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 α1-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.

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Andre White2, Margaret Della Vecchia2, and Anthony S. Rauhut 1,2, Department of Psychology1 and Neuroscience Program2, 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 α1-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 α1-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 α1 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

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Results of Experiment 1AbstractThe 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.

ProcedureAcclimation (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 (dH20) 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 (dH20) 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

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