Neurophysiology of Addiction

7/30/2019 Neurophysiology of Addiction

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Neurophysiology of AddictionDr. Shivan A. C. Mahabir

DM. Psychiatry

Part 1, Year 1



Motivation and Addiction

motivation

appetitive

aversive

a loss of flexibility and the disability to make free

decisions, i.e., extreme control of behavior, as

described in addiction, may be seen as one of the distinguishing features between

pleasure/reward and addiction. This addiction-

related behavioral inflexibility and the

impossibility of normal rewards to govern

behavior may be called motivational toxicity



Anatomy

VTA -> nucleus accumbens[mesolimbic dopamine system] –

rheostat of reward

Amygdala – assessment of appetitive/aversive

◦ Association with cues

Hippocampus – memories [limbicsystem]

Frontal cortex – integrates and

processes all information and



Dopamine

Main neurotransmitter involved inreward/addiction

Cocaine/amphetamine – block

reuptake of dopamine

Heroin/opiates – act to block inhibitory

neurons on the presynaptic terminal

so more dopamine released. Opiatesalso act directly on nucleus

accumbens to give strong reward

signal.



Glutamate

When drugs of abuse increase dopamine release from the VTA intothe nucleus accumbens, they also alter the responsiveness of theVTA and nucleus accumbens to glutamate for days.

Animal experiments indicate that changes in sensitivity toglutamate in the reward pathway enhance both the release of dopamine from the VTA and responsiveness to dopamine in thenucleus accumbens, thereby promoting CREB and delta FosB

activity it seems that this altered glutamate sensitivity strengthens the

neuronal pathways that link memories of drug-takingexperiences with high reward, thereby feeding the desire to seekthe drug.

long-term potentiation, helps memories to form and appears to bemediated by the shuttling of certain glutamate-binding receptor proteins from intracellular stores, where they are not functional,to the nerve cell membrane, where they can respond to glutamatereleased into a synapse. Drugs of abuse influence the shuttling of glutamate receptors in the reward pathway. Some findings suggestthat they can also influence the synthesis of certain glutamatereceptors.



CREB

When dopamine concentrations in the nucleus accumbensrise, dopamine responsive cells increase production of a

small signaling molecule, cAMP which activates CREB.

Chronic drug use causes sustained activation of CREB,

which controls the production of dynorphin, a naturalmolecule with opium-like effects which dampens the

reward circuitry.

Dynorphin is synthesized by a subset of neurons in the

nucleus accumbens that loop back and inhibit neurons in

the VTA. Induction of dynorphin by CREB therebystifles the brain's reward circuitry, inducing tolerance

by making the same-old dose of drug less rewarding.

The increase in dynorphin also contributes to

dependence, as its inhibition of the reward pathway

leaves the individual, in the drug's absence,



Delta Fos-B

in response to chronic drug abuse, delta FosBconcentrations rise gradually and progressively inthe nucleus accumbens and other brain regions.

Because the protein is extraordinarily stable, itremains active in these nerve cells for weeks to

months after drug administration, a persistencethat would enable it to maintain changes in geneexpression long after drug taking ceased.

Prolonged induction of this molecule causesanimals to become hypersensitive to drugs and

highly prone to relapse It might have a more general role in the

development of compulsive behavior toward awide range of rewarding stimuli.



Synaptic Changes

Chronic exposure to cocaine and other drugs of abuse is known to induce the signal-receivingbranches of nucleus accumbens neurons tosprout additional buds, termed dendritic spines,that bolster the cells' connections to other

neurons. Delta FosB may be responsible for the added

spines.

The extra connections generated by delta FosBactivity amplify signaling between the linked cells

for years and that such heightened signalingmight cause the brain to overreact to drug-related cues. The dendritic changes may, in theend, be the key adaptation that accounts for theintransigence of addiction.



Tolerance and Dependence

During prolonged drug use, and shortly after useceases, changes in the concentrations of cyclicAMP and the activity of CREB in neurons in thereward pathway predominate. These alterationscause tolerance and dependence, reducing

sensitivity to the drug and rendering theaddict depressed and lacking motivation.

With more prolonged abstention, changes indelta FosB activity and glutamate signalingpredominate. These actions seem to be the ones

that draw an addict back for more--by increasingsensitivity to the drug's effects if it is used againafter a lapse and by eliciting powerfulresponses to memories of past highs and tocues that bring those memories to mind.



Points to note

Drug withdrawal is associated with negative affect and‘dysregulation’ of reward pathways, i.e., functionalneurotoxicity .

Not only substances are addictive – also gambling,overeating, sexual and internet addictions.

Moreover, relapse vulnerability associated with functional

neurotoxicity may be enhanced during acute and chronicstress [6]. The latter may be due to the fact that stressinduces pleasure-seeking behavior, and during times of stress, the imaginable pleasure of initial drug use (and other positive cues related to drug consumption) is not forgotten.Stressful stimuli and/or exposure to low drug doses – as wellas drug-associated cues – possibly trigger craving, andfurther, they may send addicts directly back to relapse[15,16]. While pleasure, in general, is capable of reducingstress or inducing stress relieving behavior, this usefulstrategy may turn out to be detrimental and facilitate addictionin the end [



References

Principles of Neural Science 4th Ed.Eric KandelChapter 51: Motivational and AddictiveStates

Nestler EJ, Malenka RC. The addictedbrain. Sci Am 2004; 290:78 –85.

Esch T, Stefano GB. The neurobiology of pleasure, reward processes, addictionand their health implications.Neuroendocrinology Letters 2004;

25(4) :235 –251

Neurophysiology of Addiction

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