ADHD and the influence of adolescent alcohol drinking on cognition and behavior - Project Summary_________________________________________________________________________
Attention deficit hyperactivity disorder (ADHD) a highly heritable neurodevelopmental condition characterized
by inattentiveness, hyperactivity, and impulsivity. Individuals with ADHD are at a higher risk for addictive
behavior during adolescence including excessive alcohol consumption and are more likely to developing an
alcohol use disorder (AUD). Epidemiological and genetic studies indicate that ADHD and AUD have high rates
of comorbidity and share several risk-associated genes, inferring a common underlying endophenotype.
Neuroimaging studies of individuals with ADHD demonstrate delayed brain maturation particularly in the frontal
cortex. Heavy drinking during adolescence also disrupts frontal cortex development, leading to accelerated
loss of grey matter. Thus, it is likely that ADHD is likely exacerbated by heavy alcohol use during adolescence,
perpetuating ADHD and AUD symptoms in adulthood. Despite the high prevalence of ADHD individuals that
suffer from comorbid AUD, we know very little about ADHD predisposition and the impact of adolescent alcohol
exposure on frontal cortex function. To better understand the underlying neurobiology of ADHD as well as the
relationship between cognitive dysfunction and adolescent alcohol consumption, we will evaluate measures of
cognitive control and alcohol self-administration in a prominent mouse genetic model of ADHD, the Lphn3
knockout mouse. Latrophillin 3 (LPHN3) is a synaptic cell adhesion G-protein coupled receptor (GPCR)
involved in forming and maintaining glutamatergic synapses. Loss of function variants in LPHN3 have a strong
genetic association with ADHD and have been shown to be a significant risk factor for developing an AUD. We
propose a two hit model, where ADHD symptom severity can be worsened by adolescent binge drinking and
promote heavy alcohol consumption in adulthood. By focusing on frontal corticothalamic (CT) circuitry known
to mediate attention, working memory and impulsivity, we can evaluate the specific neural mechanisms
affected by adolescent alcohol and loss of Lphn3. In Aim 1 of this proposal, we will test the hypothesis that
genetic deletion of Lphn3 in the frontal cortex causes reductions in glutamate neurotransmission and that
binge-like alcohol consumption during adolescence exacerbates this effect using ex vivo electrophysiology and
spine density measurements of specific subpopulations within frontal cortex. In Aim 2, we will test the
hypothesis that Lphn3 and adolescent alcohol consumption negatively affects cognitive control and that
specific neural circuits in the frontal cortex regulate these deficits. In Aim 3, we will test the hypothesis that
Lphn3 deletion and adolescent alcohol consumption potentiate the reinforcing and motivational properties of
alcohol in a frontal CT circuit manner. Results from these studies will provide valuable information on the
interactions of alcohol with ADHD and potentially reveal novel interventions for problematic drinking in ADHD
individuals.
