addiction

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Scope

•Biological basis of addiction

•Neurotransmitters and circuits

•Transition from use to compulsion

•Excludes:

•Individual mechanism of drugs or their pharmacology

•Genetics and epigenetics

•Clinical issues such as mechanisms of tolerance, withdrawal etc

•No issues regarding treatment or medications

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The neurobiology of addiction

Model of interacting circuits in which disruptions contribute to compulsive-like behaviours

underlying drug addiction

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The neurobiology of addiction

•Three-stage addiction cycle framework:

•binge/intoxication,

•withdrawal/negative affect, and

•preoccupation/anticipation.

•multiple neuroadaptations in three corresponding domains:

•(1) increased incentive salience,

•(2) decreased brain reward and increased stress, and

•(3) compromised executive function;

•and in three major neurocircuits: basal ganglia, extended amygdala, and prefrontal cortex

Conceptual framework for the progression of addiction over time

Conceptual framework of sources of reinforcement in addiction

Allostatic change in emotional state associated with the transition to addiction

Terminology

•Impulsivity: “a predisposition toward rapid, unplanned reactions to internal and external stimuli without regard for the negative consequences of these reactions to themselves or others”.

•Compulsivity: “perseverative, repetitive actions that are excessive and inappropriate”

•Individuals move from impulsivity to compulsivity, and the drive for drugs shifts from positive to negative reinforcement. However, impulsivity and compulsivity coexist, in the stages of the addiction cycle

•Reward: any event that increases the probability of a response with a positive hedonic component

•Incentive salience: can be defined as motivation for rewards derived from both one’s physiological state and previously learned associations about a reward cue

•Conditioning: the response to previously neutral stimuli to which the drugs become paired. when a previously neutral stimulus reinforces or strengthens behaviours through its association with a primary reinforcer and becomes a reinforcer in its own right

Individuals move from impulsivity to compulsivity, and the drive for drugs shifts from positive to negative reinforcement. However, impulsivity and compulsivity coexist, in the stages of the addiction cycle

•Reward: any event that increases the probability of a response with a positive hedonic component

•Incentive salience: can be defined as motivation for rewards derived from both one’s physiological state and previously learned associations about a reward cue

Terminology

•Opponent process: The “opponent process” theory of motivation suggests that rewarding experiences engage secondary mechanisms that oppose and constrain positive emotion

•the initial, rewarding effects of drugs of abuse are followed by the emergence of a negative emotional state each time a drug is experienced, including the first

•Neuroplasticity: neuroplasticity is the capacity of neurons and neural networks in the brain to change their connections and behaviour in response to new information, sensory stimulation, development, damage, or dysfunction.

•Allostasis: Allostasis is the process by which an organism adapts to environmental and internal stressors to maintain internal stability, or homeostasis. The term literally means “stability through change”

• Allostatic load is defined as the cumulative result of an allostatic state

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Terminology

• Interoceptive awareness: the ability to sense, interpret, and respond to internal bodily signals, like your HR, breathing, hunger, and temperature. It’s considered a vital part for regulating bodily functions and maintaining homeostasis.

•‟executive functions”: the higher-level cognitive skills you use to control and coordinate your other cognitive abilities and behaviors.

•Hyperkatifeia: defined as a constellation of negative emotional or motivational signs and symptoms of withdrawal from drugs of abuse.

•negative emotion-like states, reflected by the elevation of reward thresholds, lower pain thresholds, anxiety-like behavior, and dysphoric-like responses

•Hyperalgesia: An increased sensitivity to feeling pain and an extreme response to pain.

•Hypohedonia: an abnormally reduced ability to experience pleasure or enjoyment in activities that are normally pleasurable. It’s less severe than anhedonia or depression.

Neurobiological mechanisms of the binge/intoxication stage

•intoxicating doses of alcohol and drugs release dopamine and opioid peptides into the ventral striatum, and that fast and steep release of dopamine is associated with the sensation of the so called high

•γ-aminobutyric acid (GABA), glutamate, serotonin, acetylcholine, and endocannabinoid systems that act at the level of either the ventral tegmental area or nucleus accumbens

•Every drug with addiction potential increases DA, either through direct or indirect effects on DA neurons in the ventral tegmental area (VTA) with the consequent release of DA in the nucleus accumbens (Nac)

•initial action on different molecular targets and, depending on their pharmacological effects

Schematic representation of key target sites for various drugs of abuse across the reward

circuitry.

