Stress Physiology_Addiction Presentation
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The dark side of addiction: How addictive drugs alleviate
symptoms of stress & depression
Robert HenningSulandy Reuter
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Prevalence of Depression• Estimated 350 million
people of all ages suffer from depression globally• Is the leading cause of
disability worldwide• Major contributor to the
overall global burden of disease.
http://www.who.int/mediacentre/factsheets/fs369/en/
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Davis et al (2008); Major depression and comorbid substance use disorders
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Symptoms of Depression• Symptoms persist for a long time
• Low mood• Feelings of guilt• Worthlessness• Suicidal thought• Loss of libido• Loss of interest in hobbies, friends, family• Sleep disturbances• Alterations of eating habits• Physical signs (worry, anxiety)
• Stress is often a precipitating factor in the onset and severity of depression (Russo et al., 2013)
Brian E Lennard:Psychopharmacology of Depression; Henry Stewart Talks
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Similarities between chronic stress and depression
Blackburn-Munro (2001)
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Blackburn-Munro (2001)
Depression = dysregulation of the stress response (Gold et al. (2015)
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Wong (1999)
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Trestman (1990)
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What is addiction? • Chronic, relapsing disorder that has
been characterized by • (i) a compulsion to seek and take
drugs, • (ii) loss of control over drug intake,
and • (iii) emergence of a negative
emotional state (e.g., dysphoria, anxiety, and irritability) that defines a motivational withdrawal syndrome when access to the drug is prevented
http://journal.frontiersin.org/article/10.3389/fpsyt.2013.00072/full
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The brain reward system
Russo (2013); Nature
Cocaine &
amphetamines
Opioids
Alcohol Cannabinoids Nicotine
Glucocorticoids (Koob 2000)
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Russo (2013); Nature
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Markou 1998
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Barr (2002)
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Withdrawal
Depression
Barr (2002)
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Dysregulated brain-reward system
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Drug dependence
Koob G et al. (2013)
• Neuroadaptations resulting from repeated drug use that have important motivational consequences in terms of determining the organization of the organisms behaviour
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• Leading to a state of “allostasis”
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Cycle of drug abuse
Sinha, 2001
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Activation of the HPA-axis by cocaine• Acute cocaine administration increases plasma ACTH, B-endorphin,
corticosterone (rats) and cortisol (non-human primates).• Mediated by the cocaine-induced CRH release from perivocellular
neurons in the paraventricular nucleus.• Acute cocaine administration increases secretion of cortisol and ACTH
in chronic cocaine users.• Clearly cocaine itself stimulates many of the same neurochemical and
hormonal systems also activated by exposure to stress.
Goeders 2002
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Wouldn't’t the activation of the HPA axis lead to more anxiety-like symptoms and stress?
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“Rather than producing an aversive anxiogenic response, this controlled activation of the HPA axis may result in the
production of an internal state of arousal or stimulation that is actually sought by the animal. This internal state may be analogous to novelty or sensation seeking that has been
reported in humans (e.g., thrill seekers) and suggested to be involved in drug reward.”
Goeders 2002
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The role of glucocorticoids in addiction• Primary role could be to `energize' goal directed behaviours. • Activation of glucocorticoids during stress could thus be a secondary compensatory response
which would reduce the aversive effects of stress and thus increase coping capacities. • In fact, glucocorticoids are not only activated by stress, but their secretion also precedes many
goal-directed behaviors and in particular food seeking • The action of glucocorticoid hormones in the periphery is not part of the primary response to
stress but a way for the organism to protect itself form the primary responses to stress (increased lipolysis, gluconeogenisis, anti-inflammation)
• During chronic stress the repeated increase in glucocorticoid hormones and dopamine would compensate for the aversive effects of acute stress, but could also result in sensitization of the reward system.
• This would render the subject more responsive to drugs of abuse and consequently more vulnerable to the development of addiction.
Marinelli et al., (2002)
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Cocaine in the brain…• Why cocaine seems like a way out: DOPAMINE• Dopamine acts as “pacesetter” for nerve cells • Binds to dopamine transporters – buildup • Dopamine transporters concentrated in limbic system• Nucleus accumbens (Nac) most important
• Various affects: • short term• several weeks• months, years or irreversible
Nestler, E.J. 2005. Science & Practice perspectives
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Effects of cocaine• Short term: dopamine buildup
• Powerful, intense feeling of pleasure• Imprint of feeling on memories
• Intermediate term:• Alter amount of dopamine transporters/ receptors• Gene expression in limbic system – transition to addiction?
• Long term: changes in nerve cell structure• Chronic usage – Nac neurons extend and increase dendrite
input signals• Limbic system more control?
