Characterization of behavioral changes in T-maze alternation from dopamine D1 agonists with different receptor coupling mechanisms.
Psychopharmacology (Berl)
; 240(10): 2187-2199, 2023 Oct.
Article
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| MEDLINE
| ID: mdl-37578525
ABSTRACT
RATIONALE Dopamine D1 receptor agonists have been shown to improve working memory, but often have a non-monotonic (inverted-U) dose-response curve. One hypothesis is that this may reflect dose-dependent differential engagement of D1 signaling pathways, a mechanism termed functional selectivity or signaling bias. OBJECTIVES AND METHODS:
To test this hypothesis, we compared two D1 ligands with different signaling biases in a rodent T-maze alternation task. Both tested ligands (2-methyldihydrexidine and CY208243) have high intrinsic activity at cAMP signaling, but the former also has markedly higher intrinsic activity at D1-mediated recruitment of ß-arrestin. The spatial working memory was assessed via the alternation behavior in the T-maze where the alternate choice rate quantified the quality of the memory and the duration prior to making a choice represented the decision latency.RESULTS:
Both D1 drugs changed the alternate rate and the choice latency in a dose-dependent manner, albeit with important differences. 2-Methyldihydrexidine was somewhat less potent but caused a more homogeneous improvement than CY208243 in spatial working memory. The maximum changes in the alternate rate and the choice latency tended to occur at different doses for both drugs.CONCLUSIONS:
These data suggest that D1 signaling bias in these two pathways (cAMP vs ß-arrestin) has complex effects on cognitive processes as assessed by T-maze alternation. Understanding these mechanisms should allow the identification or discovery of D1 agonists that can provide superior cognitive enhancement.Palabras clave
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MEDLINE
Asunto principal:
Dopamina
/
Agonistas de Dopamina
Idioma:
En
Revista:
Psychopharmacology (Berl)
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos