Lecture 2: Neurobiology, developing brain, early adverse experiences and addiction Flashcards
What did studies from the 50’s find?
injected a needle into certain parts of rats brain and had them press a lever to get an electric impulse.
The reward centre in the brain. When certain areas were stimulated with small amounts of electricity, rats behaved as if they received something very pleasant (e.g., food) Exact location in human brain is still subject to debate, but believed to involve the dopaminergic system and its opioid releasing neurons
What did the early research involving brain micro dialysis in rats lead to?
Stimulants and other drugs increased dopamine release in the nucleus accumbens, which is located in the ventral striatum. Led to a general theory of addiction in which addictive drugs release dopamine but psychoactive, non addictive drugs do not
What is dopamine theory?
Drugs affect dopamine levels in the brain, Directly or indirectly increase dopamine levels in the brain. Mesolimbic dopamine system is most often associated with addiction
What are amphetamines?
Amphetamines are similar in structure to dopamine. Can move from outside the neuron into the cell via dopamine transporters or directly diffusing through the neural membrane Once inside, amphetamines force dopamine out of their storage vesicles and expel them into the synapse
What is the relationship between dopamine and addiction?
Addiction is thought to be the result of repeated stimulation of the mesolimbic system, which triggers reorganization in the brains neurocircuitry
What might the changes in the brains neurocircuitry do?
These changes in the brain may mediate positive reinforcement, motivation, craving and relapse for the drug
As people become more driven to use the drug, the drive can also progress to a state of negative reinforcement (i.e., to alleviate negative symptoms associated with withdrawal)
What are the neural mechanisms underlying vulnerability to addiction?
Neuroplasticity and neuroadaptation
What is neuroplasticity?
The brains ability to reorganize itself by forming new neural connections throughout life. Allows neurons to compensate for injury and disease and to adapt to changes in the environment, important for learning and memory.
What is neuroadaptation?
The process whereby the body compensates for the presence of a chemical in the body so that it can continue to function normally
What is neuroadaptation?
The process whereby the body compensates for the presence of a chemical in the body so that it can continue to function normally. For people who abuse substances (e.g., cocaine), neuroadaptation leads to a tolerance and dependence on a substance
When does sensitization occur?
Sensitization occurs when repeated administration of a drug elicits escalating effects at a given dose.
Does dopamine theory apply to other substances? is it universal?
Nutt et al., 2015: when you provide individuals with a stimulant or another drug we are not seeing the same amount of dopamine release. The graph shows that dopamine release is not universal. However this is a very restricted study
What are the challenges to dopamine theory?
1) Lower availability of striatal dopamine receptors
(Cocaine and alcohol, but not cannabis)
2) Decreased dopamine release in dependence
(Cocaine and opiates, but not cannabis. Linked to worse treatment outcomes)
Summary of dopamine theory and addiction
Given the existing data, DA release seems to apply better to stimulants (e.g., cocaine). Mixed results from non-stimulants should have given the field pause for thought
Research has largely focused on DA in the striatum, but decision making for the most part takes place in the cortex. Da likely has other roles. We are beginning to understand, DA receptor availability linked may be linked to impulsivity (in rats) Regulate motivation to seek addictive substances.
How is the insula involved with craving and addiction?
The insula is involved in a network of brain regions that represent bodily states associated with emotions and decision making, Cue-induced craving can be conceptualized as an emotion, Drug seeking cues activate the insula and activity in the insula is linked with self reported craving
Insula, cue induced cravings and lesions
If cue-induced cigarette craving was one kind of emotional feeling, then insula lesions should disrupt craving, If craving maintained the addiction to smoking then insula lesions should make it easier to stop smoking and should also reduce the likelihood of relapse
What did Naqvi et al (2007) test in their study?
Naqvi et al (2007) tested the ideas of whether insula lesions disrupt cravings and addiction retrospectively (post lesion) in a sample of patients with damage to the brain
Naqvi et al. Method
19 patients with insula lesions, 50 lesion comparison patients with damage in areas adjacent and non adjacent to the insula,
Patients in both groups were smoking on average more than a pack per day at the time of lesion onset caused by a stroke
What were the main dependent variables of Naqvi et al. study?
