1. Anthony S. Rauhut 1,2 and André White 2, Department of Psychology 1 and Neuroscience Program 2, Dickinson College, Carlisle, PA References Discussion Abstract  When administered acutely (Day 1) and repeatedly (Day 4), the moderate propranolol dose (16 mg/kg) attenuated the hyperactive effects of methamphetamine in paired mice only. This dose did not decrease activity in the unpaired mice, suggesting that this dose attenuated methamphetamine-induced hyperactivity without non-specifically disrupting activity. However, the high propranolol dose (32 mg/kg) decreased activity in paired and unpaired mice, suggesting that this dose disrupts behavior non-specifically. Taken together, these results suggest that propranolol dose dependently attenuated the unconditioned (i.e., pharmacological) hyperactive effects of methamphetamine. These results are inconsistent with a previous study that found propranolol increased the hyperactive effects of amphetamine (Louk et al., 2003).  On Test Day 1, the test for methamphetamine conditioned hyperactivity, both propranolol doses attenuated the conditioned hyperactive response. Unpaired mice that had received either propranolol dose during the conditioning phase showed less activity than their veh-meth unpaired control group. These results suggest that these propranolol doses produced conditioned hypoactivity in the unpaired mice. Moreover, the conditioned hypoactive effect observed in the unpaired mice suggest that the decrease in activity observed in the propranolol- paired mice may stem from a non-specific effect of the drug on behavior.  Collectively, these results suggest that propranolol dose-dependently and specifically attenuated the unconditioned (i.e., pharmacological), but did not alter the conditioned (i.e., learned), hyperactive effects of methamphetamine and indicate that the β-noradrenergic system contributes to the unconditioned (i.e., pharmacological), but not the conditioned (i.e., learned), hyperactive effects of methamphetamine.. Prediction Introduction  Recent work has highlighted the contribution the noradrenergic system in mediating the unconditioned and conditioned effects of psychostimulant drugs such as amphetamine (see Weinshenker and Schroeder, 2007, for a review)  The beta-adrenergic receptor antagonist, propranolol, has been found to dose- dependently increase the hyperactive effects of d-amphetamine (Vanderschuren et al. 2003).  However, it is unknown as to the effects of propranolol on the unconditioned or conditioned hyperactive effects of methamphetamine. Purpose  The present experiment examined the ability of propranolol to alter the unconditioned and conditioned locomotor-activating effects of methamphetamine in CD1 mice. Methods Locomotor Activity Chamber Results This research was supported by a National Institutes of Health grant (DA019866), awarded to A. S. Rauhut, and “matching funds” provided by Dickinson College. Effect of Propranolol on the Unconditioned and Conditioned Hyperactive Effects of Methamphetamine in CD1 Mice Acclimation 7 Days Conditioning Phase 8 Sessions—Alternating Drug and NonDrug Sessions Drug Sessions: Mice were injected (IP) with dl-propranolol (16 or 32 mg/kg) or vehicle (dH 2 O) followed 30 minutes later by an injection (SC) of methamphetamine (1.0 mg/kg; Paired) or vehicle (saline; Unpaired) and placed immediately in the locomotor activity chambers for a 30-minute period. Non-Drug Sessions: Mice in the paired and unpaired groups received an injection (SC) of vehicle (saline) or methamphetamine (1.0 mg/kg), respectively, in their home cages. Acknowledgements 24 h Test 1 (Conditioning Test) 1 Session All mice received a vehicle (saline) injection followed immediately by a 30-minute session in the activity chambers. Test 2 (Methamphetamine Challenge) 1 Session All mice received a methamphetamine (1.0 mg/kg) injection followed immediately by a 30-minute session in the activity chambers. 1.Vanderschuren L. J. M. J.,Beemster P., Schoffelmeer A.N.M. (2003). On the role of noradrenaline in psychostimulant-induced psychomotor activity and sensitization. Psychopharmacology, 160: 176-185. 2.Weinshenker D., Schroeder J. (2007). There and Back Again: A Tale of Norepinephrine and Drug Addiction. Neuropsychopharmacology, 32: 1433-1451.  