Neurobiological mechanisms of the withdrawal/negative affect stage

•The withdrawal/negative affect stage consists of key motivational elements, such as chronic irritability, emotional pain, malaise, dysphoria, alexithymia, states of stress, and loss of motivation for natural rewards

•characterised by elevations in reward thresholds (ie, decreased reward) during withdrawal

•precede and are highly correlated with escalation in drug intake

•increases in stress and anxiety-like responses also occur that contribute greatly to the malaise of abstinence and protracted abstinence

•Chronic drug exposure-induced neurochemical changes in systems that are implicated are

•within-system neuroadaptations

•between-system neuroadaptation

Neurobiological mechanisms of the withdrawal/negative affect stage

•within-system neuroadaptations: can be defined as those in which “the primary cellular response element to the drug…adapt[s] to neutralize the drug’s effects;

•Persistence of the opposing effects after the drug disappears… produce[s] the withdrawal response

•include decreases in dopaminergic and serotonergic transmission in the nucleus accumbens during drug withdrawal

•increases in μ opioid receptor responsivity during opioid withdrawal

•Decreases in GABAergic and increases in NMDA glutamatergic transmission in the nucleus accumbens.

•decreases in reward system function might persist in the form of long-term changes that contribute to the acute withdrawal and protracted abstinence and

•could also explain the loss of interest in normal, non-drug rewards

Neurobiological mechanisms of the withdrawal/negative affect stage

•between-system neuroadaptation: neurochemical systems other than those involved in the positive rewarding effects of drugs of abuse are recruited or dysregulated by chronic activation of the reward system.

•hypothalamic-pituitary-adrenal axis and brain stress system mediated by CRF are dysregulated by the chronic administration of all major drugs with dependence or abuse potential

•brain stress systems, such as CRF, norepinephrine, and dynorphin, are recruited in the extended amygdala and lead to negative emotional states in withdrawal and protracted abstinence

•concept of anti-reward was developed: opponent processes that are a general feature of biological systems also act to limit reward

Anti-reward circuits

•engaged as neuroadaptations during the development of addiction, producing aversive or stress-like states

•are manifest when the drug is removed during acute withdrawal but also during protracted abstinence.

•The combination of decreases in reward function and increases in stress function in the motivational circuits of the ventral striatum, extended amygdala, and habenula is a powerful trigger of negative reinforcement that contributes to compulsive drug-seeking behaviour.

•Endogenous anti-stress systems: appear to buffer the brain stress systems and influence vulnerability to the development and perpetuation of addiction.

•Key neurotransmitters that act in opposition to brain stress systems include neuropeptide Y, nociceptin, and endocannabinoids

•underactivation of the anti-stress systems

Neural circuitry associated with the negative emotional state of the withdrawal/negative affect stage

Summary

•repeated drug intoxication and withdrawal leads to

•repeated hypohedonia,

•hyperkatifeia, and

•hyperalgesia and more

•hyper responses to stress

•the individual misregulates by taking more drug because it transiently prevents or relieves the negative emotional symptoms of withdrawal or hyperkatifeia

•Shifts from a homeostatic hedonic state to an allostatic hedonic state

Neurobiological mechanisms of the preoccupation/anticipation stage

•preoccupation/anticipation stage has long been hypothesised to be a key element of relapse

•been linked to the construct of craving, but craving in itself does not always correlate with relapse

•Executive control over incentive salience is essential to maintain goal-directed behaviour and the flexibility of stimulus–response associations

•the prefrontal cortex is in a good position to regulate incentive salience and conditioned behaviour when a salient cue is presented to the individual

•the prefrontal cortex sends glutamatergic projections directly to mesocortical dopamine neurons in the ventral tegmental area, thus exerting excitatory control

•Glutamatergic projections from the prefrontal cortex to the caudate and ventral striatum also modulate the control of the striatal-pallidal-thalamocortical system

Neurobiological mechanisms of the preoccupation/anticipation stage

•cue-induced craving produce activation of the prefrontal cortex, including the dorsolateral prefrontal cortex, anterior cingulate gyrus, and medial orbitofrontal cortex

•mediated by glutamate

•reported deficits in executive function that are reflected by decreases in frontal cortex activity that interfere with decision making, self-regulation, inhibitory control, and working memory,

•might involve disrupted GABAergic activity in the prefrontal cortex

•Cravings are also related to middle insular function.

