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Prazosin Attenuates the Unconditioned and Conditioned Hyperactive Effects of Methamphetamine
and Neuroscience
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4 Days — Days 2, 4, 6, 8
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Non-drug Days: 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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30 minute session in activity chamber s following vehicle
(saline) injection for all mice
Introduction
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Prazosin, an α1 receptor antagonist, blocks the locomotor-activating
effects of amphetamine in rats (Darraq et al., 1998; Drouin et al., 2002
Snoddy & Tessel, 1985).
Depletion of norepinephrine from the medial prefrontal cortex
abolishes amphetamine-produced conditioned place preference in
mice (Ventura et al., 2003).
Test Day 2: Methamphetamine challenge
1 Day - Day 10
30 minute session in activity chamber following
methamphetamine (1.0 mg/kg) injection for all mice
 Little research, however, has examined the contribution of the noradrenergic,
α1
receptor system, in mediating the unconditioned and conditioned
hyperactive effects of methamphetamine in mice.
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Prazosin Dose (mg/kg)
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Paired mice pretreated with the moderate (1.0 mg/kg) and high (2.0 mg/kg) prazosin
doses showed significantly less locomotor activity compared to veh-meth paired
control mice (left and middle panels). The low (0.5 mg/kg) and high (2.0 mg/kg)
prazosin doses decreased locomotor activity in the unpaired mice compared to their
respective veh-veh control group during the first 5 minute of the session (right panel).
* = difference of 1.0 mg/kg prazosin relative to their respective vehicle control group,
p < 0.05. # = difference of 2.0 mg/kg prazosin relative to their respective vehicle
control group, p < 0.05. $ = difference of 0.5 mg/kg prazosin relative to their
respective vehicle control group, p < 0.05
Test Day 1: Conditioning Test
Objective
The present experiment examined the ability of the α1 receptor antagonist,
prazosin, to attenuate the unconditioned and conditioned hyperactive effects of
methamphetamine.
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Prazosin Dose (mg/kg)
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Discussion
 Prazosin dose dependently attenuated the hyperactive effects of
methamphetamine following acute (Day 1) and repeated (Day 4) administrations.
The 1.0 mg/kg prazosin dose attenuated the hyperactive effect of
methamphetamine without disrupting activity in unpaired control mice. 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 Days 1 and 4, the high prazosin dose (2.0 mg/kg) did decrease behavior in
Unpaired mice, suggesting that this dose non-specifically decreased locomotor
activity.
 However, On Test Day 1 (Conditioning Test), paired mice pretreated with the
moderate (1.0 mg/kg) and high (2.0 mg/kg) prazosin doses during conditioning did
not differ from their unpaired counterparts, suggesting that these doses
attenuated the conditioned hyperactive response . Moreover, the 2.0 mg/kg
prazosin dose did not decrease behavior in unpaired mice on Test Day 1,
suggesting that attenuated conditioned hyperactive response was not due to
drug-induced disruptions in behavior.
 Collectively, these results suggest that the α1 receptor system contributes to the
unconditioned and conditioned hyperactive effects of methamphetamine and
further supports the role of the noradrenergic α1 receptor system in mediating the
unconditioned and conditioned effects of psychostimulants.
References
1. Beninger, R.J., & Hahn, B. L. (1983). Pimozide blocks establishment but not the expression of
amphetamine-produced environment-specific conditioning. Science, 220:1304-1306.
2. Darraq, L., Blanc, G., Glowinski, J., & Tassin, J-P. (1998). Importance of the noradrenalindopamine coupling in the locomotor-activating effects of d-amphetamine. Journal of
Neuroscience, 18: 2729-2739.
5. Mazurski, E. J., & Beninger, R. J. (1991). Effects of selective drugs for dopaminergic D1 and
D2 receptors on conditioned locomotion in rats. Psychopharmacology, 105:107-112.
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Acknowledgements
Locomotor Activity Chamber
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7. 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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6. Snoddy, A.M. & Tessel (1985). Prazosin: effect of psychomotor-stimulant cues and locomotor
activity in mice. European Journal of Pharmacology, 116: 221-228.
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4. Duteil, J., Rambert, F.A., Pessonnier, J., Hermant, J-F., Gombert, R., & Assous, E. (1990).
Central α-1 adrenergic stimulation in relation to the behavior stimulating effect of modafinil;
studies with experimental animals. European Journal of Pharmacology, 180: 49-58.
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3. Drouin, C., Darraq, L., Trovero, F., Blanc, G., Glowinski, J., Cotecchia, S., Tassin, J-P. (2002).
Journal of Neuroscience, 22: 2873-2884.