The main DV’s were quitting and disruption of smoking addiction. Smoking was operationalized as fulfilling all 4 criteria: Reporting quitting smoking less than 1 day after lesion onset, Reporting that they did not start smoking again after they quit, Rating the difficulty of quitting as less than three on a scale of one to seven
and Reporting feeling no urges to smoke since quitting
What were the results of Naqvi et al.’s study?
Patients with insula lesions were more likely to quit after lesion onset than comparison patients, but ns.
Among patients who did quit after lesion onset: Patients with insula lesions were more likely to experience a disruption of their smoking addiction relative to comparison patients who also quit.
What is the method in suner-soler (2011) study?
Prospective analysis of link between insula damage and quitting smoking and disruption of addiction over time.
Compared patients with insula strokes (n=27) to patients with noninsula strokes (n=83). All patients (n=110) were smoking regularly at the time of their stroke
What were the results of this study? (suner-soler, 2011)
Most patients with insula strokes were more likely to quit smoking compared to patients with non insula strokes over a 6 month follow up period and one year post stroke. Like Naqvi et al.’s study, patients with insula strokes were more likely to report a disruption of addiction compared to patients with noninsula strokes (e.g., less urges to smoke) but ns
Is cue induced craving linked to activity in the insula among other substances? Meta-analytic results: Khun et al. Schact et al and Englemann et al.
Insula was activated by cocaine cues but not by nicotine or alcohol cues. Self reported craving was correlated with insula activity for nicotine, but not for cocaine or alcohol
Alcohol cues elicited greater activity in the insula vs. control stimuli and This difference was larger for alcohol dependent drinkers vs. social drinkers
Smoking cues elicited activiation in the insula
Does the insula play a role in driving addictive behaviour in real life? Meta analytic results: Janes et al.
In treated, abstinent smokers, cue elicited activity in the insula predicted slips (non relapse smoking episodes) Cue elicited insula activity linked with interference effects in a smoking stroop behavioral paradigm
Does the insula play a role in automatic drug seeking?
No, The Insula does not play a role in automatic drug seeking (when you’re on auto pilot- e.g., wake up and smoke a cigarette). Divorced from the value of drug taking, no subjective cravings and is unaffected by insula lesions.
What role does the insula play in addiction?
When there is a conflict between drug taking and alternative goals (e.g., avoiding negative consequences), the insula motivates goal directed drug seeking behaviour that is linked to the explicit hedonic (rewarding aspect) value of drug taking. Via interoceptive representation of drug taking (E.g., the taste of alcohol)
How does the brain change over time via neuroplasticity (Dopamine) ?
Early use- goal directed drug taking is far more common
Addiction- goal directed use is less common and automatic mode is more common because of necessity for drugs
The developing brain and addiction (adolescence)
Differential rates at which certain brain structures and connections develop may underlie stereotypical adolescent behaviours (e.g., sensation seeking, and impulsive and risky decision making)Adolescence are vulnerable to addiction. Addiction-relevant subcortical circuitry, and their associated projections, implicated in reward processing, motivation and emotional reactivity seem to develop early during adolescence
What are the global dual process Models of cognitive control in Adolescents and addiction
Increased sensitivity to rewards/positive affect/motivational-cues (or “bottom-up” driven responses), and immature “top-down” frontal control of “bottom-up” responses, confer risk for the initiation and maintenance of uncontrolled behaviors, such as substance misuse. The reward part of the brain is developing faster than other parts of the brain, your “good” decision making part of the brain is not fully developed
How does the neurodevelopmental imbalance in adolescent fronto-basal ganglia limbic circuitry exacerbate this problem of vulnerability to addiction? (conrod et al.)
The neurodevelopmental imbalance in adolescent fronto-basal ganglia limbic circuitry is further prolonged or exaggerated by heavy substance use during this developmental period, resulting in more uncontrolled patterns of substance use, thereby increasing the risk for SUD- changes how the brain develops creating more sensation seeking and impulsive behaviours
What is the effect of substance misuse on reward processing? (conrod et al.)
