The dark side of addiction: How addictive drugs alleviate

symptoms of stress & depression

Robert HenningSulandy Reuter

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/

Davis et al (2008); Major depression and comorbid substance use disorders

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

Similarities between chronic stress and depression

Blackburn-Munro (2001)

Blackburn-Munro (2001)

Depression = dysregulation of the stress response (Gold et al. (2015)

Wong (1999)

Trestman (1990)

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

The brain reward system

Russo (2013); Nature

Cocaine &

amphetamines

Opioids

Alcohol Cannabinoids Nicotine

Glucocorticoids (Koob 2000)

Russo (2013); Nature

Markou 1998

Barr (2002)

Withdrawal

Depression

Barr (2002)

Dysregulated brain-reward system

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

• Leading to a state of “allostasis”

Cycle of drug abuse

Sinha, 2001

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

Wouldn't’t the activation of the HPA axis lead to more anxiety-like symptoms and stress?

“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

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)

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

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

Nestler, E.J. 2005. Science & Practice perspectives

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

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

• 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

In vivo model of stressor & cocaine relapse

Study design

Li & Kirby. 2016 European Neuropsychopharmacology

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)

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

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

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

Cannabis and pain

Nahas et al. 2012. Progress in Neuro-Psychopharmacology & Biological Psychiatry

Cannabis and depression in vivo• Male Wistar rats subjected to forced swimming tests

Réus et al. 2011. Acta Neuropsychiatrica

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.

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