Test Day 2
(Unpaired Groups Only)
Test Day 1
(Paired Groups Only)
Test Day 1
(Conditioning Test)
Hypothesis
Because the α1 receptor system has been shown to be involved in
mediating the unconditioned and conditioned effects of other
psychostimulants (e.g., amphetamine; see Weinshaker and Schoeder, 2007,
for a review), it was predicted that prazosin, a selective α1 noradrenergic
receptor antagonist (Duteil et al. 1990), should dose-dependently attenuate
the
unconditioned
and
conditioned
hyperactive
effects
of
methamphetamine.
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Support for this view comes from a number of studies
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research has suggested that the noradrenergic system, particularly
the α1 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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Drug Day 4
(Unpaired Groups)
Drug Day 4
(Paired Groups)
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and conditioned hyperactive effects of psychostimulants has been well
established (Beninger and Hahn, 1983; Mazurski and Beninger, 1991)
Drug Day 4
(Repeated Methamphetamine)
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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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Drug Day 4
Test Day 1: Conditioning Test
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 The role of the mesolimbic dopamine system in mediating the unconditioned
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Prazosin Dose (mg/kg)
Paired mice pretreated with moderate (1.0 mg/kg) and high (2.0 mg/kg) prazosin
showed significantly less locomotor activity compared to their veh-meth paired control
mice (left and middle panels). However, these prazosin doses also produced a
decrease in locomotor activity in unpaired mice relative to their veh-veh unpaired
control group (left and right panels). * = difference of 1.0 mg/kg prazosin relative to
respective vehicle group, p < 0.05. # = difference of 2.0 mg/kg prazosin relative to
respective vehicle control group, p < 0.05. $ = difference of 0.5 mg/kg prazosin
relative to respective vehicle control group, p < 0.05.
Introduction
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Methamphetamine Challenge
(Unpaired Groups Only)
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Prazosin Dose (mg/kg)
Drug Days: Injection (IP) of vehicle
(dH20) or prazosin (0.5, 1.0, or 2.0
mg/kg, IP) followed 30 minutes later
by an injection (SC) of vehicle (saline;
Unpaired) or methamphetamine (1.0
mg/kg; Paired). Then, all mice were
placed in the activity chambers for a
30-minute session.
Drug Day 1
(Unpaired Groups)
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Paired
Distance Travelled (cm)
7 Days
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Drug Day 1
(Paired Groups)
Drug Day 1
(Acute Methamphetamine)
Methamphetamine Challenge
(Paired Groups Only)
Test Day 2
(Methamphetamine Challenge)
Unpaired
Paired
Drug Day 1
Acclimation
(Handling)
4 Days — Days 1, 3, 5, 7
Test Day 2: Methamphetamine Challenge
Results
Procedure
Conditioning: Non-drug days
Dickinson College, Carlisle, PA
Distance Traveled
Methods
Conditioning: Drug days
2
Program ,
Distance Traveled
Department of
Distance Traveled (cm)
The present experiment determined the ability of the α1-noradrenergic receptor
antagonist, prazosin, to attenuate the unconditioned and conditioned
hyperactive effects in male Swiss-Webster mice. After the initial acclimation
period (7 days), the experiment lasted 10 days and consisted of 2 phases
(Conditioning and Tests). The Conditioning Phase lasted 8 days and consisted
of 4 alternating Drug and Non-drug days. During Drug Days, mice were injected
(IP) with vehicle (dH2O) or prazosin (0.5, 1.0, or 2.0 mg/kg) followed 30 minutes
later by an injection (SC) of either vehicle (saline; Unpaired mice) or
methamphetamine (1.0 mg/kg; Paired mice) before entering the activity
chamber for a 30-minute session. On Non-drug Days, mice remained in their
home cages and received an injection (SC) of vehicle (physiological saline;
Paired) or methamphetamine (1.0 mg/kg; Unpaired). The tests for conditioned
hyperactivity (Test Day 1) and methamphetamine sensitization (Test Day 2)
occurred 48 and 72 hours following the last drug days, respectively. On Test
Days 1 and 2, all mice were injected with vehicle or methamphetamine (1.0
mg/kg), respectively. Prazosin dose-dependently attenuated with unconditioned
and conditioned hyperactive effects of methamphetamine. These results
suggest the α1 receptor contributes to the development of the unconditioned
(i.e., pharmacological) and conditioned hyperactive (i.e., learned) effects of
methamphetamine.
1
Psychology
Distance Traveled (cm)
Abstract
and Anthony S. Rauhut
1,2,
Distance Traveled (cm)
Margaret Della
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Vecchia
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.
This research was supported by a National Institutes of Health
grant (DA019866), awarded to A. S. Rauhut, and “matching
funds” provided by Dickinson College.