drifting into drug dependence & beyond

Alferdose HaririSaudi psychiatric board R2

western regionalamal hospital

Revised by & Special thanks to Dr. Samara Mansour

Objectives

1-What is the Neuroanatomy & neurophysiology of the REWARD PATHWAY & why is it important to know

?2-what is the mechanisms of action of substances ? 3-What make people vulnerable for drug dependence

?4-What is the Pathophysiology of relapse ?

5-What are the Consequences of drug dependency ? Mcqs

Reward1-natural rewards

feelings of wellbeing to prevent Aversive stimuli

   a-Hunger > food    b-Solitary & Lonely >Social interaction > Praise &

touch    c-Extinction >reproduction

>>Hunger  & Extinction = death & the end of human being

Catatonia ?? 

2-Artificial reward A-DrugsB-Pathological behavior as gambling

the intrinsic purpose of an endogenous reward center is to reinforce behaviors that promote the survival of a species.   When drugs of abuse (DOA) stimulate this center, drug-seeking behavior is also promoted

The Neuroanatomy of Reward Pathway

1-ventral tegmental area (VTA ) 2-limbic system> mesolimbic system

NA hippocampus & amygdala

hypothalamus ACG

3-striatum :ventral caudate nucleus & putamen

4-prefrontal cortex (PFC ) >  mesocortical pathway

So , why to be concerned!!??

1-VTA DA neurons , tegmentum = “covering which mediate rewardN.B :Nigra strata > mediate motor

2-Limbic systemA-nucleus accumbens (NA)

important structure of the reward pathway as drugs of abuse target itInvolved in motivation , learning & reinforcement

B-Hippocampus: acquisition of new factual information and the formation

of new memories about personally experienced eventsCannabis & amnesia??

C-Amygdalaimplicated in the acquisition, storage, expression of emotional memories the amygdala is often activated outside of conscious awareness. Upon stimulation of it , inducing a desire, or wanting, for additional drug due to reward value to stimuli. Flashback?.

D-The hypothalamus a major integrative circuit between

the autonomic nervous & endocrine systems , as it express endocrine & motor component of emotionIt regulate circadian rhythm or basic drives Intoxication or withdrawal & v/s

changes??  

E-Anterior cingulate gyrusis involved in emotional self-control, cognitive function including

focused problem-solving error detection

performance monitoring detection of processing conflicts, but is influenced by

both motivation and affective state.

)NA (is connected by the median forebrain bundle (MFB) to the (VTA), the hypothalamus and the amygdala.

Experiments demonstrate that when this “power line” is cut ,

animals will decrease or stop self-administration of drugs  .

Thus, an intact MFB appears to be necessary for the “brain reward” system to function

properly .

MCQ 30-year-old man who has had many negative life experiences becomes upset

when he sees photographs of himself taken during these times. The brain area mostlikely to be activated by these photographs is the

)A (dorsolateral pre frontal cortex (B) hypothalamus(C) orbitofrontal cortex(D) reticular system(E) amygdala

3-Striatum involved in habit formation

Cognition > Attention , New learning & working memory .

4-prefrontal cortex

A-Dorsolateral prefrontal cortex (DLPFC):

Implicated in difficulties holding/maintaining several pieces of information “on line” or in short-term storage (i.e., “working memory”)It is crucial for the control and regulation of cognitive activities, including attention , sequencing events, planning and the selection of goals

B-Orbitofrontal cortex (OFC):

assessing the salience of potential rewards and punishments (immediate vs.

delayed gain)It assesses and decodes the likely value or behavioral relevance of available choices

of action and is therefore activated in decision making & impulse control

N.bThis lobe is critical In OCD also

Emotion vs cognition 1ry emotion > high DA > over ride higher cortical function as judgment & decision making  

N.b1ry emotion is the basic drives 2ry emotion as pride  These neuroadaptive responses remain engaged even in the absence of ongoing drug use and are thought to be a primary factor in drug relapse

MCQ

What is the major mechanism of action of cocaine on neurotransmitter systems in the brain?

)A (Blocks reuptake of dopamine(B) Blocks release of dopamine(C) Blocks reuptake of serotonin(D) Blocks release of serotonin

Neurophysiology

) 1 (DA does not, and of itself, induce “pleasure”

)2 (mesolimbic DA efflux increases not only in response to a reward, but also in anticipation of unexpected potential reward and during aversive statesaversive stimuli including foot shock & restraint stress , regardless of the motivational valence of the stimulus. With each repeated presentation of the stimulus, DA discharge lessens until the stimulus no longer produces a neuronal response.

GABA  

  Drugs of abuse (DOA) act on the GABA receptor to hyperpolarize neurons.  When a neuron is

hyperpolarized, it is inhibited from firing   .When neurons fire they release NT , and since drugs of abuse (DOA) inhibit these neurons, they release less GABA. The net result is disinhibition of dopaminergic neurons, making them fire more rapidly and releasing more dopamine in the reward

system  .N.BLower which include Alcohol , BNZ & barbiturates act on GABA

 Serotonin 

 is involved in the modulation of both drug self-administration and dopamine levels  .

Serotonin may be important in modulating motivational factors, or the amount of work an individual is willing to perform to obtain a drug.Also regulate mood, sleep , appetite , libido & impulse

control the relationship between serotonin and DA release is complex in that, serotonin has numerous receptor types and its regulation of DA release is at times inhibitory and at

other times excitatory.

Drugs effect on serotonin ??

Mechanisms of action

regarding NT 1-Some substances imitate NT

The more the similarities btw the substance to nt the more dependence occurs . Morphine, for example, binds to the receptors for endorphin ,while nicotine binds to

the receptors for acetylcholine .

2-Other substances increase the release of NT

E.G methamphetamine

3-while other substances block Receptors , Transporter or catalyzing enzyme

Cocaine, for example, mainly block the reuptake of DA in the synapses

Mechanisms of Action

regarding RECEPTORSDrugs that bind with ligand-gated ion channel receptors

It release 2-10 times the amount of DA that natural rewards do  

alcohol cocaine

nicotine (agonists at nicotinic cholinergic receptors). phencyclidine (PCP) (blocks NMDA glutamate receptors)

Drugs that bind with G protein-coupled receptors

Opiates tetrahydrocannabinol (THC) .

amphetamine caffeine (an antagonist at striatal adenosine A2 receptors)

Anti-Reward system

Which include stress hormones & NT CRF , ACTH & CORTISOL

norepinephrine neuropeptide Y(NPY)

dynorphin

producing aversive or stress-like states .

MCQ30-year-old woman who is withdrawing from heroin shows intense anxiety,

increased pulse, elevated bp and a hand tremor .Her symptoms improve when she was given clonidine, an alpha-2-adrenergic receptor agonist .

The area(s) of the brain most likely to be involved in the improvement in this patient’s symptoms is

)A (right parietal lobe(B) basal ganglia(C) locus ceruleus(D) raphe nuclei

Clinical correlations

Studies either adoption or twin studies.

Adoption studies allow us to separate genetic and environmental factors  . The individuals are then compared to their biological parents  .In twin studies, identical and fraternal twins are compared .

-vulnerability1-vulnerability for drug use initiation

2-vulnerability for drug dependence

vulnerability for drug initiation

the basis for drug self-medicationIs disordered of

1-emotions 2-self-esteem 3-relationships

vulnerability for drug dependence

Estimation from twin and adoption studies give ranges of 40% to 60% heritability as predisposing factorTwin studies showed that alcohol & nicotine dependence has strong genetic predisposition + parent being role model

Early experiences as it can permanently altered gene expression , synapses formation & cause

epigenetic changes

Relapse The mechanisms underlying relapse is:

-compulsive drive states, considered as

four brain pathways, each mediating a distinct relapse trigger.

How to prevent it  ??

1-priming The abstinent, addicted brain is subsequently primed to return to drug use when triggered by a single use of drug as its the most potent stimulus to renew drug use

Stimulation of D2 receptors in the NAc induces drug-triggered relapse, whereas psychotropic that stimulate D1 receptors block drug-triggered relapseThis is due to that D2 receptors act on inhibitory G proteins that reduce cAMP production

2-cue-induced reinstatement routinely observed in the clinical setting, prompting the admonition for drug dependents patients to avoid the “people, places, and things” that have been associated with their drug use.repeated use of drugs strengthens both stimulus-response and stimulus-reward associations, thus sensitizing the mesolimbic pathway and internally linking the association between the substance and its associated drug cues

& craving .

3-Craving

The compulsive drive toward drug use is complemented by deficit in inhibitory restraint as impulse control & decision making 2ry to Lesions of the OFC synaptic

plasticity & stimulus-reward associations . Person become concern about drugs more than his essential needs as his reasoning & judgment got impaired not due to underlying psychosis but his PFC got affected

Drugs that act on craving??

4-stress-induced reinstatement.Stress increases the self-administration of drugs of abuseRelease of stress by drugs as gush of DA occurred> relief Drugs affect emotion regulation as it down regulate Receptors (hide) >no more euphoria as before > so he take drugs to only feel normal & he need to overdose to feel the desired euphoria

Stress management??     

Consequences

1-Alter Gene expression

Chronic use of drugs will through dysregulation of intracellular signaling cascades, leads to the dysregulation of specific transcription factors which causes changes in histone acetylation and even DNA methylation

2-Alter synaptic plasticity

• Addictive drugs induce long-term neuroadaptations at the structural, cellular, molecular, and genomic levels .

• Coincident activation of DA D1 receptors and glutamate NMDA receptors plays a critical role in shaping synaptic configurations and neural ensembles which was supposed to release more NT >>decline in cognitive function ??

N.b• Synapses are mainly formed during 1st 2 y of life

& during adolescent years

3- TRANSITION from Homeostasis to Allostasis

Allostatic load is the consequence of repeated deviations from homeostasis that take on the form of changed set points that require increasing amounts of energy to defend, and ultimately reach, the level of pathologyAll drugs of abuse produce elevation in brain reward thresholds during acute withdrawal & lowering stress axis tone

Figure modified with permission from Koob & Le Moal (2006)

Evidence by PET scan

References

Synopsis Kaplan & sadockhttp://ibgwww.colorado.edu/cadd/a_drug/essays/essay4.htm

https://www.drugabuse.gov/publications/drugs-brains-behavior-science-addiction/drugs-brain

www.annualreviews.org AddictionandtheBrainAntirewardSystemBarbra behavioral scienceDescriptive psychopathology

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1920543/pdf/nihms17876.pdf