after receive ethanol (2 g/kg). The impact of PrPC on ethanol SLA alteration was confirmed by the blockade of PrPC after i.c.v. infusion of anti-prion protein antibody in C57BL/6 mice [distance travelled (m): PBS+ethanol: 14,4+2,4; á-GST-PrPC(150 ng/ul)+ethanol: 24,3+4,3]. Prnp0/0 mice were not susceptible to acquire rapid tolerance [latency to fall (s): Day 2: Prnp+/+: 7,5+1,2; Prnp0/0: 2,5+2,3]. In CPP the lowest ethanol dose tested (0.5 g/kg, i.p.) induced rewarding effects only in Prnp0/0 mice [postconditioning (s): Prnp+/+: 45,6+15,4; Prnp0/0: 122,0+61,0], while the highest ethanol dose tested (2 g/kg, i.p.) induced rewarding effects only in Prnp+/+ mice [postconditioning (s): Prnp+/+: 86,2+22,4; Prnp0/0: 13,0+8,2]. Prnp0/0 mice showed decreased ethanol consumption when compared to control group [10% EtOH consumption (g/kg/day): Prnp+/+: 14,1+3,3; Prnp0/0: 5,9+0,7]; [20% EtOH consumption (g/kg/day): Prnp+/+: 15,9+3,3; Prnp0/0: 11,8+1,0]. Treatment with SCH-23390, but not with sulpiride, blocked the ethanol intake in Prnp0/0 mice [10% EtOH consumption (g/kg/5 hours): Prnp0/0: 4,1+0,5; Prnp0/0+SCH-23390: 2,3+0,4; Prnp0/0+sulpiride: 3,4+0,5]. Pretreatment with anti-prion protein antibody also reduced ethanol intake in C57BL/6 mice [10% EtOH consumption (g/kg/5 hours): PBS: 6,8+0,5; á-GST-PrPC(150 ng/ul): 2,9+0,5]. The autoradiography for D1 receptors showed diminished receptor density in the STR of Prnp0/0 mice when compared to Prnp+/+ [D1 receptor (µCi/g): Prnp+/+: 1,4+0,1; Prnp0/0: 0,9+0,04]. Conclusion: Our results indicate the participation of PrPC in ethanol addictive properties, probably related with the blockade of plasticity processes and the concomitant DA modulation at the mesocorticolimbic pathway.