Dopamine modulation

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Jeremy Seamans and Daniel Durstewitz (2008), Scholarpedia, 3(4):2711. doi:10.4249/scholarpedia.2711 revision #90663 [link to/cite this article]
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Curator: Daniel Durstewitz

This article will briefly cover: basic dopamine neuron physiology and electrophysiology of dopamine modulation of cortex.


Basic electrophysiology of dopamine neurons

Dopamine (DA) neurons show two predominant patterns of firing activity termed tonic and phasic (Grace 1991, 2000). Tonic activity consists of a regular spike firing pattern of ~1-6 Hz that DA neurons usually exhibit in the absence of salient stimuli (Grace and Bunney, 1984b; Schultz et al, 1997). Tonic firing patterns maintain basal extracellular levels of DA in afferent regions, and can be affected by visceral stimuli that can moderately increase or decrease efferent DA levels to provide a “tone” on DA receptors (Grace, 1991). These levels recorded using in vivo microdialysis are on the order of 0.3 to 15nM in the striatum and PFC (Devoto et al, 2001; Garris et al, 1993; Garris and Wightman, 1994; Hernandez and Hoebel, 1995; Hildebrand et al, 1998; Ihalainen et al, 1999; Izaki et al, 1998; Shoblock et al, 2003). Phasic activation of DA neurons increases their firing rates to ~20Hz (Grace and Bunney, 1984a; Kiyatkin and Zhukov, 1988; Kiyatkin and Stein, 1995), which also results in significant but transient increases in extracellular DA concentrations (Phillips et al, 2003; Williams and Millar, 1990; Lavin et al, 2005). Changes in the firing rate of DA neurons can evoke a wide range of effects on efferent neurons by increasing or decreasing levels of DA (Phillips et al., 2003; Williams and Millar, 1990; Lavin et al. 2005).

Physiological effects of dopamine in target areas

In vivo physiology

Some of the key early in vivo electrophysiological investigations in striatum showed that exogenously applied DA (either by bath application in vitro or by microiontophoresis in vivo) moderately depolarized, and/or hyperpolarized, neurons by 5 - 7 mV (Herrling and Hull, 1980; Herrling, 1981; Bernardi et al., 1982; Uchimura et al., 1986). The effects of exogenous DA on spontaneous firing of striatal and PFC neurons were generally suppressive. This led many investigators to call DA an ‘inhibitory ‘ transmitter (Connors 1970; Mantz et al., 1992), although recent electrophysiological data suggest that DA is more appropriately defined as a neuromodulator. A modulator should induce little or no change to basal neuronal activity, but will potentiate or attenuate responses evoked by another transmitter substance (Barchas et al., 1978). In the striatum or nucleus accumbens, the bulk of studies showed that DA, either iontophoretically applied or synaptically released by stimulation of the VTA, suppressed synaptically evoked glutamatergic inputs (e.g. from the hippocampal or amygdala to the nucleus accumbens) or glutamate evoked excitation (Reader et al., 1979; Hirata and Mogenson, 1984; Hirata et al., 1984; Vives and Mogenson, 1986; Yim and Mogenson, 1984; Yang and Mogenson, 1986; White and Wang, 1986). However, paradoxically, when iontophoretically co-applied with glutamate or GABA at very low iontophoretic doses, DA potentiated glutamate excitation in striatum, accumbens, substantia nigra pars reticulata, and somatosensory cortex (Chiodo and Berger, 1986; Waszcak and Walters, 1983; White and Wang, 1986; Hu and White, 1997).

In PFC, VTA activation or DA exerted a predominately `inhibitory' effect on spontaneous firing of single pyramidal cells recorded extracellularly in vivo (Bunney and Aghajanian 1976; Ferron et al, 1984; Godbout et al, 1991; Mantz et al, 1992; Mora et al, 1976; Pirot et al, 1992; Sesack and Bunney 1989; Tseng et al, 2006) which typically lasts for 100-200ms. Local iontophoretic application of DA also decreased the spontaneous firing of PFC neurons recorded extracellularly in vivo and this spike suppression was reduced by a D2, but generally not by a D1 antagonist (Parfitt et al, 1990; Pirot et al, 1992). Accordingly, D2 agonists were more effective than D1 agonists in replicating the DA-mediated inhibition of spontaneous firing (Thierry et al, 1998). However, Sesack and Bunney (1989) found that iontophoretic application of a D2 agonist directly onto single PFC neurons in vivo failed to mimic the DA-mediated firing suppression. Moreoever, a D2 antagonist caused an increase in evoked spike firing of striatal neurons recorded intracellularly in vivo (West and Grace 2002).

