Extra-striatal D2/3 receptor availability in youth at risk for addiction

Abstract

The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control, and altered sensitivity to rewards and punishments (i.e., externalizing features). To test these associations in humans, we measured type-2/3 dopamine receptor (DA 2/3 R) availability in youth at high vs. low risk for substance use disorders (SUDs). In this study, N = 58 youth (18.5 ± 0.6 years) were recruited from cohorts that have been followed since birth. Participants with either high (high EXT; N = 27; 16 F/11 M) or low pre-existing externalizing traits (low EXT; N = 31; 20 F/11 M) underwent a 90-min positron emission tomography [ 18 F]fallypride scan, and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile scale (SURPS), and Sensitivity to Punishment (SP) and Sensitivity to Reward (SR) questionnaire. We found that high vs. low EXT trait participants reported elevated substance use, BIS-11, SR, and SURPS impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [ 18 F]fallypride binding potential (BP ND) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in midbrain dopamine cell body regions, but, across all participants, low midbrain BP ND values were associated with low SP scores. Together, the results suggest that altered DA 2/3 R availability in terminal extra-striatal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity (i.e., an internalizing feature).

Extrastriatal Dopamine D2/3 Receptor Availability in Alcohol Use Disorder and Individuals at High Risk

“…Whereas in the direct group comparison, there was no significant difference between the BP of LR and AUD subjects as well as LR and HR subjects, dopamine D2/3 availability was altered in the rACC and vlPFC of HR compared to AUD subjects. This finding is in line with the work of Jaworska et al [21] which observed higher levels of extrastriatal postsynaptic D2/3 receptors in adolescents at HR for developing an addiction. Further, Pfeifer et al [51] observed higher extrastriatal BP to be correlated with the subjective effect of liking alcohol after an acute intravenously applied alcohol infusion revealing a potential clinical link.…”

The associations of comorbid substance use disorders and psychiatric conditions with adolescent brain structure and function: A review

“…OFC volume and connectivity, and amygdala connectivity are associated with substance use, SUD and subclinical anxiety and depression measures; however, these brain measures have yet to be informative in clinical diagnoses [73,82,96,122]. Interestingly, studies indicated that blunted striatal activity was associated with depressive symptoms, but not substance use or SUD [57,97], in contrast to our original hypothesis [60]. These neural findings are highly congruent with the epidemiological literature: Externalizing disorders have been more consistently linked with SUD than internalizing disorders [44].…”

“…Abnormalities in the structure, function, and chemistry of differentiable neural pathways are suggested to underlie the increased risk of SUD within each class of psychopathology. While adolescents with externalizing symptoms at risk of SUD demonstrate weaker prefrontal activity and cortical thinning, their counterparts with internalizing symptoms show blunted striatal activity [52,60]. This suggests unique neural pathways to SUD in each class of psychopathology.…”

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

“…We show the comparisons between tracers in Fig. S2b for the following neurotransmitter receptors/transporters: 5-HT1 A [12,105], 5-HT1 B [12,39,105], 5-HT2 A [12,105,124], 5-HTT [12,105], CB 1 [64,79], D 2 [2,55,101,117], DAT [29,104], GABA A [29,78], MOR [57,126], and NET [27,48]. Here we make some specific notes: (1) 5-HTT and GABA A involve comparisons between the same tracers (DASB and flumazenil, respectively) but one map is autoradiography-informed (see [12] and [78]) and the other is not [29,30,105]; (2) raclopride is a popular D 2 tracer but has unreliable binding in the cortex, and is therefore an inappropriate tracer to use for mapping D 2 densities in the cortex, but we show its comparison to FLB457 and another D 2 tracer, fallypride, for completeness [2,22,55]; (3) the chosen carfentanil (MOR) map was collated across carfentanil images in the PET Turku Centre database-since our alternative map is a partly overlapping subset of participants, we did not combine the tracers into a single mean map [57,126].…”