Drug Addiction

Mohsin Aziz 1

DRUG ADDICTION

Mohsin Aziz 2

Mohsin Aziz

BSc., Pharm.D, RPh.

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Definitions:

Drug Abuse:• Drug abuse is any recurrent use of drug that is

illegal or causes harm to individual.• Using a drug as a habit• Use of a drug to an extent that it produces

impairment of social, psychological or physiological functioning.

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Tolerance: Reduction in pharmacological effects on repeated administration of drug, requiring escalation of dose to maintain same effects. Physical Dependence: The state of response to a drug whereby removal of the drug evokes unpleasant symptoms, usually the opposite of drug effects.

Definitions:

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Withdrawal Symptoms ( Abstinence

Syndrome) :• Signs and symptoms that follows the abrupt

discontinuation or reduction in the use of a substance or after blockage of the actions of a substance with antagonists.

• Tend to be opposite to original effects of drug.• Evidence of physical or psychological

dependence.

Definitions:

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Psychological Dependence: The state of response to a drug whereby the drug taker feels compelled to use the drug and suffers anxiety if doesn’t take drug. Reinforcement: Refers to the capacity of drugs to produce Hedonic (pleasureable) effects that make user wish to take them again. (Reward of Drug)

Definitions:

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Drug Addicition : Drug addiction is a chronic, relapsing disorder in which compulsive drug-seeking and drug-taking behavior persists despite serious negative consequences. The Stages of Addiction• Exposure• Compulsion• Loss of control

Definitions:

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How does a brain become addicted….???

• A person takes a drug of abuse.• Drug activates the same brain circuits as do behaviors

linked to survival, such as eating, bonding and sex. • The drug causes a surge in levels of a brain chemical

called dopamine, which results in feelings of pleasure. The brain remembers this pleasure and wants it repeated.

• Just as food is linked to survival in day-to-day living, drugs begin to take on the same significance for the addict. The need to obtain and take drugs becomes more important than any other need, including truly vital behaviors like eating. The addict no longer seeks the drug for pleasure, but for relieving distress.

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How does a brain become addicted….???

Acutely, addictive drugs are both • rewarding (i.e., interpreted by the brain as intrinsically

positive) and • reinforcing (i.e.,behaviors associated with drug use

tend to be repeated). • With repeated use, however, addictive drugs produce

molecular changes that, within a vulnerable brain, promote continued drug-taking behavior in a manner that becomes increasingly difficult to control. The central feature of addiction is compulsive drug use—the loss of control over the apparently voluntary acts of drug seeking and drug taking.

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Why do some people become addict while others do not………???????????

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Biochemical Mechanism Of Drug

Addiction

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Where Drugs Act

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• ventral tegmental area (VTA) • (lateral) hypothalamus (LH) • nucleus accumbens (NAc) • frontal cortex (FC) - key portions - prefrontal cortex (pfc) - orbitofrontal cortex (ofc)

Medial Forebrain Bundle

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Dopaminergic Mesolimbic Pathway

A prevailing view is that the primary brain circuits relevant to drug addiction (responsible for activation of neurochemical reward pathways) involve dopaminergic mesolimbic pathways.

The mesolimbic dopamine system extends from dopamine (DA)1 -containing cell bodies within the ventral tegmental area (VTA) in brainstem to the nucleus accumbens (NuAcc) (part of the basal ganglia), prefrontal cortex and amygdala.

The hypothesis is that many abused substances (except the benzodiazepines) enhance dopamine release in

• nucleus accumbens or • prefrontal cortex or both.(Ó 2000 Blackwell Science Ltd, Journal of Clinical Pharmacy and Therapeutics, 25.)

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Cocaine, for example, The primary mechanism of action believed to be related to its misuse is the inhibition of the dopamine transporter, which is responsible for the reuptake of dopamine into the presynaptic nerve terminal. Inhibition of the dopamine transporter (DAT) increases the synaptic concentrations of dopamine, enabling more activation of DA receptors.

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Effects of Drugs on Dopamine Release

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Natural Rewards Elevate Dopamine Levels

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NEUROCHEMICAL REWARD PATHWAY• The mesolimbic dopamine system, including

its projections to the nucleus accumbens, and local GABAergic afferents, has been most clearly associated with the habit-forming aspects of drugs of abuse.

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ANTI-REWARD SYSTEMS• Negative reinforcement (in the form of

dysphoric affective and physical withdrawal symptoms) plays an important.

• Hence, cessation of drug-taking results in physical and affective motivation to take drug again and again.

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Effets of chronic Drug Use• Studies have showed that chronic

administration of drugs of abuse, among many other changes, induces higher levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine synthesis.

• Chronic drug exposure causes:

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• decreased levels of neurofilament (NF) proteins (major structural determinants of neurons)

• increased glial fibrillary acidic protein (GFAP), which are major structural determinants of glia within the VTA.

• Together, these neuroadaptations identified in the VTA are suggestive of a state of neuronal injury

• reductions in NF proteins in the VTA might result in reductions in the caliber of the neuronal processes and possibly an overall decrease in their size.

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Biochemical

Mechanism of Drug Addiction

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Since each addictive drug has a specific molecular

target to activate mesolimbic system,

Three classes can be distinguished:

First Group,binds Gio-coupled receptors,eg.,Opioids,Canbinoids,LSD etc.

Second group,binds to Ion Channels,eg.,Nicotine,Alcohol,BZD.

Third group,binds to transporters of biogenic amines,eg.,Cocaine,amphetamine

Mechanism Of drug Addiction

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The Common Signaling Pathway of All these drugs is:


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Activation Of Dopamine receptors D1 D5

Activation of G Protien Gs

Activation of Adenyl Cyclase

AC converts ATP into cAMP

Causes phosphorylation of cAMP dependent Protein Kinase A,DARPP-32 ( 32kDa-Dopamine and cAMP regulated Phosphoprotein)

This phosphorylated DARPP-32 act as an inhibitor of Protein Phosphatase(dec. cAMP) such as protein phosphatase-1 and Calcineurin


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Thus acting parallel to PK and Inc Phosphorylation

An amplifying mechanism.

On chronc administration these drugs inc, activity of AC in nAcc;

Morphine,for example, dec. AC

Dec. in AC leads to secondary rise in AC expression

Inc. AC exp. Leads to tolerance

On cessation of morphine excessive cAMP production occurs (withdrawal Symptoms)


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Chronic treatment inc. amount of not only AC itself but also of other components of signaling pathways i.e. G proteins and various PKs.

This inc. in cAMP leads to inc. in cAMP dep. PKs which control the activity of :

Ion channels (making cells more excitable)

Various Enzymes

Transcription factors ( particularly cAMP response element-binding protein CREB is upregulated in nAcc)

CREB plays Key role in var. cAMP sig. pathways.


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And After all these changes what

Happens………????????

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H.P RANG, et al.RANG AND DALE’S Pharmacology.6th edition.Churchill livingstone.2007

Betram G. KATZUNG.Basic and Clinincal Pharmacology.10th edition.Mc Graw Hill.2007

Goodman & Gillman’s Manual of Pharmacology and Therapeautics.Laurence L.Brunton, Keith L.Parker edis.Mc Graw Hill.USA.2008

Jennifer Chao and Eric J. Nestler. MOLECULAR NEUROBIOLOGY OF DRUG ADDICTION. Department of Psychiatry and Center for Basic Neuroscience, The University of Texas,Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas.2004

Robinson TE, Berridge KC. 2003. Addiction.Annu. Rev. Psychol. 54:25–53 Koob GF, Le Moal M. 2001. Drug addiction,dysregulation of reward, and

allostasis.Neuropsychopharmacology 24:97–129 Nestler EJ, Aghajanian GK. 1997. Molecular and cellular basis of addiction. Science 278:58–63 Nestler EJ. 2001. Molecular basis of longterm plasticity underlying addiction. Nat. Rev. Neurosci. 2:119–28 Foote SL, Bloom FE, Aston-Jones G.1983. Nucleus locus ceruleus: new evidence of

anatomical and physiological specificity. Physiol. Rev. 63:844–914

REFERENCES

Drug Addiction

Health & Medicine

Transcript of Drug Addiction