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 14cm 3 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