CH 9.4 (Psychopharm)

3 stage model

Development of addiction has been conceptualized as a repeating cycle

• helpful for understanding the neurobiology of addiction, including neural circuits and transmitters implicated in each

Preoccupation stage

Anticipation of obtaining and using the substance “rewarding”

Escalating use

Which for some substances results in drug binges and intoxications

Withdrawal

Associated negative effects after cessation of drug use

Reward circuit

Mediates the acute rewarding and reinforcing effects of most recreational drugs

• drugs will activate this differently

Mesolimbic DA pathway

From the VTA to the NAcc has a central role in reward circuit

• all recreational drugs activate this pathway

• Different location in the circuit have receptors for each type of addictive drug

Drug reward and reinforcement

Activation of the mesolimbic DA pathway from the VTA to the NAcc plays a central role in

• by enhancing VTA firing

• Increasing extracellular DA levels in the NAcc

Burst firing

What type of firing do abused drugs mimic?

D1 receptors

Receptors implicated in addiction/reward

Higher levels of DA needed to activate ______

• achieved during drug use bc large bursts of DA cause activation

D2 receptors

Have higher affinity for DA

Incentive sensitization theory of addiction

Distinction between liking (user moves to) versus wanting (motivates to seek) a reward

Incentive salience

Motivator for continued drug use

Dopaminergic system

Necessary for rewarding effects of psychostimulants, for other drugs, it contributes to reward, but is not required.

Endogenous opioid and cannabinoid systems

Other systems involved with drug reward and incentive salience drive the binge intoxication stage

Reward-prediction error

the difference between the reward an individual expects and the reward they actually receive

• DA neuronal firing may be to signal the difference between the prediction of receiving a reward and actual occurrence of the reward

Withdrawal/ negative affect stage

Is characterized by stress and the recruitment of an antireward system

Hyperkatifeia

Negative emotional state evoked by drug withdrawal

• proposed to be one of the core features of addictive disorders

• Occurs because brain rewires to use antireward system

• Does not depend on physical withdrawal symptoms

• Can be applied to wider range of drugs (eg cocaine)

Slide 85

Neuroadaptations

The transition from positive to negative reinforcement in the addiction cycle, occurs in multiple neural circuits.

Within system adaptations

In the reward circuit, resulting in progressive down regulation of activity

Between system adaptations

Gradual recruitment of the antireward system

Antireward system

In the extended amygdala, is gradually recruited

• activated my NE, CRF, and dynorphin

Model is relevant for negative reinforcement, produced by relief from both the psychological and physical symptoms of abstinence.

Antireward system two major functions:

• put a limit or brake on reward. Balance reward/aversive

• Mediate some of the aversive effects of stress

Nondependent individual

Drug use is supported mainly by positive reinforcement

• Primarily mediated by the reward system

• Little by the antireward system

Dependent individual

The reward system has been down regulated and the anireward system has been recruited.

• the antireward system involving NE and CRF acting in the central amygdala

Brain imaging studies

Has revealed structural and functional abnormalities in the prefrontal cortex in addicts

PFC role in

Executive functioning ( higher order cognitive abilities)

Regulation of emotional and motivational processes

Dorsal Lateral PFC To the Dorsal Lateral caudate nucleus

Important for executive function

Ventromedial circuit

VmPFC connects to anterior cingulate cortex (ACC) with the NA

• motivation and drive

Orbitofrontal circuit

From OFC to vmcaudate

• behavioral inhibition and impulse control

Dysfunction non he PFC

And associated circuitry

• hypothesized to play a key role in the preoccupation and anticipation stage of the addiction cycle

Preoccupation/anticipation stage

Characterized by intrusive thinking, drug craving, and lack of impulse control

Intrusive thinking

Linked to abnormal activity in pathways from PFC, hippocampus, and amygdala TO ventral striatum

Cue induced craving

Correlates with activation of the DLPFC, OFC, ACC, dorsal and ventral striata, and insula

Insula

Implicated in motivational regulation, including drug craving and control over drug use

Thalamus

Relays drug induced interoceptive stimuli (internal cues produced by drug taking) to the insula

• mediates the conscious awareness of these stimuli

Pleasure and desire for the drug

Projections of the insula to the ventromedial prefrontal cortex and amygdala

• modulated by input from VTA dopaminergic neurons

• transform interoceptive information into feelings of

Transition to uncontrolled drug use

Involves different brain areas:

• behavioral control switches from striatal areas associated with goal directed behavior to other areas associated with habitual behavior

• Move from taking for pleasure to automatic, habitual and compulsive

Habbit learning

Transition from the ventral stratum (particularly NA) to dorsal striatum (caudate putamen)

Addiction leads to

Decrease in striatal da neurotransmission

• reduced striatal da release and lower D2 receptor binding in dependent SS ( both vulnerability and repeated use)

go system

That motivates and activated learned responses

Stop system

Pulls back on the reins

• includes the PFC and component of corticostriatal circuitry

Initial drug use

Invokes an enhancement of the go system

• as seen in the process of incentive sensitization and the transition of drug use from goal directed behavior to behavioral habit

• Progressive dysfunction of the stop system

• LEADS TO intrusive thinking, drug craving, and loss of impulse control

Long lasting changes in the brain that underlie persistence

Altered gene expression And changes in synaptic plasticity/strength in the reward/antireward system result in:

Methylation

Often condenses genes thus with chronic use, gene desensitized = inactivates/silences the gene

• drug challenge met with repression

Acetylation or phosphorylation

Lead to chromatic opening primed gene for expression = over express gene

• drug challenge met with robust gene activation

Non-coding RNAs

There are several types, leads to gene regulation

Hyperacetylation of histones H3 and H4

Located in the dorsal striatum or NAcc by several addictive drugs

Come back to slide 101

Drug induced plasticity

Is located at excitatory (glutamatergic) or inhibitory (GABAergic) synapses

After single infection of cocaine in mice

= enhanced responsiveness of synapses between incoming GLU fibers and postsynaptic neurons in the VTA

• not long term

• Same with alcohol nicotine and amphetamine

Persistent plasticity of NAcc glutamatergic synapses

Mediated by altered AMPA receptors subunit composition

• they become permeable to Ca+ (more GLU)

• is a key component of an animal model of drug craving incubation

• 3-4 weeks of withdrawal strengthening the synaptic connection

Disease model

Also called medical model

• most widely accepted

• Largely based on evidence for dysregulation of brain function

Moral model

Addiction was seen as a sign of personal and moral weakness

Criticism for disease model

• brain alteration alone does not prove that addiction is a disease

• There is no single diagnostic test to confirm a substance use disorder

• Empirical evidence raises doubt that heave drug use is outside the user’s control

Non disease theories

Argue that addicts choose to use drugs because it served a purpose

• alleviating emotional, lack of positive reinforcers, or available reinforcers fail to provide sufficient motivation (lack of natural reinforcers)

Contingency manegement

Behavioral intervention in which the user is regularly subjected to using testing and receives reinforcement for each negative test