1. Left and Right Panels. Mice treated with prazosin were less active than their vehicle-paired counterparts (left panel). Time course analysis shows paired prazosin mice were less active than paired vehicle mice early in the session (right panel). The error bars are representative of ± S.E.M.. Asterisks represent significant differences from the vehicle-paired mice, p< 0.05. Left, Middle and Right Panels. Paired mice pretreated with the moderate (1.0 mg/kg) or the high (2.0 mg/kg) prazosin doses during conditioning did not differ from their unpaired counterparts (left panel). Paired mice pretreated the high prazosin dose (2.0 mg/kg) during conditioning did not differ from methamphetamine paired control mice. # = difference of 2.0 mg/kg prazosin relative to their respective control group, p < 0.05.  Experiments1 and 2  On Test Days 2 (Methamphetamine Sensitization Tests), pre- and post-session administration of prazosin attenuated the sensitizing effects of methamphetamine. Moreover, the time course analysis of the data revealed that these attenuating effects occurred during the early part of the locomotor activity session (i.e., within the first 15 minutes of the session). These results are consistent with previous studies that have reported that prazosin dose dependently attenuates the hyperactive effects of amphetamine (Snoddy & Tessel, 1985; Darraq et al., 1998; Drouin et al., 2002).  On Test Days 1 (Conditioning Tests), paired mice pretreated before or after with a high prazosin dose (2.0 mg/kg) showed an attenuated conditioned hyperactive response. Moreover, the 2.0 mg/kg prazosin dose did not decrease behavior in unpaired mice on Test Days 1, suggesting that attenuated conditioned hyperactive response was not due to drug-induced disruptions in behavior.  Collectively, these results suggest that the α 1- noradrenergic receptors contribute to the development of the unconditioned (i.e., pharmacological) as well as the conditioned (learned) hyperactive response to methamphetamine, possibly by disrupting memory consolidation processes. Future research will more completely explore this idea. Left and Right Panels. Mice treated with prazosin were less active than their vehicle-paired counterparts (left panel). Time course analysis shows paired prazosin mice were less active than paired vehicle mice early in the session (right panel). The error bars are representative of ± S.E.M.. Asterisks represent significant differences from the paired vehicle mice, p< 0.05. André White 2, Margaret Della Vecchia 2, and Anthony S. Rauhut 1,2, Department of Psychology 1 and Neuroscience Program 2, Dickinson College, Carlisle, PA References Discussion Methods Results of Experiment 2 Acknowledgements Pre- and Post-Session Administration of Prazosin Disrupts Development of Methamphetamine Conditioned Hyperactivity  Recent research has suggested that the noradrenergic system, particularly the α 1 -noradrenergic receptor system, interacts with the dopaminergic system and contributes to the unconditioned and conditioned hyperactive effects of psychostimulants (see Weinshaker and Schoeder, 2007, for a review).  Support for this view comes from a number of studies o Prazosin, an α 1 -noradrenergic receptor antagonist, blocks the locomotor-activating effects of amphetamine in rats (Darraq et al., 1998; Drouin et al., 2002 Snoddy & Tessel, 1985). o Depletion of norepinephrine from the medial prefrontal cortex abolishes amphetamine- produced conditioned place preference in mice (Ventura et al., 2003).  Little research, however, has examined the contribution of the noradrenergic α 1 receptor in mediating the unconditioned (pharmacological) and conditioned (learned) hyperactive effects of methamphetamine in mice. 1.Darraq, L., Blanc, G., Glowinski, J., & Tassin, J-P. (1998). Importance of the noradrenalin-dopamine coupling in the locomotor-activating effects of d-amphetamine. Journal of Neuroscience, 18: 2729-2739. 2.Drouin, C., Darraq, L., Trovero, F., Blanc, G., Glowinski, J., Cotecchia, S., Tassin, J-P. (2002). Journal of Neuroscience, 22: 2873-2884. 3.Snoddy, A.M. & Tessel (1985). Prazosin: effect of psychomotor-stimulant cues and locomotor activity in mice. European Journal of Pharmacology, 116: 221-228. 4.Ventura, R. Cabib, S, Alcaro, A Orsini, C, & Puglisi-Allegra, S. (2003) Norepinephrine in the Prefrontal Cortex is Critical for Amphetamine-Induced Reward and Mesoaccumbens Dopamine Release. Journal of Neuroscience, 23 (5): 1879-1885. 