Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling

Abstract

SummaryRecent reports have shown that the selective dopamine D 1 -like agonist SKF 83822 [which stimulates adenylate cyclase, but not phospholipase C] induces prominent behavioral seizures in mice, whereas its benzazepine congener SKF 83959 [which stimulates phospholipase C, but not adenylate cyclase] does not. To investigate the relative involvement of D 1 vs D 5 receptors in mediating seizures, ethological behavioral topography and cortical EEGs were recorded in D 1 , D 5 and DARPP-32 knockout mice in response to a convulsant dose of SKF 83822. SKF 83822-induced behavioral and EEG seizures were gene dose-dependently abolished in D 1 knockouts. In both heterozygous and homozygous D 5 knockouts, the latency to first seizure was significantly increased and total EEG seizures were reduced relative to wild-types. The majority (60%) of homozygous DARPP-32 knockouts did not have seizures; of those having seizures (40%), the latency to first seizure was significantly increased and the number of high amplitude, high frequency polyspike EEG events was reduced. In addition, immunoblotting was performed to investigate downstream intracellular signalling mechanisms at D 1 -like receptors following challenge with SKF 83822 and SKF 83959. In wild-types administered SKF 83822, levels of ERK1/2 and GluR1 AMPA receptor phosphorylation increased two-fold in both the striatum and hippocampus; in striatal slices DARPP-32 phosphorylation at Thr34 increased five-fold relative to vehicle-treated controls. These findings indicate that D 1 , and to a lesser extent D 5 , receptor coupling to DARPP-32, ERK1/2 and glutamatergic signalling is involved in mediating the convulsant effects of SKF 83822.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

“…An alternative interpretation of the lack of effect of SKF 83959 on extinction is based on work identifying SKF 83822 as a protein kinase A (PKA)-coupled D1/5 receptor agonist and SKF 83959 as a phospholipase C (PLC)-coupled D1/5 receptor agonist (O'Sullivan et al, 2008;Beaulieu et al, 2015). According to this interpretation, activating PKA-coupled, but not PLC-coupled D1/5 receptors can enhance fear extinction.…”

“…SKF 83822 and SKF 83959 (Tocris) were dissolved in 10% DMSO (dimethyl sulfoxide in distilled water) and administered subcutaneously. Drug dosing for SKF 83822 (0.1, 1, 2 mg/kg) and SKF 83959 (0.1, 1, 10 mg/kg) were estimated based on doses used by O'Sullivan et al (2008).…”

Monoaminergic Mechanisms in Epilepsy May Offer Innovative Therapeutic Opportunity for Monoaminergic Multi-Target Drugs

“…Initially, the majority of results on D 1 -like receptor agonist effects on behavioral seizure thresholds clearly indicated proconvulsant effects (Starr, 1996). Nevertheless, recent reports showed that D 1 -like receptor agonists, linked to stimulation of adenylate cyclase (AC; but not phospholipase C, PLC), led to prominent behavioral seizures in rodents, whereas D 1 -like receptor agonists, linked to stimulation of phospholipase C (PLC, but not AC), did not (O'Sullivan et al, 2008). The D 5 R belongs to the D 1 -like receptor family and upon its activation mainly increased excitation is observed, although less prominent in comparison with D 1 R activation and subsequent increases in cAMP (O'Sullivan et al, 2008).…”

Regulation of the ERK pathway in the dentate gyrus by in vivo dopamine D1 receptor stimulation requires glutamatergic transmission

“…In addition, several reports highlight that modulation of D1Rs could impact on the seizure threshold. Indeed, the administration of D1R-like agonist induces seizures (Gangarossa et al, 2011;O'Sullivan et al, 2008) and decrease seizure threshold in the pilocarpine model (al-Tajir et al, 1990;Alam and Starr, 1992). Moreover, D1R neuron-ablated mice displayed spontaneous stereotyped seizures, which have been associated to cell loss, astrogliosis and microgliosis in the dentate gyrus (Gantois et al, 2007).…”