Neurobiology of Addiction Ahmed Albehairy, M.D Psychiatry Consultant, MOHE
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.
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
vulnerabilityThere are different influences ofenvironmental versus genetic factors onthe transition from initiation of drug use,to regular drug use to drug addiction/dependence ,and then potentially to relapse.
vulnerability Env.factors—100% of cases Genetic factors for addiction 30-60% Drug iduced effects with some genetic factors– 100% of casesMary etal., neurobiology of addiction, nature neuroscience, vol8, 1450-1457 ,november 2005
Vulnerability- Difficulties in studying , ?? Assessment of phenotype.- Impulsivity is relate to low 5HT level,- - Aggression ,depression and early alc. use.
VulnerabilityLoss 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.
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.
Neuroanatomical involvement in AddictionAcute, Chronic, Relapse phases ( habits, learning, conditioning, reinstatements , craving, ( & response to stress
Current opinion in pharmacology , 2005, neurobiology of craving, 2005, 5:9-19
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 .
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).
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.
Chronic Action of Drug AbuseCircuit 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.
Chronic Action of Drug AbuseCellular 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)
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 .