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 group  rats 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 ) -> 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 ) and adults(PND ) 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 ) and Adults(PND ) Control- sterile water (IG); same regimen Blood(200µl) collected(tip of tail)  min after ethanol dose 2 nd, 4 th and 6 th 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) 1 st 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. 2 nd 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 regulation  susceptible 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