Brain and BehaviourWeek 8 Lecture 2:

Addiction

Dr M J Morgan

Lesion/ imaging studies establish important brain circuits for specific behaviours.

But what of underlying neurobiological processes that mediate behaviour?

Pharmacology – BehaviourUnderstanding the mechanism of actions of drugs, provides information on underlying neural processes that control specific behaviours.

The natural reward system – hijacked by drugs of abuse

Mesocorticolimbic pathway: ventral tegmental area nucleus accumbens ventral tegmental area prefrontal cortex

Neurotransmitter - dopamine

PETSCAN

Where do drugs of abuse act?

Binding sites of cocaine following acute administration

Fowler et al (1989) Synapse 4: 371-377

Striatum:contains the

nucleus accumbens

How do we know this pathwayis involved in reward ?

Damage to the nucleus accumbens decreases self-administration of heroin.

Mesocorticolimbic pathway needed for drug to have a rewarding effect.

Control group

Damage to nucleus accumbens

ANIMAL STUDIES: self-administration model

Natural reinforcers (e.g. food and sex) increaseextracellular Dopamine in the Nucleus Accumbens

All known addictive drugs activate this system

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EmptyBox Feeding

Di Chiara et al.

FOOD

Drug of abuse Dopamine release

in the mesocorticolimbic

pathway

Sensation of rewardNatural

reward

Increased activation of

pathway

(dopamine levels measured by microdialysis)

Drugs of abuse maintain dopamine release in the nucleus accumbens shell after repeated exposure - hijack the reward pathway.

pre-exposed animalsnaïve animals

The mesocorticolimbic dopamine systemDopamine neurons projecting from ventral tegmental area (VTA) to nucleus accumbens (NAcc) and prefrontal cortex (PFC)Critical pathway for reward and reinforcement

mouse /rat

Natural reinforcers (e.g. food and sex) increase release of extracellular DA in Nacc

The mesocorticolimbic dopamine system

All known addictive drugs activate this system

Behaviours leading to activation tend to be repeated (are reinforced)

Blockade of DA in this region attenuates most measurable reinforcing and rewarding effects of addictive drugs

Activation by addictive drugs much more powerful and reliable than activation by natural reinforcers (they hijack the system)

Psychomotor stimulants - cocaine and amphetamine

Potentiate monoaminergic transmission by inhibition of dopamine (DA), serotonin (5-HT) and norepinephrine (NE) reuptake transporters

Cocaine blocks and inhibits transporter to prolong pool of extracellular DA

Amphetamine reverses transporter to increase extracellular DA levels

Action at dopamine transporter (DAT)most directly related to reinforcing effects

Cocaine and amphetamine extracellular DA in NAcc

Psychomotor stimulants - cocaine and amphetamine

Potentiate monoaminergic transmission by inhibition of dopamine (DA), serotonin (5-HT) and noradrenaline (NE) reuptake transporters

But subjective effects probably mediated by action of drugs at other sites:

Feelings of euphoria, speeding etc. through activation of this pathway or actions at transporters located elsewhere

In animal studies:DAT transporter knockouts still show some behavioural response to cocaine.Only triple knockout (DAT, SERT and NET) show no drug action

Extracellular 5-HT and NA

Opiates (e.g. morphine and heroin)Act at endogenous opioid receptors (Gi/Go coupled)

Inhibitory - decrease adenylyl cyclase activity- lead to open K+ channels, closed Na+ channels

Different subtypes on different cells in different brain regions (, , )

Most of morphine’s analgesic and rewarding properties are through actions at (mu) receptors

Subjective effects:

Euphoria and intense rush with heroin compared to morphine due to route of administration and entry to brain (seconds vs minutes)

Relaxing effects – inhibition of Noradrenergic pathways

Physical dependence – compensatory changes in these pathways (Week 7)

Opiates (e.g. morphine and heroin)

But also, as with other drugs of abuse also impact on function of the Dopaminergic reward pathways

Reward and reinforcement by:

a) Disinhibition of DA neurons in VTA (DA neurons fire tonically but are inhibted by GABA interneurons - receptor activation on GABA neurons inhibits them from firing - relieving inhibition on DA neurons

b) Action at opiate receptors in the NAcc - independent of DA release ( or )

DA independent action in NAcc

DA neuron firing

DA release in NAcc

Opiate action in VTA to increased DA releaseDisinhibition of DA neurons in VTA through inhibition of GABA interneuron

NAcc

Morphine acts at mu opioid receptor (inhibitory)

firingDANo inhibition

inhibition

Normal reward systemCortical control of VTA firing

PFC

NAcc

VTAglu GABA

Dopamine

VTA

Alcohol (EtOH)

- GABAA agonist (inhibitory)

-NMDA antagonist (blocks excitation)

- also affects glycine, nicotinic & serotonin receptors

- Large doses inhibit functioning of most voltage gated channels (sedation)

Subjective effects of EtOH

Low doses of alcohol - mild euphoria and anxiolytic effects

Higher doses - poor coordination, amnesia, sedation

Chronic alcoholism - Korsakoff’s Amnesia(caused by neurodegeneration – not an effect of alcohol itself but thiamine deficiency)

Alcohol (EtOH)

