Psychopharmacology (2003) 170:167–177
DOI 10.1007/s00213-003-1528-5
ORIGINAL INVESTIGATION
Stephen C. Fowler · Brenda Birkestrand · Rong Chen ·
Elena Vorontsova · Troy Zarcone
Behavioral sensitization to amphetamine in rats:
changes in the rhythm of head movements during focused stereotypies
Received: 25 January 2003 / Accepted: 17 April 2003 / Published online: 24 June 2003
Springer-Verlag 2003
Abstract Rationale: The indirect-acting dopamine ago-
nist amphetamine induces in rats, motor stereotypies that
have served as the primary behavioral end points in
studies related to schizophrenia, drug abuse, and l-dopa-
induced dyskinesias. Despite the experimental importance
of this rodent response to this drug, little is known about
the rhythmic character of the behavior and how such
rhythms change (or sensitize) in response to repeated
treatment with amphetamine. Objective: To address this
lack of quantitative information, the rhythms of focused
stereotypies (characterized by a lack of locomotion and
rapid head movements) were measured in a force-plate
actometer that permitted the quantification of behavioral
rhythmicity. Methods: Focused stereotypies were induced
by d-amphetamine sulfate (2.5 and 5.0 mg/kg) after acute
and repeated treatment with fixed doses of the drug in
separate groups of rats, and the drug-induced behaviors
were recorded in 1-h sessions in the actometer. Re-
sults: The two doses of amphetamine produced focused
stereotypies characterized by a 10-Hz rhythm of head
movements. Detailed analyses of the data for 5.0 mg/kg
amphetamine showed that the rhythm in the 10-Hz region
of the power spectrum increased significantly within a 1-h
period, while five intermittent, repeated drug treatments
significantly reduced the rhythm, possibly reflecting
either tolerance or sensitization. Conclusions: Aside from
providing a new quantitative approach to studying
focused stereotypies, these observation direct attention
to the possibility that practice-mediated processes in-
volved in motor skill enhancement may be a part of the
neural adaptations that parallel the development of
sensitization to indirect-acting dopamine agonists.
Keywords Amphetamine · Sensitization · 10-Hz rhythm ·
Focused stereotypy · Dopamine · Force-plate actometer ·
Spatial confinement · Head movements · Rat
Introduction
Drug-induced behavioral stereotypies are characterized
by relatively enduring, repetitive, apparently purposeless
movements in rodents. Stereotypies induced by drugs that
result in excess brain dopamine function have been linked
to schizophrenia (e.g. Robinson and Becker 1986), the
stereotypies observed in persons with mental retardation
(e.g. Bodfish et al. 1996), and dyskinesias associated with
l-dopa therapy in Parkinson disease (Graybiel et al.
2000). In addition, induction of sensitization of focused
stereotypies (i.e. increasing effect of a constant dose given
in a pulsatile, repeated treatment schedule) by d-amphet-
amine (Amp) has been theoretically (e.g. Robinson and
Berridge 1993) and empirically (e.g. Adinoff et al. 2001;
Wyvell and Berridge 2001) linked to brain processes
underlying addiction. Sensitization has also been impli-
cated in the progressive development of dyskinesias
attendant upon chronic l-dopa therapy (Graybiel et al.
2000). Despite widespread scientific interest in stereo-
typies and sensitization, quantitative operational defini-
tions of “repetitive” and “rhythmic” have generally not
been used to characterize these phenomena. We report
here the results from a new, instrument-based method of
measuring rodent behavior (i.e. the force-plate actometer;
Fowler et al. 2001) that reveals, in a quantitative manner,
that focused stereotypies induced by Amp are character-
ized by a fundamental movement rhythm of about 10 Hz.
We also show that this movement rhythm reliably
changes in response to sensitization induced by intermit-
tent Amp treatment. Although a wide range of drug-
induced rodent behaviors has been labeled as stereotypies
S. C. Fowler (
)
) · B. Birkestrand · R. Chen
Department of Pharmacology and Toxicology,
University of Kansas,
5064 Malott Hall, 1251 Wescoe Hall Drive, Lawrence,
KS 66045-2505, USA
e-mail: scfowler@ku.edu
Tel.: +1-785-8640715
Fax: +1-785-8645219
S. C. Fowler · E. Vorontsova · T. Zarcone
Life Span Institute,
University of Kansas,
Lawrence, Kansas, USA