Targeting the dopamine D₁ receptor or its downstream signalling by inhibiting phosphodiesterase‐1 improves cognitive performance

Abstract

Background and PurposeInsufficient prefrontal dopamine 1 (D1) receptor signalling has been linked to cognitive dysfunction in several psychiatric conditions. Because the PDE1 isoform B (PDE1B) is postulated to regulate D1 receptor‐dependent signal transduction, in this study we aimed to elucidate the role of PDE1 in cognitive processes reliant on D1 receptor function.Experimental ApproachCognitive performance of the D1 receptor agonist, SKF38393, was studied in the T‐maze continuous alternation task and 5‐choice serial reaction time task. D1 receptor/PDE1B double‐immunohistochemistry was performed using human and rat prefrontal brain sections. The pharmacological activity of the PDE1 inhibitor, ITI‐214, was assessed by measuring the increase in cAMP/cGMP in prefrontal brain tissue and its effect on working memory performance. Mechanistic studies on the modulation of prefrontal neuronal transmission by SKF38393 and ITI‐214 were performed using extracellular recordings in brain slices.Key ResultsSKF38393 improved working memory and attentional performance in rodents. D1 receptor/PDE1B co‐expression was verified in both human and rat prefrontal brain sections. The pharmacological activity of ITI‐214 on its target, PDE1, was demonstrated by its ability to increase prefrontal cAMP/cGMP. In addition, ITI‐214 improved working memory performance. Both SKF38393 and ITI‐214 facilitated neuronal transmission in prefrontal brain slices.Conclusion and ImplicationsWe hypothesize that PDE1 inhibition improves working memory performance by increasing prefrontal synaptic transmission and/or postsynaptic D1 receptor signalling, by modulating prefrontal downstream second messenger levels. These data, therefore, support the use of PDE1 inhibitors as a potential approach for the treatment of cognitive dysfunction.

Phosphodiesterase 1b (PDE1B) Regulates Spatial and Contextual Memory in Hippocampus

“…In a test of rat object recognition memory, ITI-214 augmented memory at 1 or 3 mg/kg when dosed before training, 3 h after training, or before testing. Additional studies demonstrated a reversal of MK-801 induced working memory deficits in a T-maze spontaneous alternation task, here again at doses of 1–3 mg/kg (Pekcec et al, 2018). In contrast, DNS-0056 only enhanced contextual memory when given either before or immediately after acquisition of contextual fear.…”

Therapeutic targeting of 3′,5′-cyclic nucleotide phosphodiesterases: inhibition and beyond

“…The broad PDE1 inhibitor ITI-214, which shows picomolar IC50s for PDE1A, PDE1B and PDE1C in enzymatic assays and >1000-fold selectivity versus its nearest neighbor PDE4 (95,96), is being explored for CNS and non-CNS indications. ITI-214 demonstrates cognition-enhancing effects in rodent models of long-term memory and working memory deficits (95)(96)(97), mimicking effects of a dopamine receptor 1 (D1) agonist (97) and occurring at doses that leave efficacy of the antipsychotic risperidone intact (95). Although the target mediating the cognition-enhancing effects of ITI-214 remains undetermined, PDE1B may be the most likely candidate given its expression in D1-expressing neurons (97) along with the fact that the a PDE1B-selective inhibitor showed similar cognition-enhancing effects (98).…”

“…ITI-214 demonstrates cognition-enhancing effects in rodent models of long-term memory and working memory deficits (95)(96)(97), mimicking effects of a dopamine receptor 1 (D1) agonist (97) and occurring at doses that leave efficacy of the antipsychotic risperidone intact (95). Although the target mediating the cognition-enhancing effects of ITI-214 remains undetermined, PDE1B may be the most likely candidate given its expression in D1-expressing neurons (97) along with the fact that the a PDE1B-selective inhibitor showed similar cognition-enhancing effects (98). ITI-214 was moved into the clinic, with potential applications for cognitive deficits associated with schizophrenia, AD, and Parkinson's Disease (96), with safety and tolerability established in healthy volunteers and patients with schizophrenia (Table 3).…”

Phosphodiesterase 1 Bridges Glutamate Inputs with NO- and Dopamine-Induced Cyclic Nucleotide Signals in the Striatum

“…Although PDEs have been evaluated as therapeutic targets for a wide variety of pathologies (Keravis & Lugnier, 2012;Ahmad et al, 2015) including neuropsychiatric disorders (Menniti et al, 2006;Reneerkens et al, 2009;Schmidt, 2010), the lack of specificity of early PDE1 inhibitors such as zaprinast and vinpocetine rendered uncertain the actual involvement of PDE1 in the effects reported in preclinical and clinical pharmacological studies (Ahn et al, 1989;Vemulapalli et al, 1996;Sitges & Nekrassov, 1999;Sitges et al, 2005;Lugnier, 2006;Medina, 2011). More recently, selective PDE1 inhibitors have been developed (Maurice et al, 2014): the PDE1 inhibitor ITI-214 was shown to enhance memory processes and cognitive performance (Snyder et al, 2016;Pekcec et al, 2018), while Lu AF64196 was used to examine PDE1 function in the Cerebral Cortex DOI:10.1093/cercor/bhz041…”