Jeremy K. Seamans

Dopamine Receptor Signaling

The D1-like (D1, D5) and D2-like (D2, D3, D4) classes of dopamine receptors each has shared signaling properties that contribute to the definition of the receptor class, although some differences among subtypes within a class have been identified. D1-like receptor signaling is mediated chiefly by the heterotrimeric G proteins Gαs and Gαolf, which cause sequential activation of adenylate cyclase, cylic AMP-dependent protein kinase, and the protein phosphatase-1 inhibitor DARPP-32. The increased phosphorylation that results from the combined effects of activating cyclic AMP-dependent protein kinase and inhibiting protein phosphatase 1 regulates the activity of many receptors, enzymes, ion channels, and transcription factors. D1 or a novel D1-like receptor also signals via phospholipase C-dependent and cyclic AMP-independent mobilization of intracellular calcium. D2-like receptor signaling is mediated by the heterotrimeric G proteins Gαi and Gαo. These pertussis toxin-sensitive G proteins regulate some effectors, such as adenylate cyclase, via their Gα subunits, but regulate many more effectors such as ion channels, phospholipases, protein kinases, and receptor tyrosine kinases as a result of the receptor-induced liberation of Gβγ subunits. In addition to interactions between dopamine receptors and G proteins, other protein:protein interactions such as receptor oligomerization or receptor interactions with scaffolding and signal-switching proteins are critical for regulation of dopamine receptor signaling.

The computational role of dopamine D1 receptors in working memory

The prefrontal cortex (PFC) is essential for working memory, which is the ability to transiently hold and manipulate information necessary for generating forthcoming action. PFC neurons actively encode working memory information via sustained firing patterns. Dopamine via D1 receptors potently modulates sustained activity of PFC neurons and performance in working memory tasks. In vitro patch-clamp data have revealed many different cellular actions of dopamine on PFC neurons and synapses. These effects were simulated using realistic networks of recurrently connected assemblies of PFC neurons. Simulated D1-mediated modulation led to a deepening and widening of the basins of attraction of high (working memory) activity states of the network, while at the same time background activity was depressed. As a result, self-sustained activity was more robust to distracting stimuli and noise. In this manner, D1 receptor stimulation might regulate the extent to which PFC network activity is focused on a particular goal state versus being open to new goals or information unrelated to the current goal.

Mesocortical Dopamine Neurons Operate in Distinct Temporal Domains Using Multimodal Signaling

In vivo extracellular recording studies have traditionally shown that dopamine (DA) transiently inhibits prefrontal cortex (PFC) neurons, yet recent biophysical measurements in vitro indicate that DA enhances the evoked excitability of PFC neurons for prolonged periods. Moreover, although DA neurons apparently encode stimulus salience by transient alterations in firing, the temporal properties of the PFC DA signal associated with various behaviors is often extraordinarily prolonged. The present study used in vivo electrophysiological and electrochemical measures to show that the mesocortical system produces a fast non-DA-mediated postsynaptic response in the PFC that appears to be initiated by glutamate. In contrast, short burst stimulation of mesocortical DA neurons that produced transient (<4 s) DA release in the PFC caused a simultaneous reduction in spontaneous firing (consistent with extracellular in vivo recordings) and a form of DA-induced potentiation in which evoked firing was increased for tens of minutes (consistent with in vitro measurements). We suggest that the mesocortical system might transmit fast signals about reward or salience via corelease of glutamate, whereas the simultaneous prolonged DA-mediated modulation of firing biases the long-term processing dynamics of PFC networks.

Ethanol Inhibits Persistent Activity in Prefrontal Cortical Neurons

Cognitive functions supported by neurons in the prefrontal cortex (PFC) are disrupted by acute and chronic exposure to alcohol, yet little is known about the mechanisms that underlie these effects. In the present study, in vivo and in vitro electrophysiology was used to determine the effects of ethanol on neuronal firing and network patterns of persistent activity in PFC neurons. In vivo, ethanol (0.375–3.5 g/kg) dose-dependently reduced spike activity in the PFC measured with multielectrode extracellular recording in the anesthetized rat. In an in vitro coculture system containing slices of PFC, hippocampus, and ventral tegmental area (VTA), ethanol (25–100 mm) decreased persistent activity of PFC neurons, but had little effect on firing evoked by direct current injection. Persistent activity was often enhanced after ethanol washout and this effect was maintained in cultures lacking the VTA. A low concentration of the NMDA antagonist APV (5 μm) mimicked the inhibition of ethanol of persistent activity with no change in activity after washout. Ethanol inhibition of spontaneous and VTA-evoked persistent activity was enhanced by the D1 dopamine receptor antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride]. The results of this study show that ethanol inhibits persistent activity and spike firing of PFC neurons and that the degree of ethanol inhibition may be influenced by D1 receptor tone. Ethanol-induced alterations in the activity of deep-layer cortical neurons may underlie some of the behavioral effects associated with ethanol intake.

Working Memory in Prefrontal Cortex and its Neuromodulation

Working memory is conceptually different from short-term memory and likely relies on different neurobiological substrates. Working memory may be defined as the capacity to use mnemonic information to plan and organize forthcoming action. These processes rely on the prefrontal cortex (PFC), and neurons in this region appear to encode mnemonic information and forthcoming responses based on memory. The task related activity of PFC neurons and overall working memory performance is strongly regulated by dopamine. Dopamine might bias networks of PFC neurons to enter different processing modes, causing PFC networks to either process memory related information in a flexible manner (state 1) or to strongly maintain a single goal state in memory even in the presence of distracters (state 2). Dopamine levels in PFC fluctuate during different cognitive and emotional states, and such fluctuations could switch PFC networks between these two states. Dopamine may therefore dynamically regulate how PFC networks “work with memory” to guide future thought or action.