BRAIN RESPONSES TO ALCOHOL CUES IN YOUTH AT RISK FOR SUBSTANCE USE DISORDERS (SUDS): A FUNCTIONAL MAGNETIC RESONANCE IMAGING STUDY
Authors: Nikolic *Maja , Cox Sylvia M L , Jaworska Natalia , Castellanos-Ryan Natalie , Dagher Alain , Vitaro Frank , Brendgen Mara , Parent Sophie , Boivin Michel , Côté Sylvana , Tremblay Richard E , guin Jean R Sé , Leyton Marco 
Published: February 2025

Abstract

Background
Adolescent alcohol use is the norm, but only some develop a substance use disorder (SUD). The most common vulnerability traits are characterized by diverse externalizing (EXT) behaviors (e.g., poor impulse-control and emotion regulation). Preliminary studies suggest that this increased risk may be influenced by altered mesocorticolimbic processing of drug and non-drug reward-related cues. The effects are complex. Whereas functional magnetic resonance imaging (fMRI) measured responses to alcohol cues are elevated in young adults with an alcohol use disorder compared to healthy drinkers (1), high-risk youth who have not developed an SUD are reported to poorly differentiate cues associated with high vs low reward; e.g., monetary reward (2).

Aims & Objectives
Measure brain activation responses to alcohol and non-alcohol cues in high- vs low- EXT youth who have been followed since birth.

Method
Seventy-one longitudinally followed young social drinkers (age 18.5±0.6) underwent fMRI scans and completed the Alcohol Use Disorders Identification Test (AUDIT), Barratt Impulsiveness Scale (BIS- 11), Substance Use Risk Profile Scale (SURPS), and Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ). fMRI blood-oxygen-level-dependent (BOLD) activations were measured while participants received 1ml beverage tastants consisting of their preferred alcohol beverage, their preferred fruit juice, and water. Fourteen participants were excluded due to image quality issues, resulting in a final sample of 57, 27 high EXT (15F/12M) and 30 low EXT (20F/10M). As previously reported, most of these participants also had [18F]fallypride (47/57) and [11C]ABP688 (47/57) positron emission tomography scans and the high EXT group exhibited widespread increases in dopamine DRD2/3 receptors (3) and decreases in type 5 metabotropic glutamate receptors (4).

Results
As anticipated, high vs low EXT participants had higher AUDIT scores, alcohol binge occasions, lifetime uses of cannabis, impulsivity scores (SURPS and BIS-11), and prevalence of psychiatric disorders (mostly mood, anxiety, ADHD, and mild SUDs). For the alcohol (vs water) fMRI contrast, both groups exhibited activations in the thalamus, but only the high EXT group had significant activations in the anterior and posterior cingulate cortex, right calcarine, and post central gyrus. Significant group differences, in comparison, were only seen when contrasting the two flavored reward cues, alcohol vs juice. Whereas the low EXT group exhibited larger mesocorticolimbic BOLD responses to alcohol (vs water) than juice (vs water), these responses were undifferentiated in the high EXT group.

Discussion & Conclusion
The results add to the evidence that, in high-risk youth, mesocorticolimbic activations poorly distinguish reward-related cues, extending this observation to alcohol vs juice. The neurotransmitters mediating these responses remain unknown, but disrupted differentiations of reward- related cues might erode the ability to make optimal choices, increasing the risk for SUDs and their commonly comorbid conditions.

References
1. Tapert, S. F., Cheung, E. H., Brown, G. G., Frank, L. R., Paulus, M. P., Schweinsburg, A. D., Meloy, M. J., &Brown, S. A. (2003). Neural response to alcohol stimuli in adolescents with alcohol use disorder. Archives of General Psychiatry, 60(7), 727–735.
2.Bü chel, C., Peters, J., Banaschewski, T., Bokde, A. L. W., Bromberg, U., Conrod, P. J., Flor, H., Papadopoulos, D., Garavan, H., Gowland, P., Heinz, A., Walter, H., Ittermann, B., Mann, K., Martinot, J.-L., Paillè re-Martinot, M.-L., Nees, F., Paus, T., Pausova, Z., … IMAGEN consortium. (2017). Blunted ventral striatal responses to anticipated rewards foreshadow problematic drug use in novelty-seeking adolescents. Nature Communications, 8, 14140.
3.Jaworska N, Cox SML, Tippler M, Castellanos-Ryan N, Benkelfat C, Parent S, Dagher A, Vitaro F, Boivin M, Pihl RO, Cô té S, Tremblay RE, Sé guin JR, Leyton M. (2020) Extra-striatal dopamine2/3 receptor availability in youth at-risk for addictions. Neuropsychopharmacology, 45(9), 1498-1505.
4.Cox SML, Tippler M, Jaworska N, Smart K, Castellanos-Ryan N, Durand F, Allard D, Benkelfat C, Parent S, Dagher A, Vitaro F, Boivin M, Pihl RO, Cô té S, Tremblay RE, Sé guin JR, Leyton M. (2020) mGlu5 receptor availability in youth at risk for addictions: effects of vulnerability traits and cannabis use. Neuropsychopharmacology, 45(11), 817-1825.