Effects on Reward Circuitry

1) EtOH leads to increased DA release in NAcc

NMDA antagonism of cortical inputs to VTA may lead to increased DA release in NAcc

1) Supression of cortical output2) No activation of GABA interneuron3) DA neuron disinhibited in VTA and able to fire

Ethanol rewarding effects blocked by DA receptor antagonists in NAcc

PFC

NAcc

firingNo excitation

No inhibitionfiringDA

alcohol

1

3

2

Alcohol (EtOH)

Effects on Reward Circuitry

2) Involvement of Opiate system

Naltrexone (an opiate antagonist)

- reduces EtOH self administration in animals

- used as a treatment to reduce EtOH consumption, relapse and craving in alcoholics

(DA independent effects on reward)

Nicotine

Action at nicotinic acetylcholine receptors (nAChRs)

-Ligand gated ion channels located pre or post-synaptically(present throughout brain, excitatory or

modulatory)

-Presynaptic receptors - influx of Ca2+ - transmitter release

Unlike cocaine and opiates - powerfully reinforcing in absence of subjective euphoria

Prolonged activation of nicotinic receptors leads to desensitization first cigarette of day – subjective response(rapid desensitization of receptors)subsequent cigarettes – less obvious reported effects(overnight – normalization of receptor state)

NicotineEffects on Reward Circuitry

Nicotine treatment increases DA release in the NAcc

Release of DA likely due to:

a) activation of ACh receptors on cell body in the VTA (increasing cell firing)

b) facilitation of DA release by pre-synaptic receptors in NAcc

Opiate system involvement

Both opiate and DA antagonists can block nicotine-induced behaviours and self administration

(Naltrexone is on trial as a drug to aid smoking cessation)

Presynaptic activity DA release

Postsynaptic activity

DA neuron firing

DA release in NAcc

Drugs

More DA release in the NAcc

Drug taking is reinforced

But how do we get addicted?

Natural rewards

DA release in the NAcc

Behaviours associated with stimuli are reinforced

We repeat those behaviours

Natural reward systems

Experiential – learn what, when and where rewards are likely.

Understanding actions of drugs of abuse – understand the reward system

Tolerance - diminishing effect of drug after repeated administration- need more drug to get the same effect

Dependence - physical or emotional - adaptive state- homeostatic response to repeated drug administration

- unmasked by withdrawal (e.g. heroin - cold turkey)

Sensitization - repeated administration elicits escalating effects- effect of psychostimulants (used in animal models)

Addiction - compulsive taking- craving and relapse - persistent for many years

HOMEOSTATIC -COMPENSATORY CHANGES

ASSOCIATIVE LEARNING PROCESSES

Physical dependence to opiates (Week 6 Lecture 2)

Chronic activation of opiate receptors leads to homeostatic mechanism that compensates for the functional changes leading to tolerance and physical dependence

Locus coeruleus neurons - activated by multiple pathways, ionotropic (e.g. glutamate) metabotropic (e.g. Gs coupled)

Acute morphine - acutely inhibits firing of LC neurons through Gi pathway

Chronic treatment - LC neurons return to their normal firing rates(Gs pathway component upregulate to match Gi)

Withdrawal - dramatic increase in LC firing(In absence of Gi inhibiton Gs hypersensitive)

Gs Gi

Gs

Gi

Gs Gi

Gi

Gs

Physical Dependence to alcohol

Acute effects of alcohol-agonist at GABAA receptor ( )-antagonist at NMDA receptor ( )

Cells inhibited from firing Cl- Na+

in

out

Cl- Cl-

Chronic alcoholDown regulation of GABAA receptorsUpregulation of NMDA receptors

In presence of alcohol firing ratesreturn to normal

Cl- Na+

in

out

Na+

Withdrawalin absence of alcoholbalance shifts to excitationphysical symptoms - agitation, tremors, hypertension, seizures Na+

in

out

Na+ Na+ Na+ Na+

Emotional Dependence (e.g. psychomotor stimulants)

- dysphoria, anhedonia, anxiety on withdrawal

Compensatory changes in VTA / NAcc to lower DA transmission:

Blockade of reuptake - too much DA in NAcc synapses

Compensatory change - less DA release in NAcc

In presence of drug - normal DA function in NAcc

In absence of drug - not enough DA for natural rewarding stimuli - anhedonia, dysphoria etc.

Emotional Dependence (e.g. psychomotor stimulants)Neurobiological explanation:

Increased activity at D1 receptors (Gs coupled) in NAcc

Adenylyl cyclase – cAMP - PKA activation

Phosporylation of CREB (transcription factor)

Increased dynorphin (DYN) synthesis (neuropeptide - endogenous opioid)

dynorphin released in VTAacts at Kappa opioid R

Inhibits VTA neuron firingand Nacc DA release

Less DA release in Nacc

Tolerance - diminishing effect of drug after repeated administration- need more drug to get the same effect

Dependence - physical or emotional - adaptive state- homeostatic response to repeated drug administration

- unmasked by withdrawal (e.g. heroin - cold turkey)

Sensitization - repeated administration elicits escalating effects- effect of psychostimulants (used in animal models)

Addiction - compulsive taking- craving and relapse - persistent for many years

HOMEOSTATIC -COMPENSATORY CHANGES

ASSOCIATIVE LEARNING PROCESSES