SEX- AND AGE-SPECIFIC EFFECTS OF PRENATAL ALCOHOL EXPOSURE AND EARLY LIFE ADVERSITY ON DOPAMINE D4 RECEPTOR EXPRESSION IN SPRAGUE DAWLEY RATS

Brain dopamine D4 receptors are critical modulators of cognition, emotion, and reward processing, yet their developmental regulation under early stress remains poorly understood. This study examined how prenatal alcohol exposure (PAE) and early-life adversity (ELA), modelled via limited bedding, affect D4 receptor expression in male and female rats during early (postnatal day [P]30) and late adolescence (P45). We quantified D4 receptor expression in the prefrontal cortex (PFC), striatum, hypothalamus, and medial amygdala using immunohistochemistry. ELA emerged as the primary modulator of D4 receptor expression, with age- and sex-specific effects: in the dorsal striatum, ELA reduced D4 receptor expression in late adolescent females, while late adolescent ELA males showed increased D4 expression in the nucleus accumbens shell. In the PFC, ELA disrupted the typical increase in D4 receptors across adolescence in males resulting in reduced expression by late adolescence relative to normally reared animals. Conversely, PAE had minimal effects on D4 receptor expression, except for a modest increase in striatal D4 receptors in males. Notably, D4 receptor expression followed distinct developmental trajectories, increasing in cortical areas and declining in subcortical areas between P30 and P45, consistent with normative maturation patterns. Region-specific alterations in D4 receptors may underlie ELA-related increases in vulnerability to cognitive inflexibility, impaired executive function, and/or altered reward sensitivity. Although ELA had more pronounced effects than PAE on D4 receptor expression, individuals with PAE are at increased risk of experiencing ELA, therefore understanding the combined effects remains clinically relevant.