Nestler, E.J. 2005. Science & Practice perspectives
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Nestler, E.J. 2005. Science & Practice perspectives
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Cocaine induces neuronal cell death • PC12 dopaminergic neuronal model• Cocaine increases DNA fragmentation
in a time-dependent manner • Cocaine increases cleavage of caspase 3
Lepsch et al. 2009. Molecular Brain
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Possible link between cocaine and stress?• Influence of corticosterone on cocaine self-administration• Rats adrenalectomized (sham controls)• Subgroups of adrenalectomized receive corticosterone supplementation • Choice of 2 holes: active (dispensing intravenous cocaine) or inactive
Derosche et al. 1997. The Journal of Pharmacology and Experimental Therapeutics
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• Influence of corticosterone on reinstatement of cocaine self-administration• Corticosterone dose-dependently increased the number of nose-pokes only in
the active hole (inverted U shape)
Derosche et al. 1997. The Journal of Pharmacology and Experimental Therapeutics
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In vivo model of stressor & cocaine relapse
Study design
Li & Kirby. 2016 European Neuropsychopharmacology
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Results showed that pre-treatment with the CRF1 receptor antagonist antalarmin (20 mg/kg) blocked resumption of lever pressing suggesting that the CRF1 receptor is involved in the reinstatement to alcohol
seeking in the cue-induced relapse model.
Galesi et al (2016)
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Hypothesis: Chronic ‘binge’ cocaine administration may serve as a chronic pharmacological stressor leading to a hyperactivity of the stress-responsive hypothalamic- pituitary-adrenal (HPA) axis and
alterations in its feedback mechanisms
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Cannabis• One of the most widely abused substances throughout the
world• Primary psychoactive ingredient: delta 9-
tetrahydrocannabinol• Bind to cannabinoid receptors (CB1 and CB2) to exert effect• Behavioural effects: euphoria, relaxation, altered time
perception, lack of concentration• Physiological changes: change in heart rate and blood
pressure, vasodilation, ↑ appetite and thirst, ↓ respiratory rate
Sharma et al. 2012. Iranian Journal of Psychiatry
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Effects of cannabis• Analgesic effects: antinociceptor?• Acute pain: opium-endorphin system, euphoria• Inflammatory pain: inhibition of COX-2 and prostaglandin• Anesthetic action: increase effectiveness of sedation• Antiemetic effects: alleviate nausea• Antiglaucoma effects: reduce pressure, decreasing prostaglandin?• Appetite stimulation: inconclusive
Nahas et al. 2012. Progress in Neuro-Psychopharmacology & Biological Psychiatry
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Cannabis and pain
Nahas et al. 2012. Progress in Neuro-Psychopharmacology & Biological Psychiatry
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Cannabis and depression in vivo• Male Wistar rats subjected to forced swimming tests
Réus et al. 2011. Acta Neuropsychiatrica
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In conclusion…• Chronic stress and depression result in a dysregulated HPA-axis• Stress increases vulnerability to drug abuse (Sinha, 2001)• CRF antagonist antalarmin significantly reduced addictive-like behaviors in rats
(Galesi 2016)• Most common drugs (nicotine, cocaine, amphetamines, opiates, marijuana)
stimulate brain reward pathways as well as activating the stress system (Sinha 2001).• Activation of the stress system increases dopaminergic neurotransmission in brain
reward pathways.• Long-term drug abuse leads to HPA-axis dysregulation as well as neuroadaptations in
the mesolimbic dopaminergis system (Sinha, 2001)• This leads to an allostatic state and addiction.
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References• http://www.who.int/mediacentre/factsheets/fs369/en/• Koob G; Addiction is a reward deficit and stress surfeit disorder; Psychiatry (2013)• Galesi FL et al.; Role of Hypothalamic-Pituitary-Adrenal axis and Corticotropin-Releasing Factor stress system on cue-
induced relapse to alcohol seeking; European journal of pharmacology (2016) 788:84-89.• Markau A et al.; Neurobiological similarities in depression and drug dependence: a self-medication hypothesis.
Neuropsychopharmacology (1998) 18:135-174 • Barr A et al.; A ‘crash’ course on psychostimulant withdrawal as a model of depression; TRENDS in Pharmacological
Sciences (2002) 23:10 • Gold PW, Chrousos GP; Organization of the stress system and its dysregulation in melancholic and atypical depression:
high vs low CRH/NE states; Molecular Psychiatry (2002) 7: 254-275• Sinha R; How does stress increase risk of drug abuse and relapse? Psychopharmacology (2001) 158:343-359• Sarnyai Z et al.; Neuroendocrine-Related Effects of Long-Term, ‘Binge’ Cocaine Administration: Diminished Individual
Differences in Stress-Induced Corticosterone Response; Endocrinology (1998) 68:334-344• Piazza PV et a;.; Glucocorticoids as a biological substrate of reward: physiological and pathophysiological implications;
Brain circuit reviews (2015) 25:359-372• Koob G et al.; Drug Addiction, Dysregulation of Reward, and Allostasis; Neuropsychopharamcaology (2000) 24