Based on previous research involving amphetamine (Vanderschuren et al., 2003), it was predicted that propranolol would dose-dependently enhance the unconditioned and conditioned hyperactive effects of methamphetamine in CD1 mice. Left, Middle and Right Panels. The moderate propranolol dose (16 mg/kg) attenuated the activity of the paired mice after acute methamphetamine administration, without affecting the unpaired control mice. The high propranolol dose (32 mg/kg) decreased activity in paired and unpaired mice. * = difference of 16 mg/kg propranolol from respective vehicle control mice, p < 0.05. # = difference of 32 mg/kg propranolol from respective vehicle control mice, p < 0.05. Left, Middle and Right Panels. Neither propranolol dose (16 or 32 mg/kg) significantly attenuated the hyperactivity following the methamphetamine challenge, ps > 0.05. However, as can be seen in the figures, the moderate propranolol dose (16 mg/kg) tended to attenuate activity in the paired mice without altering activity in the unpaired mice. Left, Middle and Right Panels. The moderate propranolol dose (16 mg/kg) attenuated the activity of the paired mice after repeated methamphetamine administration, without affecting the unpaired mice. The high propranolol dose (32 mg/kg) decreased activity in paired and unpaired mice. * = difference of 16 mg/kg propranolol from respective vehicle control mice, p < 0.05. # = difference of 32 mg/kg propranolol from respective vehicle control mice, p < 0.05.. Left, Middle and Right Panels. Paired mice that had received the moderate (16 mg/kg) and high (32 mg/kg) propranolol doses during conditioning showed less activity than the veh- meth paired control mice, suggesting propranolol attenuated the conditioned hyperactive response. However, unpaired mice that had received the moderate and high propranolol doses also showed less activity relative to the unpaired veh-meth control mice, suggesting that these propranolol doses produced conditioned hypoactive responses. * = difference of 16 mg/kg propranolol from respective vehicle control mice, p < 0.05. # = difference of 32 mg/kg propranolol from respective vehicle control mice, p < 0.05. Recent work has highlighted the contribution the noradrenergic system in mediating the unconditioned and conditioned effects of psychostimulant drugs such as amphetamine. The present experiment examined the contribution of the β- noradrenergic receptor system in mediating the unconditioned (i.e., pharmacological) and conditioned (i.e., learned) hyperactive effects of methamphetamine. To this end, mice underwent an 8-day conditioning procedure involving two different, alternating session types (Drug and Non-drug sessions). On Drug Sessions (1, 3, 5 and 7), mice were injected (IP) with vehicle (dH 2 O) or propranolol (16 or 32 mg/kg) and were injected (SC) 30 minutes later by either vehicle (saline; Unpaired) or methamphetamine (1.0 mg/kg; Paired). On Non-drug Sessions (2, 4, 6 and 8), mice were injected (SC) with either vehicle (saline; Paired) or methamphetamine (1.0 mg/kg; Unpaired) in their home cages. The test session for conditioned hyperactivity (Test 1) and methamphetamine sensitization (Test 2) occurred 48 and 72 hours, respectively, after the last drug session. On Test Sessions 1 and 2, all mice received an injection of vehicle (saline) or methamphetamine (1.0 mg/kg), respectively. Propranolol dose-dependently attenuated the unconditioned hyperactive effects of methamphetamine, with the moderate propranolol dose (16 mg/kg) attenuating activity in paired mice without altering activity in unpaired mice. However, both propranolol doses attenuated activity during the test for conditioned hyperactivity in paired and unpaired mice. No reliable group differences were detected on Test Session 2. Collectively, these results suggest that propranolol dose-dependently blocked the unconditioned, but not the conditioned, hyperactive effects of methamphetamine and indicate that the β-noradrenergic system is contributes the unconditioned (i.e., pharmacological), but not the conditioned (i.e., learned), hyperactive effects of methamphetamine.