Social defeat stress, Social defeat stress, sensitization, and intravenous sensitization, and intravenous
cocaine self-administrationcocaine self-administration
By Jasmine Yap and Klaus Miczek
Behavior sensitization is proposed to be very important in compulsive drug use and many psychotic disorders
Will examine the relationship between between behavioral sensitization induced by social defeat or amphetamine, and intravenous cocaine self-administration
Strong connections between stress experiences and drug addiction– Acute administration of cortisol increases
craving of cocaine in dependent individuals
Process of sensitization– Repeated, intermittent administration leads to
progressively increased ( or sensitized) locomotor response
– Important in transition from recreational to compulsive drug addicts
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
Social stress episodes and psychostimulants have similar effects on mesocorticolimbic dopamine systems
Methods & MaterialsMethods & Materials
Adult male CFW mice– 55 to 60 days old– 25 g – On 12 hour light/dark cycle
Intruder mice– Housed individually in clear cages
28cm x 17cm x 14cm3
Resident mice– Housed in pairs with a female for 3 weeks
Facilitates display of aggression Insures resident always wins confrontation
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
Locomotor activity assessed
Social defeat stress ( 10 days)– Injected with saline– Subjected to social defeat
Broken into 3 phases– Instigation
– Defeat
– Threat
Instigation– Intruder placed in protective cage with
perforated walls in resident’s cage for 5 min 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.
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
Mice either 10 daily defeats or 10 daily injections of amphetamines– Check for behavioral sensitization 10 days after
last encounter or injection To check, were given 1.0 or 1.5 mg/kg injection
Conditioned to nose-poke
Nose-poke– 1 day after amphetamine challenge– Conditioned to nose-poke an illuminated hole
for food – 5 days– Implanted with jugular catheter
5 days post surgery– Acquisition phase for 5 days
Received 1 mg/kg infusion of cocaine on a fixed ratio 2 schedule
Then allowed to self administer daily for 3 hrs or until 50 infusions
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
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
Repeated amphetamine injections led to progressive increase in locomotor activity during induction phase
Mice with a history of repeated defeats show sensitized locomotor response to increasing doses of amphetamine
Amphetamine pretreated mice show increased drug taking during acquisition phase of self-administration
Repeated, intermittent social defeat stress is sufficient to induce behavioral cross-sensitization to amphetamines– Repeated defeats are comparable to repeated
low doses (1.0 mg/kg) of amphetamines
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
Repeated social defeat increases Fos expression in mesocorticolimbic system– In VTA, prelimbic and infralimbic cortical
areas, NAC shell and core, and Amygdala
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
Suggests VTA, PFC and Amygdala crucial to mediate social defeat stress-induced sensitization– May play role in transition to compulsive drug
abuse
Glutamate critical in developing stress-induced sensitization due to effects on NMDA and AMPA receptors