5.Weinshenker, D. & Schroeder, J.P. (2007). There and back again: a tale of norepinephrine and drug addiction. Neuropsychopharmacology, 32: 1433-1451. Left, Middle and Right Panels. Only paired mice that were pretreated with veh-meth during conditioning differed from their unpaired counterparts (veh-veh; left panel), suggesting that all prazosin doses attenuated the challenge with methamphetamine. Paired mice that were pretreated with the high prazosin dose (2.0 mg/kg) differed from their veh-meth paired control mice (middle panel). Group differences were not detected in unpaired mice (right panel). # = difference of 2.0 mg/kg prazosin relative to respective control group, p < 0.05. Introduction Locomotor Activity Chamber Results of Experiment 1Abstract The present experiments determined the ability of pre- and post-session administration (Experiments 1 and 2, respectively) of the α1-noradrenergic receptor antagonist, prazosin, to disrupt the development of conditioned hyperactivity and sensitization to methamphetamine in male Swiss Webster mice. In Experiment 1, after the initial acclimation period (7 days), the experiment consisted of 2 phases (Conditioning and Tests). The Conditioning Phase lasted 8 days and consisted of 4 alternating chamber and home-cage days. During the chamber days (1, 3, 5 and 7), mice were administered an injection (intraperitoneal; i.p.) of either vehicle (distilled water) or prazosin (0.5, 1.0, or 2.0 mg/kg), followed 30 minutes later by an administration (subcutaneous; s.c.) of either vehicle (saline; Unpaired mice) or methamphetamine (1.0 mg/kg; Paired mice), and then placed in the locomotor activity chambers for a 30-minute session. On home-cage days (2, 4, 6 and 8), mice remained in their home cages and were administered an injection (s.c.) of either vehicle (saline; Paired mice) or methamphetamine (1.0 mg/kg; Unpaired mice). The tests for conditioned hyperactivity (Test Day 1) and methamphetamine sensitization (Test Day 2) occurred 48 and 72 hours following the last chamber day, respectively. Experiment 2 was identical to Experiment 1 with the exception that Unpaired and Paired mice were administered an injection of either vehicle or methamphetamine (1.0 mg/kg), respectively, placed in the locomotor activity chambers for a 30-minute period, and then were administered an injection of either vehicle or prazosin (2.0 mg/kg) immediately after the 30-minute locomotor activity session on chamber days. Pre-session administration of prazosin dose-dependently blocked both the conditioned hyperactive and sensitizing effects of methamphetamine (Experiment 1) whereas post-session administration of prazosin only attenuated these effects (Experiment 2). These results suggest that α1-noradrenergic receptors contribute to the development of the conditioned (i.e., learned) and sensitizing (i.e., pharmacological) hyperactive responses to methamphetamine in mice. Moreover, the ability of post- session administration of prazosin to attenuate the development of methamphetamine conditioned hyperactivity may suggest that prazosin blunts the development of conditioned hyperactivity by disrupting memory consolidation processes. This research was supported by a National Institutes of Health grant (DA019866), awarded to A. S. Rauhut and funds provided by Dickinson College. Procedure Acclimation (Handling) 7 Days Test Day 1: Conditioning Test (Day 9) 30 minute session in activity chamber s following vehicle (saline) injection for all mice Conditioning Chamber days (4 Days) (Days 1, 3, 5, 7) Chamber Days: Experiment 1: Pre-Session Prazosin Administration Injection (IP) of vehicle (dH 2 0) or prazosin (0.5, 1.0, or 2.0 mg/kg) 30 minutes prior to activity chamber.. An injection (SC) of vehicle (saline; Unpaired) or methamphetamine (1.0 mg/kg; Paired) immediately before all mice were placed in the activity chambers for a 30-minute session. Experiment 2: Post-Session Prazosin Administration An injection (SC) of vehicle (saline; Unpaired) or methamphetamine (1.0 mg/kg; Paired) immediately before all mice were placed in the activity chambers for a 30-minute session. Injection (IP) of vehicle (dH 2 0) or prazosin (2.0 mg/kg,) after the 30-minute session. Conditioning Home-cage days (4 Days) ( Days 2, 4, 6, 8) Home-cage Days: Experiments 1 and 2 Injection (SC) of either vehicle (saline) or methamphetamine (1.0 mg/kg, SC) for paired and unpaired animals, respectively, in their home cages. Test Day 2: Methamphetamine challenge (Day 10) 30 minute session in activity chamber following methamphetamine (1.0 mg/kg) injection for all mice 24 h SFN Poster# 669.19/FF12