1. Neurobiology of Addiction
Ahmed Albehairy, M.D
Psychiatry Consultant, MOHE

2. A Story
Nurobiological
- Environment, Explanation:
vulnerability. -Genetic aspects.
- choice, decision
making.
- Pleasure & reward. - Neuroanatomical
- Motivation. regions related to the
- Acute abuse. functions.
- Learning,
Conditioning &
reinforcement.
- Compulsive behavior. - Synaptic system:
- Chronic, regular use. NTS,
- Craving, with cues & receptors,
stress. Molecular changes
- Relapse neuroadaptation.
- Signal transduction,
chr. ,gene,& proteins.

3. vulnerability
- Vulnerability to develop a drug addiction is influenced
by a combination of genetic and environmental factors.
- Family & twin epidemiological studies show that genes
contribution in addiction reaches
up to 30 – 60 %.
- Most evident genes are those of ald dhgnze of alcohol
and genetic variance in opiate addiction.
Mary etal., neurobiology of addiction, nature neuroscience, vol8, 1450-1457 ,november 2005

4. vulnerability
There are different influences of
environmental versus genetic factors on
the transition from initiation of drug use,
to regular drug use to drug
addiction/dependence ,
and then potentially to relapse.

5. Vulnerability and personality traits

6. vulnerability
Env.factors—100% of cases
Genetic factors for addiction 30-60%
Drug iduced effects with some genetic factors–
100% of cases
Mary etal., neurobiology of addiction, nature neuroscience, vol8, 1450-1457
,november 2005

9. Vulnerability
- Difficulties in studying , ?? Assessment of phenotype.
- Impulsivity is relate to low 5HT level,
- - Aggression ,depression and early alc. use.

10. Vulnerability
Loss of impulse control , d.t impaired inhibition
effect of frontal cortex esp. in adolescence!!!,
neurodevelopment process and reproductive
hormones later in adolescence modulate
impulse of control.
HPA axis hporesposiveness is related to heroin
dependence,
HPA axis hperresponsiveness is related to
cocaine dependence.

11. Vulnerability
- 118G variant of u receptor had more favorable clinical response to
ttt of alc . By opoiod antagonist.
- Low activity of methionine is related to inc. risk of alc.
( COMT gene related).
- Short SERT gene promoter inc. depression and suicidal ideation.
- ALD1B,ALD1C,ALDH genes are protective against alcoholism.
- Low expression of MAOA gene in maltreated children inc. the
risk of developing ASPD , aggression.
- Risk taking , novelity seeking related to D2- D4 genes, ANKK
GENE.

12. Acute, Chronic, Relapse phases
of Addiction

13. Neuroanatomical involvement in
Addiction
Acute, Chronic, Relapse phases
( habits, learning, conditioning,
reinstatements , craving,
( & response to stress

15. Current opinion in pharmacology , 2005, neurobiology of craving, 2005, 5:9-19

17. Sex Differences in the Addiction Process
Drug abuse and addiction are problems often attributed tomen, -
.women are also clearly affected
- Women more susceptible to drug addiction than men.
- Women tend to use drugs more days, get addicted in less time, and
greater severity of abuse.
- women compared to men have higher levels of drug craving when
exposed to drug cues.
- Women have greater activation, in stress induced, of the inferior
frontal cortex, left insula, dorsal anterior cingulate cortex, and right
posterior cingulate cortex
- Women have greater activation of the anterior cingulate cortex, in
cues craving.
- Men have greater activation to cues craving of , the amygdala, insula,
ventral cingulate cortex, and orbitofrontal cortex .

18. Investigating Molecular Pathways
of addiction

30. Acute Action of Drug Abuse
- However the drugs of abuse has a desperate mechanisms of
action and pharmacological effects, all drugs of abuse cause a
common effect after acute and chronic exposure ( addiction).
- All drugs of abuse converge in a common circuity of the brain
limbic system, VTA-NAC pathway. ( activation of dopaminergic
transmission in the NAC And endogenous opoiod and
cannabinoid systems).

31. Acute Action of Drug Abuse
- Stimulant directly inc. dop.transmission in the NAC.
- Opiate indirecly inhibit GABergic neurons in VTA, disinhibit VTA
dop.neurons.----- inc dop transmission.
- Nicotine and alcohol stim, endogenous opoiod.
- Opiate stim . Endogenous cannabinoid.
- Nicotine stim . Directly VTA dop. directly via cholinergic receptors.
- Nicotine stim indirectly , by stim of nicotine receptors on glutametergic
receptors which innervate dopamine cells of VTA from AMYGDALA.
- Alcohol promote GABA A – inhibition of GABergic neurons in VTA, disinhibit
VTA dop.neurons.----- inc dop transmission.
- Alcohol inhibit GABA in NAC.
- Cannabinoid ++++ CB1on NAC,GABA & GLUTAMITERGIC receptors on NAC
- PCP inhib. Postsynaptic NMDA ( GLUTAMATE ) om NAC.
FINALLY ALL INC. DOPAMINE , CANNABINOID, OPOIOD.

33. Chronic Action of Drug Abuse
Circuit level adaptation:
Chronic exposure to drugs of abuse --- adaptation in dopamine functions.
- Impaired homeostatic response of dopamine:
- tolerance , negative emotional symptoms as dop. Dec.
- dec. level of dopamine transmission and normal reward respond .
- sensitization of dop. System , so craving for drugs, cue.
- changes in CRF Systems, CRF NEURONS IN AMYGDAL respond for
discontinued drug as withdrawel emotional and somatic sx.
- hypofrontality, dec control by glutametergic pathways from frontal
areas to VTA – NAC
- changes in glutametergic transmission from working memory,
attention and behav. Disinhibition, executive functions areas, -------
impulsivity, compulsivity and facilitate cues craving.

34. Chronic Action of Drug Abuse
Cellular and molecular adaptation:
Long term potentiation in VAT – NAC system.
- Hypersensitization ( craving, relapse) of VTA to dopamine due to
- +++ of glutamate receptors (GLuR1),inc TH, //inc CREB,(???)
- Changes in NAC, inc ΔFosB & Dec CREB( inc. beh response to drug),
- BDNF ( as long it accumelate it increase the incubation period of relapse).
- inc ΔFosB , arborization .( memory cues, craving )
- CRF gene functions r affected by inc CREB---Hyperactivity of CRF (response to
stress).
- Hypofrontality // inc in CREB, shif of D2 ( normal reward) TO D1 ( drug reward)
by inc in ASG3 , cystine-glutamate transporter
- , .( impulsivity & compulsivity)

36. A Hijacking of Neural Systems
Related to the Pursuit of Rewards
An explanation of addiction
• - long-term memories persist for many years or even a
lifetime .
From this point of view,
sensitized dopamine responses to drugs and drug cues
might lead to enhanced consolidation of drug-related
associative memories,
but the persistence of addiction would seem to be based
on the remodeling of synapses and circuits that are
thought to be characteristic of long-term associative
memory .

37. Thank you