Relation between alcohol abuse and impulsivity

- Jayandra Chiluwal

• Excessive alcohol drinking- third leading cause of preventable deaths

• Shortens life by 30 years • High level of alcohol drinking among

adolescents and young adults- major public health concern

• Impulsivity associated with alcoholism

Grahame et. Al.

• High impulsivity prevalent in drug addicts and alcoholics vs non addicts

• May be considered as a candidate endophenotype(measurable, heritable biological state that is hypothesized to underlie and precede the development of a disorder, and a

presumably closely related to the particular alleles that cause a disorder) • Whether impulsivity could be an

endophenotype or result of history of deug use?

• Drug reward not along with impulsivity results in addiction.

• Impulsivity - valuing smaller immediate rewards vs larger delayed rewards.

• Delay discounting task(DDT)- extent to which time degrades the subjective rewarding value of the delayed reinforcer.

• Replicated lines of High Alcohol Preferring(HAP) mice, Low Alcohol Preferring(LAP) and Low drinking progenitor mice(HS/Lbg) used

• Based on high and low alcohol preference on free choice between alcohol and water

• Over generations, alleles get concentration in two opposite directions

• If impulsivity an endophenotype, selection for high vs low ethanol should be different

Materials and methods

• Parents of HAP1 and HAP2(gen. 34 and 23 respectively) had 84%

• Parents of LAP2(gen 23) – 6% • HS/Lbg- 15% • HAP2/LAP2 – 2 cohorts of 24(12m/12f) each • HAP1/HS/Lbg- 1 cohort of 24

Delay Discounting Task

Figure 2

Table 2

To summarize

• Genetic risk factor for alcoholism may be related in part to impulsivity

• Whether high impulsivity causes high alcohol drinking is unknown

Mejia-Toiber et. al.

• Young drinkers(<25) high impulsivity, novelty seeking & low harm avoidance

• Anxiety like behavior may be affected by drinking

• Increased impulsive choice in adult abstinent alcohlics & heavy drinkers vs light drinkers

• No study on long term effects of binge ethanol exposure during adolescence/adulthood on impulsivity

• Neither in anxiety during W or W/o a history of ethanol exposure

• Aim- To investigate impulsive choice and anxiety in rats exposed to Chronic Intermittent Ethanol(CIE) during adolescence/adulthood

Materials and Methods

• Adolescent experimental grouprats born in lab from pregnant Wistar rats

• Adult experimental group rats aged 134 Post natal days(PND)

• Both from Charles River • Delay discounting Task

Chronic Intermittent Ethanol

• Adolescent(PND 28-53) and Adult(PND-146-171) -> exposed to CIE or water Intragastrically(IG)

• 1-5g/kg of 25% (v/v) ethanol 3 times a day on a 2 day on 2 day off regimen Total seven 2-day ons

• Same regimen with sterile water

Acute Saline/Ethanol Challenge

• Acute saline/ethanol(0.5, 1 and 2 g/kg IP) in a volume of 1ml/kg, 15 minute before session

• During adulthood to adolescents(PND 144-163) and adults(PND 251-270)

• Once per week

4-day Binge

• 1-4g/kg of a 25% (v/v) ethanol solution(IG) in sterile solution twice per day w/ 6-hour interval for 4 days

• Adolescents(PND 181-184) and Adults(PND 271-274) • Control- sterile water (IG); same regimen • Blood(200µl) collected(tip of tail) 60-90 min after

ethanol dose • 2nd, 4th and 6th binge days during CIE, on last injection

of 4-d binge & ethanol challenge after DDT

Light potentiated startle and Acoustic startle response

• 4 blocks 2 sessions(2 blocks each) • 1st block (in dark)

- 5 min- undisturbed; 5 min 65 db white noise(throughout) - 30 startle stumuli(10 each of 90, 95 and 105 db) in every 30 sec.

• 2nd block same; In dark LPS; In light ASR

DDT

• Immediate reward-1 pellet; delayed reward 4 pellets

• Each session- 5 blocks of 12 trials each(first 2-forced then 10-free)

• Reward delay 0, 10, 20, 40 and 60 s for 5 blocks

• Impulsive choice- Choice of large reward for each delay block per session

Results

A- Significant difference in Large reward choice in Young adults: Saline vs Ethanol B- No significant E- # significant less choice of large reward by young adults in higher alcohol conc.

Highlights

• CIE exposure and age had no effect on baseline impulsive choice

• Ethanol increased impulsivity in younger adult rats regardless of CIE exposure

• CIE withdrawal-induced decrease in anxiety and arousal were not age specific

• Subsequent ethanol withdrawal produced age-dependent increases in anxiety

Neurobiology of Adolescent Brain and behavior

• Adolescence: Period of development associated with progressively greater efficiency of cognitive control capacity.

• Depends upon maturation of Pre frontal cortex yet different in adolescent from child-hood and adulthood

• Adolescents characterised as impulsive and greater risk takers

Neurobiological model of Adolescence

Model showing development of Ventral striatum and PFC in humans

-Due to earlier maturation of sub cortical projections relative to top-down PFC the behavior in adolescents is non-linear

Phenotype of Adolescents

• Lapses in ability to resist temptation • Sensitivity to rewards and incentives • Making riskier decisions in presence of peers

vs alone

Neurobiology of Adolescence

• Prefrontal cortex involved in cognitive control • Striatum in detecting and learning about novel

and rewarding cues • Very early activity of striatum- reward based

associations• Later development of PFC optomizez greater

gains

• Studies have found greater density of dopamine receptors D1 and D2 in striatum- early adolescences, followed by loss in later stages

• May have a relation in sensitivity to rewards • Some hormonal changes as well

Ventral Striatal activity(Galvan et. al.)

• fMRI confirmed that high risk associated with Striatum

• Ventral striatum play a role in excitement• While recent studies show: Impulsivity inversely

correlate with volume of ventromedial Prefrontal cortex

• Somerville et. al. tested child to adult with go/no go task(social cues-happy faces) adolescent failed to show age-dependent improvement

• Individuals with less top-down regulationsusceptible to alcohol and substance abuse (shown in study based on populations showing impairments in PFC before alcohol and drug exposure)

Take home

• Impulsivity may be an endophenotype • Binge alcohol consumption in early

adolescence may lead to impulsivity - In adults- anxiety

• Combination of PFC and striatum circuitry has a role to play

• Some adolescents will be more prone to risky behavior