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Pre- and Post-Session Administration of Prazosin Disrupts Development of Methamphetamine Conditioned Hyperactivity
and Anthony S. Rauhut
1,2,
Abstract
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Depletion of norepinephrine from the medial prefrontal cortex abolishes amphetamineproduced conditioned place preference in mice (Ventura et al., 2003).
(learned)
hyperactive
effects
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Home-cage Days:
Experiment 1: Pre-Session Prazosin
Administration
Experiments 1 and 2
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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.
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1.0
(Day 10)
30 minute session in activity chamber following methamphetamine (1.0
mg/kg) injection for all mice
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Veh/Veh
0.5 Praz/Veh
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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.
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Paired
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Prazosin DosePrazosin
(mg/kg)
Dose (mg/kg)
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0.5 Praz/Meth
1.0 Praz/Meth
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Prazosin
Prazosin Dose
(mg/kg) Dose (mg/kg)
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This research was supported by a National Institutes of Health
grant (DA019866), awarded to A. S. Rauhut and funds provided
by Dickinson College.
Drug Day 1
(Unpaired Groups)
Drug Day 1
(Paired Groups)
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Acknowledgements
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Distance Traveled (cm)
Distance Traveled (cm)
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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.
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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.
Unpaired
Paired
3. Snoddy, A.M. & Tessel (1985). Prazosin: effect of psychomotor-stimulant cues and
locomotor activity in mice. European Journal of Pharmacology, 116: 221-228.
5. Weinshenker, D. & Schroeder, J.P. (2007). There and back again: a tale of
norepinephrine and drug addiction. Neuropsychopharmacology, 32: 1433-1451.
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Session Minute
Unpaired
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Paired
References
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Veh/Veh
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1.0 Praz/Veh
2.0 Praz/Veh
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Veh/Meth
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1.0 Praz/Meth
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 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.
2. Drouin, C., Darraq, L., Trovero, F., Blanc, G., Glowinski, J., Cotecchia, S., Tassin, J-P.
(2002). Journal of Neuroscience, 22: 2873-2884.
Drug Day 1
(Unpaired Groups)
Drug Day 1
(Paired Groups)
Discussion
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.
Results of Experiment 2
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Test Day 2: Methamphetamine challenge
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30 minute session in activity chamber s following vehicle (saline) injection
for all mice
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(Day 9)
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Test Day 2
Methamphetamine Challenge
(Unpaired Groups)
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0.5 Praz/Meth
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(Acute Methamphetamine)
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Test Day 1: Conditioning Test
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Session Minute
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Experiment 2: Post-Session Prazosin
Administration
24 h
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Test Day 2
(Methamphetamine
Challenge)
Drug Day 1
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.
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Test Day 2
Methamphetamine Challenge
(Paired Groups)
Unpaired
Paired
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Injection (SC) of either vehicle (saline) or
methamphetamine (1.0 mg/kg, SC) for paired and
unpaired animals, respectively, in their home
cages.
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Session Minute
Test Day 2
(Methamphetamine Challenge)
Distance Traveled (cm)
Chamber Days:
Injection (IP) of vehicle (dH20) or prazosin (2.0
mg/kg,) after the 30-minute session.
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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.
Distance Traveled (cm)
( Days 2, 4, 6, 8)
Injection (IP) of vehicle (dH20) or prazosin (0.5,
1.0, or 2.0 mg/kg) 30 minutes prior to activity
chamber..
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(Days 1, 3, 5, 7)
Locomotor Activity Chamber
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(Acute Methamphetamine)
Home-cage days (4 Days)
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Test Day 1
Drug Day
1
(Conditioning
Test)
Conditioning
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Prazosin Dose (mg/kg)
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7 Days
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2.0
1.0
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Acclimation (Handling)
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Procedure
Chamber days (4 Days)
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Methods
Conditioning
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conditioned
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 Little research, however, has examined the contribution of the noradrenergic α1 receptor in mediating
and
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Distance Traveled (cm)
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Veh/Veh
0.5 Praz/Veh
1.0 Praz/Veh
2.0 Praz/Veh
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Prazosin Dose (mg/kg)
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).
the unconditioned (pharmacological)
methamphetamine in mice.
Veh/Meth
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1.0 Praz/Meth
2.0 Praz/Meth
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Support for this view comes from a number of studies
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Unpaired
Paired
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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).
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Distance Traveled (cm)
 Recent
o
Dickinson College, Carlisle, PA
Test Day 1
(Unpaired Groups)
Test Day 1
(Paired Groups)
Test Day 1
(Conditioning Test)
Distance Travelled (cm)
Introduction
o
and Neuroscience
2
Program ,
Results of Experiment 1
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.

Department of
1
Psychology
Distance Traveled (cm)
Margaret Della
2
Vecchia ,
Distance Traveled (cm)
André
2
White ,
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Session Minute
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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.
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