Transcript Social defeat stress, sensitization, and intravenous cocaine self

Social defeat stress,
sensitization, and intravenous
cocaine self-administration
By Jasmine Yap and Klaus Miczek

Behavior sensitization is proposed to be
very important in compulsive drug use and
many psychotic disorders
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Will examine the relationship between
between behavioral sensitization induced by
social defeat or amphetamine, and
intravenous cocaine self-administration
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Strong connections between stress
experiences and drug addiction
– Acute administration of cortisol increases
craving of cocaine in dependent individuals
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Process of sensitization
– Repeated, intermittent administration leads to
progressively increased ( or sensitized)
locomotor response
– Important in transition from recreational to
compulsive drug addicts
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Intermittent exposure to social defeat stress
results in increased dopamine levels in the
nucleus accumbens (up to 65%) and in other
mesocorticolimbic regions such as the
prefrontal cortex

Social defeat modulates changes in:
– circadian rhythmicity,
– long lasting neural adaptations in immediate
early gene expression,
– induces cross-sensitization to psychostimulants
– Decrease in cell proliferation in dentate gyrus
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Social stress episodes and psychostimulants
have similar effects on mesocorticolimbic
dopamine systems
Methods & Materials
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Adult male CFW mice
– 55 to 60 days old
– 25 g
– On 12 hour light/dark cycle
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Intruder mice
– Housed individually in clear cages
 28cm x 17cm x 14cm3
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Resident mice
– Housed in pairs with a female for 3 weeks
 Facilitates display of aggression
 Insures resident always wins confrontation
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Amphetamine sensitization:
– Intraperitoneal injections with D-amphetamine
sulfate or saline for 10 days
– Locomotion assessed on days 1,4,7,10 for 15
min. before and 30 min after injection
– Expression of sensitization tested on day 20
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Locomotor activity assessed
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Social defeat stress ( 10 days)
– Injected with saline
– Subjected to social defeat
 Broken into 3 phases
– Instigation
– Defeat
– Threat
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Instigation
– Intruder placed in protective cage with
perforated walls in resident’s cage for 5 min
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Unrestricted auditory, olfactory, and visual contact
Defeat
– Intruder placed in cage unprotected
– Allowed to be attacked until assumes defeat
posture and held for 3 sec.
Defeat Posture
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Threat phase
– Intruder is placed in resident cage in a
protective cage for 5 additional min
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10 days after last encounter
– Given saline injection and locomotor activity
assessed for 20 min
– Then given either cumulative doses of
amphetamines of 1.0, 1.8, and 3.0 mg/kg and
locomotor activity was assessed for 20 min
– Or single amphetamine doses of 1.0, 1.5, 2.0, or
2.5 mg/kg and activity assessed for 45 min
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Amphetamine
sensitization
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Cumulative
dose
Single dose
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Mice either 10 daily defeats or 10 daily
injections of amphetamines
– Check for behavioral sensitization 10 days after
last encounter or injection
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To check, were given 1.0 or 1.5 mg/kg injection
Conditioned to nose-poke
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Nose-poke
– 1 day after amphetamine challenge
– Conditioned to nose-poke an illuminated hole
for food
– 5 days
– Implanted with jugular catheter
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5 days post surgery
– Acquisition phase for 5 days
 Received 1 mg/kg infusion of cocaine on a fixed
ratio 2 schedule
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Then allowed to self administer daily for 3
hrs or until 50 infusions
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Socially defeated mice
– Start acquisition phase of cocaine self-
administration on day 20 for 5 days
– Self administration begins during period of
cross-sensitization to psychostimulants
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After acquisition phase
– Begin progressive ratio sessions of 0.3 mg/kg
per infusion for 3 days to determine the
breaking point
– Between sessions allowed to self-administer 1.0
mg/kg for 3 hrs a day to prevent extinction
Results
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Repeated amphetamine injections led to
progressive increase in locomotor activity
during induction phase
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On day 20 the amphetamine injected mice
show sensitized response to low doses of
amphetamines
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Mice with a history of repeated defeats
show sensitized locomotor response to
increasing doses of amphetamine
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Defeat-stressed mice show sensitized
response to 1.5 mg/kg of amphetamine
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Defeat-stressed and non-stressed did not
differ in cocaine self-administration
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Amphetamine pretreated mice show
increased drug taking during acquisition
phase of self-administration
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Amphetamine sensitized mice slightly
higher levels of cocaine infusions during
last 2 days
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Repeated, intermittent social defeat stress is
sufficient to induce behavioral crosssensitization to amphetamines
– Repeated defeats are comparable to repeated
low doses (1.0 mg/kg) of amphetamines
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A single exposure to social defeat is
sufficient to induce sensitized behavioral
response to future challenges with a
psychomotor stimulant
– Does not produce significant Fos expression in
VTA
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Repeated social defeat increases Fos
expression in mesocorticolimbic system
– In VTA, prelimbic and infralimbic cortical
areas, NAC shell and core, and Amygdala
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Zif268 mRNA expression is decreased in
the prefrontal cortex and decreased in
central and basolateral amygdala 60 days
later
– Zif268 is indicator of synaptic activity
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Suggests VTA, PFC and Amygdala crucial
to mediate social defeat stress-induced
sensitization
– May play role in transition to compulsive drug
abuse
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Glutamate critical in developing stressinduced sensitization due to effects on
NMDA and AMPA receptors
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Map
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Rats with previous social defeats
– Exposure to olfactory, visual, and auditory cues
increase dopamine release and acquire cocaine
seeking behavior in half the time of nonstressed animals