1. Stress and neuroimmune response as biomarkers of cocaine and alcohol used disorders
Dr. Marta Rodríguez Arias
Universitat de València

2. Strong and chronic stresses have marked effects on animal bodies and can induce various disorders
Different neurobiological, chemical and behavioral actions are initiated to resolve this situation: CRF, sympathetic response and neuroimmune response
Social conflicts frequently occur in animal and human societies, and unavoidable stresses can worsen the quality of life in both animals and humans: depression, anxiety or PTSD
Rodríguez-Arias et al., 2013

3. metabolic syndrome (weight gain and insulin and leptin resistance)
Animals subjected to chronic SOCIAL DEFEAT are good models for gaining an understanding of psychiatric disorders and abnormal behaviors in animals.
Nestler and Hyman 2010
Chronic social defeat stress involves subjecting rodents to repeated bouts of social subordination, after which time the rodents show a range of depression-like symptoms:
anhedonia
social withdrawal
metabolic syndrome (weight gain and insulin and leptin resistance)

5. Stress is a risk factor for the initiation, maintenance and escalation of drug consumption and for relapse after periods of detoxification
Drug addiction is a chronic multifactorial relapsing disorder that is a result of the interaction between biological and environmental factors
There is a narrow relationship between stress and addiction brain systems, and stressful experiences modify the activity of brain areas involved in the rewarding effects of psychostimulants

6. Rodríguez-Arias et al., 2013

7. Social defeat in mice: COCAINE
COCAINE-INDUCED CPP 1 MG/KG
Montagud-Romero et al., 2017

8. Social defeat in mice: COCAINE
COCAINE IV SELF-ADMINISTRATION

9. Social defeat in mice: ETHANOL
Social stress and Ethanol
Oral ethanol self-administration
Rodríguez-Arias et al., 2014

10. Social defeat in mice: ETHANOL
Oral ethanol self-administration *
Rodríguez-Arias et al., 2014

11. Social defeat in mice: ETHANOL
Ethanol-induced CPP

12. NEUROINFLAMATION REWARD SOCIAL STRESS COCAINE ETHANOL DA SYSTEM
GLUTAMATE
NEUROINFLAMATION
EPIGENETICS
CRF

13. Neuroinflamation Increases Rewarding effect cocaine / ethanol
Social defeat
Neuroinflamation

14. BLOOD BRAIN BARRIER (BBB)
BBB dysfunction has been associated with several neurological disorders as multiple sclerosis or Parkinson and Alzheimer disease
Methamphetamine or MDMA administration also alter the integrity of BBB

15. BBB NUCLEUS ACCUMBENS (comparable results in hippocampus)
Rodríguez-Arias et al., 2017 Addiction Biology

16. BBB NUCLEUS ACCUMBENS (comparable results in hippocampus)
Rodríguez-Arias et al., 2017 Addiction Biology

17. NI BBB Social stress-induced NI response CYTOKINES
Pfau an dRusso, 2015)

18. Il-6 plasma Il-6 striatum Social stress-induced NI response
(comparable results in hippocampus and cortex)

19. Il-6 plasma after cocaine-induced CPP
Social stress-induced NI response
Il-6 plasma after cocaine-induced CPP
***

20. CX3CL1 striatum CHEMOKINES: CX3CL1 (Fractalkine)
Social stress-induced NI response
CHEMOKINES: CX3CL1 (Fractalkine)
CX3CL1 striatum
(comparable results in hippocampus and cortex)

21. Social stress-induced NI response
CX3CL1 striatum after ethanol oral self-administration *

22. Cocaine-induced CPP 1 mg/kg
Social stress-induced NI response
Cocaine-induced CPP 1 mg/kg
INDOMETACINE

23. Social stress-induced NI response
Ethanol oral self-administration

24. HETEROGENEOUS RESPONSE
RSD
INCREASE REWARDING EFFECT

25. (Finnell y Wood, 2016)

26. Resilient: social behavior
NI response in Resilient / susceptible subjects
Resilient: social behavior
20 min after RSD
Previous levels 26
Hodes et al., 2014

27. NI response in Resilient / susceptible subjects
RSD induced increase in the rewarding effects of cocaine *

28. NI response in Resilient / susceptible subjects
RSD induced increase in the rewarding effects of cocaine *

29. RSD RESILIENT SUSCEPTIBLE Increase rewarding effects cocaine / ethanol
Higher levels of NI mediators
RESILIENT
NO changes rewarding effects cocaine / ethanol
Lower levels of NI mediators

30. NI response mediates these social stress effects
Social stress induces long-lasting increase in the rewarding effects of cocaine and ethanol
NI response mediates these social stress effects
There is an heterogeneous response: susceptible and resilient subjects
Levels of peripheral NI mediators (e.g. cytoquines) can be a useful biomarker of susceptible individuals exposed to social stress

31. Dr. Marta Rodríguez Arias
Ministerio de Economía y Competitividad (MINECO), Dirección General de Investigación [grant number PSI R].
Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) RD12/0028/0005 y RD16/0017/0007 and Unión Europea, Fondos FEDER “una manera de hacer Europa”
Dr. Marta Rodríguez Arias
Universitat de València