The striatum and its ventral extension, the nucleus accumbens, are involved in behaviors as diverse as motor planning, drug seeking, and learning. Invariably, these striatally mediated behaviors depend on intact dopaminergic innervation. However, the mechanisms by which dopamine modulates neuronal function in the striatum and nucleus accumbens have been difficult to elucidate. Recent electrophysiological studies have revealed that dopamine alters both voltage-dependent conductances and synaptic transmission, resulting in state-dependent modulation of target cells. These studies make clear predictions about how dopamine, particularly via D1 receptor activation, should alter the responsiveness of striatal neurons to extrinsic excitatory synaptic activity.

Dopaminergic modulation of neuronal excitability in the striatum and nucleus accumbens.

Dopamine receptors: Molecular biology, biochemistry and behavioural aspects

https://www.cell.com/cell/pdf/0092-8674(94)90026-4.pdf

Elimination of cocaine-induced hyperactivity and dopamine-mediated neurophysiological effects in dopamine D1 receptor mutant mice

The interactions between N-methyl-D-aspartate (NMDA) and D(1) dopamine receptors in the rat prefrontal cortex were examined using whole-cell recordings from pyramidal neurons. The effects of NMDA, the D(1) agonist SKF38393, or both compounds combined were tested on measures of cell excitability. Both NMDA (10-100 microM) and SKF38393 (5-10 microM) independently increased the number of spikes and decreased the latency of the first spike evoked by intracellular depolarizing current pulses. Combining low doses of NMDA (5 microM) and SKF38393 (2 microM) resulted in a marked increase of cell excitability. This synergism was blocked by SCH23390, protein kinase A (PKA) inhibitors, and the Ca(2+) chelator BAPTA, and reduced by nifedipine. These results indicate the presence of a dopamine- glutamate interaction in the prefrontal cortex at the postsynaptic level, by which D(1) dopamine receptors may maintain NMDA- mediated responses in prefrontal cortical pyramidal neurons through both a PKA-dependent pathway and Ca(2+)-dependent mechanisms.

D1 Dopamine Receptors Potentiate NMDA-mediated Excitability Increase in Layer V Prefrontal Cortical Pyramidal Neurons

Opposite modulation of cortical N-methyl-D-aspartate receptor-mediated responses by low and high concentrations of dopamine.

The electrophysiological effects of three selective D 1 dopamine (DA) receptor agonists, which exhibit different potencies and efficacies for stimulation of adenylate cyclase, were compared in the rat nucleus accumbens (NAc) using single unit recording and microiontophoretic techniques. The partial agonists SKF 75670 and SKF 38393, and the full agonist SKF 81297 produced nearly identical current-response curves for the inhibition of firing of NAc neurons. In rats acutely depleted of DA byα-methyl-p-tyrosine (AMPT) pretreatment, all three D 1 agonists enabled the inhibition of firing produced by the selective D 2 receptor agonist quinpirole, with SKF 38393 exerting the greatest efficacy, followed by SKF 81297 and SKF 75670. Thus, no apparent relationship was found between the previously reported ability of these compounds to stimulate cyclic adenosine monophosphate (cAMP) production and their ability either to inhibit the firing of NAc neurons or to enable quinpirole-mediated inhibition of firing in DA-depleted rats. In addition, the membrane-permeable cAMP analog 8-bromo-cAMP also caused a current-dependent inhibition of the firing of NAc neurons, but failed to enable quinpirole-mediated inhibition in AMPT-pretreated animals. These results suggest either that only a small percentage of D 1 receptors need to be stimulated to produce these electrophysiological effects, or that D 1 receptors exist within the rat NAc which are linked to transduction mechanisms other than, or in addition to, adenylate cyclase.

X. T. Hu

Papers

Relationship between D1 dopamine receptors, adenylate cyclase, and the electrophysiological responses of rat nucleus accumbens neurons.