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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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social defeat stress sensitization and intravenous cocaine self administration

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
  • 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 materials
Methods & 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
    • 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.
Threat phase
    • Intruder is placed in resident cage in a protective cage for 5 additional min
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
Amphetamine sensitization
  • Cumulative dose
  • Single dose
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
    • 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
On day 20 the amphetamine injected mice show sensitized response to low doses of amphetamines
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
Amphetamine sensitized mice slightly higher levels of cocaine infusions during last 2 days
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
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 non-stressed animals