Vulnerability to substance abuse: The striatal dopamine response to drug challenge
Notice bibliographique
Résumé
Drug addiction is a worldwide problem that imposes significant costs on society. Aggravating the problem is that we continue to have a poor understanding of vulnerability factors and treatment targets. To date the best implicated brain system is the ascending mesolimbic dopamine cell pathway and its regulation by descending cortical input. The present thesis first reviews the literature describing possible roles of dopamine in addiction, and the relationship between pre-frontal cortical function and striatal dopamine. The body of the thesis consists of three data chapters.In the first study we examined the possibility that young people at elevated risk for addiction based on a multi-generational family history (FH) of substance use problems might have perturbed mesolimbic dopamine responses. As a test, we used positron emission tomography (PET) with [11C]raclopride to measure d-amphetamine (0.3 mg/kg, p.o.) induced striatal dopamine responses in: (1) high-risk young adults with a multigenerational FH of substance use disorders (FH+exposed), (2) stimulant drug-naïve healthy controls with no known risk factors for addiction (Ctls_naive), and (3) subjects matched to the high-risk group on personal drug use but without a FH of substance use problems (Ctls_exposed). We found that compared to either control group, the FH+exposed subjects exhibited smaller [11C]raclopride responses, with the largest effect in the right ventral striatum. Together, the results suggest that young people at familial high-risk for substance use disorders have decreased dopamine responses to an amphetamine challenge, an effect that predates the onset of addiction. In the second study we examined the variability in the striatal dopamine response to d-amphetamine as a function of cortical thickness. Marked individual differences in these responses are seen in laboratory animals, related in part to input from the prefrontal cortex, and substance dependent individuals are reported to have significant cortical thinning. Based on these observations, we measured the relation between cortical morphology and drug-induced striatal dopamine release in healthy adults. As expected, d-amphetamine produced significant reductions in [11C]raclopride binding potential in the striatum. There was substantial individual variability in this response, which was correlated with cortical thickness in the frontal lobe as a whole. A thicker cortex correlated with a smaller dopamine response. While prefrontal regulation of striatal function has been well studied, it was unclear if the thickness of the prefrontal cortex was an acceptable proxy to the function of that region. These results suggest it is. In the third study we applied the analysis of cortical thickness to all three groups described in the first study. Of particular interest was whether the blunted amphetamine-induced dopamine response seen in the family history positive group was related to alterations in cortical thickness. The same methods described in the second study were applied to the data from the first. We found that 1) FH+exposed subjects had thicker cortex, 2) as in the Ctls_naive, cortical thickness correlated with the dopamine response in FH+exposed subjects.Together, the studies provide evidence of a pre-existing or rapidly developing neurobiological difference in individuals at high risk for addictions. If vulnerable individuals can be identified reliably, it might be possible to provide early preventative interventions.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».