1. Effects
of
Orexin
and
Kappa
Opiate
Receptor
(KOR)
Pharmacology
on
Cocaine-­‐Induced
Behaviors
Stacia
Lewandowski;
Taylor
A.
Gentile;
Steven
J.
Simmons;
John
W.
Muschamp,
Ph.D.
Center
for
Substance
Abuse
Research
(CSAR);
Temple
University,
School
of
Medicine;
Philadelphia,
PA;
19140
Orexins
(hypocretins)
are
neuropeptides
in
the
lateral
hypothalamus
(LH)
that
project
to
other
brain
structures
including
the
ventral
tegmental
area,
nucleus
accumbens,
dorsal
raphe,
and
locus
coeruleus.
Accordingly,
orexin
transmission
has
demonstrated
to
be
involved
in
arousal,
wakefulness,
attention
and
motivated
behavior
through
signaling
via
two
predominantly
excitatory
G-­‐protein
coupled
receptor
subtypes
(Ox1R
and
Ox2R).
Additionally,
orexin
is
co-­‐localized
with
dynorphin,
a
neuropeptide
involved
in
depressive-­‐like
states,
stress
and
drug-­‐
seeking
behavior
through
binding
to
inhibitory
G-­‐protein
coupled
kappa-­‐opioid
receptor
(KOR).
Our
laboratory
has
preliminary
evidence
demonstrating
that
suvorexant,
a
dual
orexin
receptor
antagonist
used
clinically
to
treat
insomnia,
attenuates:
(i)
cocaine-­‐induced
impulsivity,
(ii)
affective
reactivity
to
cocaine
as
assessed
through
recording
50-­‐kHz
ultrasonic
vocalizations,
and
(iii)
intravenous
self-­‐administration
of
cocaine
[(earned
by
performing
a
number
of
lever-­‐presses
that
was
increased
iteratively
for
each
trial
according
to
a
predetermined
exponential
function
(i.e.
a
progressive-­‐ratio
schedule)].
The
present
study
sought
to
explore
the
effects
of
suvorexant
and
norbinaltorphimine
(norBNI),
a
selective
KOR
antagonist,
on
cocaine-­‐induced
orexin
activity
[inferred
from
immunohistochemical
visualization
and
quantification
of
gene
products
promptly
expressed
by
orexin
neurons
after
protracted
neuronal
depolarization].
[Male]
Sprague-­‐Dawley
rats
received
a
30-­‐minute
pre-­‐treatment
of
either
suvorexant
(30
mg/kg,
i.p.),
norBNI
(10
mg/kg,
i.p.)
or
vehicle
(DMSO)
followed
by
acute
treatment
of
either
cocaine
(10
mg/kg,
i.p.)
or
vehicle
(saline).
All
animals
were
immediately
perfused
with
paraformaldehyde
and
their
brains
collected
for
histological
processing
and
immunolabeling.
Bilateral
coronal
sections
(40
µM)
containing
LH
were
collected
on
a
cryostat
and
underwent
immunofluorescent
labeling
of
orexin-­‐A
and
cFos
proteins.
Results
from
the
present
study
address
relationships
between
the
drug-­‐induced
activity
of
orexin-­‐dynorphin
and
behaviors
that
model
reward,
reinforcement,
human
substance
abuse.