an Opiate-Dependent?Like Reward
State in Na?ve Rats
Hector Vargas-Perez,1* Ryan Ting-A Kee,2 Christine H. Walton,3 D. Micah Hansen,3
Rozita Razavi,1 Laura Clarke,2 Mary Rose Bufalino,2 David W. Allison,3
Scott C. Steffensen,3 Derek van der Kooy1,2
The neural mechanisms underlying the transition from a drug-nondependent to a drug-dependent state
remain elusive. Chronic exposure to drugs has been shown to increase brain-derived neurotrophic factor
(BDNF) levels in ventral tegmental area (VTA) neurons. BDNF infusions into the VTA potentiate several
behavioral effects of drugs, including psychomotor sensitization and cue-induced drug seeking. We found
that a single infusion of BDNF into the VTA promotes a shift from a dopamine-independent to a
dopamine-dependent opiate reward system, identical to that seen when an opiate-na?ve rat becomes
dependent and withdrawn. This shift involves a switch in the g-aminobutyric acid type A (GABAA) receptors
of VTA GABAergic neurons, from inhibitory to excitatory signaling.
The ventral tegmental area (VTA) serves
as an anatomical locus controlling the
switch from an opiate-nondependent to
an opiate-dependent state (1, 2). In nondependent
rats, opiate reward is mediated by a
dopamine-independent neural system, involving
the brainstem tegmental pedunculopontine nucleus
(TPP) (3). Once chronically exposed to opiates
and in a state of withdrawal, opiate reward switches
to a dopamine-dependent system (3). It has been
observed that the switch between the two motivational
systems is due to a switch in g-aminobutyric
acid type A (GABAA) receptor functioning in
VTA GABAergic neurons, from an inhibitory to
an excitatory signaling state (fig. S1) (2).
Brain-derived neurotrophic factor (BDNF) is
capable of producing this change in GABAergic
response, from inhibitory to excitatory, as has
been observed in the hippocampus during epileptic
seizures (4) and in the spinal cord during
neuropathic pain (5). BDNF is present in the
VTA (6), and its TrkB receptors are present on
both GABA (fig. S2) and dopamine VTA
neurons (7, 8). Chronic exposure to drugs of
abuse increase BDNF levels in VTA neurons
1Department of Molecular Genetics, University of Toronto, 160
College Street, Toronto, Ontario M5S 3E1, Canada. 2Institute
of Medical Science, University of Toronto, 160 College Street,
Toronto, Ontario M5S 3E1, Canada. 3Department of Psychology,
Brigham Young University, Provo, UT 84602, USA.
*To whom correspondence should be addressed. E-mail:
vargashector@yahoo.com
1732 26 JUNE 2009 VOL 324 SCIENCE Science
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