A Postsynaptic Interaction between Dopamine D₁and NMDA Receptors Promotes Presynaptic Inhibition in the Rat Nucleus Accumbens via Adenosine Release

Abstract

The mechanism underlying dopamine D 1 receptor-mediated attenuation of glutamatergic synaptic input to nucleus accumbens (NAcc) neurons was investigated in slices of rat forebrain, using whole-cell patch-clamp recording. The depression by dopamine of EPSCs evoked by single-shock cortical stimulation was stimulus-dependent. Synaptic activation of NMDA-type glutamate receptors was critical for this effect, because dopamine-induced EPSC depressions were blocked by the competitive NMDA receptor antagonist D/L-2-amino-5-phosphonopentanoate (AP5). Application of NMDA also depressed the EPSC, and both this effect and the dopamine depressions were blocked by the A 1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), implicating adenosine release in the EPSC depression. A 1 receptor agonists also depressed EPSCs by a presynaptic action, causing increased paired-pulse facilitation, but this was insensitive to AP5. Activation of D 1 receptors enhanced both postsynaptic inward currents evoked by NMDA application and the isolated NMDA receptor-mediated component of synaptic transmission.The biochemical processes underlying the dopamine-induced EPSC depression did not involve either protein kinase A or the production of cAMP and its metabolites, because this effect was resistant to the protein kinase inhibitors H89 and H7 and the cAMP-specific phosphodiesterase inhibitor rolipram. We conclude that activation of postsynaptic D 1 receptors enhances the synaptic activation of NMDA receptors in nucleus accumbens neurons, thereby promoting a transsynaptic feedback inhibition of glutamatergic synaptic transmission via release of adenosine. Unusually for D 1 receptors, this phenomenon occurs independently of adenylyl cyclase stimulation. This process may contribute to the locomotor stimulant action of dopaminergic agents in the NAcc.

Dopaminergic signaling in dendritic spines

“…In the nucleus accumbens, most studies report that DA attenuates corticoaccumbal glutamatergic input by acting on D1-class receptors [6]. This attenuation, according to one proposed mechanism, is mediated by an inhibitory feedback action of adenosine, liberated following facilitation of NMDARs by D1-mediated PKC activation in postsynaptic neurons [58] layer PFC synapses and hippocampal-PFC synapses, agonists of D1-class receptors facilitated, whereas antagonists impaired, NMDAR-dependent LTP via cAMP-dependent mechanisms [63][64]. Acting at both D1-and D2-class receptors, DA at high concentrations facilitates LTD, whereas at low concentrations promotes LTP [65].…”

“…In the nucleus accumbens, most studies report that DA attenuates corticoaccumbal glutamatergic input by acting on D1-class receptors [6]. This attenuation, according to one proposed mechanism, is mediated by an inhibitory feedback action of adenosine, liberated following facilitation of NMDARs by D1-mediated PKC activation in postsynaptic neurons [58]. However, this view remains controversial [59].…”

Amethystic agents influencing toxicodynamics of ethanol

“…Тормозные процессы, инициируемые этим нуклеозидом, реализуются с вовлечением и других нейромедиаторных систем. Так, активация пресинаптических А 1 -рецепторов сопровождается угнетением экзоцитоза глутаминовой кислоты и развитием тормозных процессов в ЦНС [70].…”

“…По-видимому, активация аденозиновых рецепторов при экспозициях к этанолу сопровождается модуляцией и других нейромедиаторных систем, общим итогом которой является развитие седативного действия [70,73].…”

Effects of Chronic Alcohol Exposure on Kainate Receptor-Mediated Neurotransmission in the Hippocampus

“…First, even when these indirect pathways are blocked in other bram regions, KA does not produce a potentiation of elPSC amplitude. Second, both GABAB and adenosine receptor modulation of GABAergic synaptic transmission have been demonstrated in the NAcc (Uchimura and North, 1990;Tao et al 1996;Harvey and Lacey 1997;and Steffensen et al 2000). However, pretreatment with antagonists for both of these receptor systems (SCH 50911; and theophylline; GABAB and adenosine receptor antagonists, respectively) had no effect on the KA receptor-mediated potentiation of elPSCs observed in the current study (data not shown).…”