Social defeat stress sensitization and intravenous cocaine self administration
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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

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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

  • 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

  • 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.


Defeat Posture


  • 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


  • 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


Results


  • 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


  • Defeat-stressed mice show sensitized response to 1.5 mg/kg of amphetamine


  • Defeat-stressed and non-stressed did not differ in cocaine self-administration


  • 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


  • Map


  • 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


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