The DA modulation of excitability in PFC neurons appears to depend strongly on GABA activation. Pirot et al (1992) showed that the GABA antagonist bicuculline blocked the iontophoretic DA and VTA-mediated inhibition of spontaneous firing in 57% and 51% of cells respectively. Moreover a D2 antagonist reduced the DA-mediated and VTA-stimulation induced inhibition of spontaneous firing in PFC in 89% and 54% of cells respectively. Furthermore, depleting DA stores by pre-treatment with a-methyl-p-tyrosine reduced the number of cells inhibited by VTA stimulation to 39% and in this subset of cells the VTA-induced inhibition was no longer influenced by sulpiride (a D2 antagonist) but was blocked by bicuculline.

In summary, in PFC DA application or VTA stimulation induces a relatively short-lasting inhibition of spontaneous firing. This seems to be mediated partly directly through activation of VTA GABA afferents (Carr & Sesack 2000), and partly through D2-mediated enhancement of GABAergic neurons and/or currents in PFC.

In vivo intracellular recordings have shown for some time that stimulation of the VTA evokes an EPSP in the PFC (Bernardi et al. 1982; Lewis & O’Donnell 2000; Lavin et al. 2005). Accordingly there have been suggestions that DA neurons may also co-release glutamate (Chuhma et al., 2004; Sulzer et al. 1998; Dal Bo et al. 2004; Lavin et al. 2005; Lapish et al. 2007). Recent data clearly show that there is a substantial portion of neurons within midbrain DA rich regions that express the vesicular glutamate transporter 2 (Hur and Zaborszky, 2005; Kawano et al. 2006; Yamaguchi et al. 2007), although the proportion of these that also contain DA is unclear as is their functional relevance. We have argued that release or co-release of glutamate from midbrain neurons may be a good candidate to signal fast events by DA neurons, given that DA itself is poorly suited for this purpose (Lapish et al. 2007).

However, dopamine can potently modulate fast events in the striatum that are associated with learning (Day et al. 2007). Using in vivo recordings from the striatum, Reynolds et al. (2001) found that stimulation of the substantia nigra induced potentiation of synapses between the cortex and the striatum with the degree of potentiation correlating with the time taken by the rats to learn a lever press behavior. This suggests that dopamine can act as a positive reinforcer via potentiation of inputs to the striatum. Yet the dopamine modulation appears to be input selective. Goto & Grace (2005) reported that tonic and phasic DA release selectively modulates hippocampal inputs to the ventral striatum via D1 receptors and prefrontal cortical inputs through D2 receptors while manipulation of D1 and D2 receptors could selectively affect behaviors mediated by different brain regions. Likewise, dopamine released by either electrical stimulation or amphetamine has been shown to act via D2 receptors to inhibit the activity of subsets of corticostriatal terminals (Bamford et al. 2004). Therefore dopamine may act as a filter for selecting particular inputs, and thereby exert selective effects on corticostriatal inputs that underlie various behaviors.