Drug-dependent adolescents demonstrate heightened drug cue-reactivity relative to nondependent adolescents
What is the effect of substance misuse on Neural correlates of behavioral control
Behavioral task performance studies are inconsistent (some show impairments in the ability to withhold a response, while others do not). By contrast, fMRI studies consistently demonstrate inhibition related activation differences between substance users and controls within brain regions implicated in behavioral inhibition. Go-no go tests
What is the effect of substance misuse on Stress and HPA reactivity
Flatter diurnal cortisol slopes (people who don’t experience a rise in cortisol in the morning) may be a risk factor for escalation into heavier drinking in adolescents and adults
Findings from Longitudinal research on cannabis
heavy use trajectories from 14 to 16 years of age predicted reduced growth in cognitive functions over time (i.e.,decision making, and spatial working memory)
Findings from longitudinal research on Alcohol
More alcohol use days predicted worse verbal memory, and visuospatial ability. Post drinking effects and greater drug use predicted worse psychomotor speed
Early adverse experience and DA system at the molecular level in rats
Stress in offspring (due to separation from mother) may change the expression and function of DA neurons, receptors and transporters observed in the key DA-innervated brain regions. Quality of maternal care received early in life influences development of the mesolimbic da system in the offspring
Early adverse experience and DA system at the neuroendocrine level in humans and rats
Stress may shift levels of stimulus evoked DA release. DA release in response to stress
Early adverse experience and DA system at the behavioural level for rats
Rodents exposed to early maternal deprivation show heightened reactivity to novelty in adulthood. Novelty-seeking behavior predicts rodent sensitivity to rewarding properties of addictive substances and subsequent vulnerability to addictive behavior. Rodents with early deprivation display heightened sensitivity to the effects of addictive substance (e.g., cocaine and amphetamine. They also learn to selfadminister these substances faster and maintain longer period of self-administration
early adverse experience and DA system at the behavioural level for humans
Novelty seeking or sensation seeking a trait characterized by a heightened tendency toward novel and intense sensations and experiences, often leading to impulsive risk taking and/or active pursuit of rewards.
Positive link between early adversity and novelty seeking in community and high-risk samples. Novelty seeking is positively correlated with a rise in DA release in the VS in response to amphetamine, as well as the individual’s self-reported wanting of the drug
Early adverse experience and the OT(oxy tocin) system at the molecular level with rats
Observed or experimentally induced low levels of maternal care (e.g., grooming) experienced early in life are directly associated with reduced density of OT receptors
Early adverse experience and the OT system at the neuroendocrine level for rats, monkeys and humans
Lower OT levels in those exposed to adversity/stress
Early adverse experience and the OT system at the behavioural level for rats, monkeys and humans
Social impairments
Early adverse experience and the GT system at the molecular level for rats
Early deprivation produces long term abnormalities in GC functions
Early adverse experience and the GT system at the Neuroendocrine level for rats, monkeys, humans
Increased reacitivity of the HPA axis in response to stress (rats and monkeys). Cortisol levels altered, but direction of effect is mixed (humans)
Early adverse experience and the GT system at the Behavioural level
Molecular and neuroendocrine alterations of the GC system diminish the capacity to effectively respond to stresss
What happened after repeated exposure to addictive substances?
Aberrant DA release and neuroadaptations that blunt DA release
Normal release of GCs as well as HPA axis activity level progressively decrease. But, in withdrawal, HPA activity is intensified in response to stress, potentially leading to continued substance seeking and/or relapse
OT decreases and neuroadaptations occur the reduce the synthesis of OT.
What were the intergenerational effects?
- Impaired maternal care can shape the early life experience of their offspring
- Transition to motherhood is associated with neuroadaptations in DA, OT and GC systems
- Substance using mother may be more vulnerable to dysregulated functions in the DA, OT, and GC systems relative to non unsing mothers
- DA,OT and GC systems central to maternal care may be co-opted in maternal substance addiction
What is the DA system?
The dopamine system, Positive valence systems: approach motivation and reward valuation
What is the OT system
Oxytocin system, Social processes: affiliation, attachment and social processes
What is the GT system
Glucocorticoid system, negative valence systems: loss or threat (stress)