•The insula has an interoceptive function that integrates autonomic and visceral information with emotion and motivation, thus providing conscious awareness of these urges

Neurobiological mechanisms of the preoccupation/anticipation stage

•In general, the consequences of structural, transcriptomal and functional alterations in the PFC that contribute to SUDs are evident in three inter-related domains

•PFC dysfunction can lead to a loss of inhibitory control that may manifest as increased impulsivity and heightened stressor reactivity

•changes in attentional bias resulting from altered PFC function contribute to the exaggerated salience/influence of drug-associated cues

•impaired decision making in individuals with SUDs can fuel persistent use and contribute to many of the deleterious effects of SUDs on other aspects of life

Memory Systems and the Addicted Brain

•Our brains are designed to learn. Learning about our environments and retrieving accurate information from memory storage is critical

•Drugs of abuse can positively affect all of these factors, increasing attention, motivation, and arousal,

•the behaviors leading to drug use and the stimuli encountered during drug exposure are strongly encoded.

•DRUG-INDUCED ALTERATIONS TO LEARNING AND MEMORY

•ASSOCIATIVE LEARNING

•TRANSLATING MEMORY TO ACTION

•HABIT FORMATION

Memory Systems and the Addicted Brain

•functions for the hippocampus, dorsal striatum, and amygdala

•The hippocampus mediates a cognitive/spatial form of memory

•the dorsal striatum mediates stimulus–response (S–R) habit memory

•The amygdala mediates stimulus-affect-associative relationships, while also having a modulatory role of emotional arousal on other types of memory.

•drugs can modulate memory function of each of these brain regions.

•Thus, drugs can potentially enhance their own self-administration via augmenting consolidation of the drug-related memories encoded by the hippocampus, amygdala, and dorsal striatum

Memory Systems and the Addicted Brain

•Traditionally, acquisition, consolidation, and retrieval have been considered the three cornerstones of the learning and memory process

•in the process of retrieving information from long-term storage the memory becomes “destabilized.” That is, memory becomes labile and subject to disruption.

•it is then restored, or “restabilized” in long-term memory in a process termed reconsolidation, which requires many of the same molecular mechanisms essential for initial consolidation

•Every time a drug-associated memory is retrieved and reconsolidated into long-term memory the reconsolidation process may also be stronger resulting in progressively more drug-associated memories with repeated use

•this may make drug-associated memories particularly difficult to disrupt

multiple memory systems view of drug addiction

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What does it all mean

•Two opposing systems can therefore be postulated: a Go system and a Stop system.

•The Go system could drive craving and engage habits via the basal ganglia

•the signalling pathways that contribute to the transition from moderate to uncontrolled excessive drug and alcohol intake and to dependence as ‘go pathways

•addiction is thought to be a maladaptive form of learning and memory and go‑pathway molecules that have been linked to synaptic plasticity, learning and memory.

•The Stop system could control assessment of the incentive value of choices and suppression of affective responses to negative emotional signals

•a Stop system would inhibit the Go craving system and stress system

•the endogenous pathways that work in the opposite direction to the go pathways, and thus promote resilience against the development of dependence and keep drug and alcohol intake in moderation

Neuronal Circuitry of Addiction

Outstanding questions

•How do the specific levels of drug-induced adaptations interact and influence each other to result in complex behavioral changes?

•Which molecular pathways and circuits could serve as the most promising potential therapeutic targets for Substance use disorder?

•Which mechanisms determine individual vulnerability to excessive substance consumption?

•SUD is a polygenic disorder. How is it possible that manipulating single genes in animal models can result in animals that are resilient or vulnerable to SUD?

•Are there additional, currently unknown variants that confer susceptibility for or resilience against developing problem Drug use and SUD?

Summary

•Substance use disorders are complex, multistage diseases

•disturbances in three major neurocircuits:

•(i) basal ganglia-driven binge/intoxication stage, (ii) extended amygdala-driven withdrawal/negative affect stage, and (iii) prefrontal cortex-driven preoccupation/anticipation stage

•In these three domains, neurotransmitter-specific and neuromodulator-specific neuroplastic changes are seen in multiple subsystems

•Molecular genetic mediation and epigenetic changes in these same circuits provide pre-existing vulnerabilities to addiction, increased susceptibility to environmental risk factors, and targets for development of novel treatments and resilience to relapse.