In vitro physiology: Intrinsic currents

In the PFC, Penit-Soria et al. (1987) first reported that DA at high concentrations (400 mM) and in the presence of DA uptake blocker nomifensine increased neuronal excitability of PFC neurons recorded intracellularly in brain slices. Consistent with these initial findings, DA via D1 receptors has been shown to increase the excitability of PFC neurons in vitro (Henze et al. 2000; Ceci et al 1999; Wang & O’Donnell, 2001; Lavin & Grace; 2002; Cépeda et al. 2000; Shi et al. 1997 but see Geijo-Barrientos & Pastore (1995) and in vivo (Lavin et al., 2005). Gulledge & Jaffe (1998; 2001) in a thorough series of investigations showed that it was possible to get both a decrease and increase in depolarizing pulse evoked firing of PFC neurons in vitro by a single brief application of DA. They observed that bath-applied DA initially reduced spike firing evoked by intracellular depolarizing pulses via D2 receptor activation that subsided in the 10-15 min after DA application. This was followed by an increase in evoked spiking that typically lasted for the duration of the experiment (>30 mins), indicating a biphasic effect of DA. A similar biphasic effect of DA on excitatory and inhibitory transmission has also routinely been observed in tissue from the hippocampus, PFC and entorhinal cortex (Gribkoff & Ashe 1984; Huang & Kandel 1995; Seamans et al. 2001a,b; Caruana et al. 2006).

The effect of DA on intrinsic excitability of pyramidal neurons appears to be determined by a variety of cellular mechanisms. The initial decrease in excitability may be due to an increase in a hyperpolarization-activated conductance, Ih as shown in entorhinal cortex neurons (Rosenkranz & Johnston 2006). In addition, down-regulation of transient Na+ currents by a D1-PKA-DARPP-32 pathway has been shown to decrease excitability of striatal cells (Schiffmann, et al., 1995; Calabresi, et al., 1987; Stanzione et al., 1984; Cantrell et al., 1997; 1999). On the other hand, the mainly D1-dependent increase in pyramidal cell excitability may be partly due to a D1/D5 receptor-mediated enhancement of the persistent Na+ current INaP which has been reported in some studies (Yang & Seamans 1996; Gorelova & Yang 2000) but not others (Geijo-Barrientos & Pastore 1995; Maurice et al. 2001). Although the D1-mediated increase in excitability is well accepted, the contribution of INap modulation to this effect is one of the most controversial issues in the area and remains unresolved.

In striatal and PFC neurons, D1 receptor stimulation also decreases the slowly inactivating K current and this effect can occur directly via PKA and/or cAMP phosphorylation of the K channel (Surmeier and Kitai, 1993; Yang & Seamans 1996; Dong, et al., 2003). Hence this mechanism may profoundly contribute to the D1-mediated increase in excitability, especially at depolarized membrane potentials or at long post-drug intervals.

In addition, DA has been shown to modulate high voltage-activated Ca2+ currents in several types of vertebrate and invertebrate neurons in vitro (Paupardin-Tritsch et al. 1985; Marchetti et al. 1986; Surmeier et al. 1995). In striatal neurons held at depolarized potentials D1 agonists or cAMP analogs prolonged slow subthreshold depolarizations via an increase in L-type Ca2+ currents (Song & Surmeier 1996; Hernández-López et al. 1997). In contrast D1 agonists or cAMP analogs reduced N- and P-type Ca2+ currents via PKA and PP1 (Surmeier et al. 1995). In rat layer V-VI PFC pyramidal neurons, following blockade of Na+ and K+ channels, a Ca2+ mediated ‘hump’ potential (>50 ms), and plateau (>100ms) can be evoked (Seamans et al. 1997). Direct D1/5 receptor stimulation suppressed full Ca2+ spikes mediated by N/P-type Ca2+ currents (Yang & Seamans 1996) and these effects were prevented by a PKC inhibitor (Young and Yang, 2002). In contrast the nimodipine-sensitive Ca2+-subthreshold ‘hump’ potential most likely generated by L-type channels in basal dendrites (Seamans et al., 1997; Antic et al. 2003) was augmented transiently (~ 7 mins) by D1/5 receptor agonists (Young and Yang, 2002) and this interaction was blocked by PKA inhibitor. Therefore, in both striatum and PFC there is opposing D1 mediated modulation of L- and N/P-type Ca2+ currents although the intracellular cascades involved may differ between regions. Since N/P- and L-type Ca2+ channels have different distributions across the somato-dendritic extent (Westenbroek et al. 1990, 1992), their opposing modulation via D1 may yield differential effects for proximal (enhanced) vs. distal (diminished) excitability.

D1 receptors also enhance excitability of fast spiking parvalbumin positive interneurons by regulating K+ currents (Gorelova, et al., 2002; Kroner et al. 2005). Although in adolescent rats and monkeys the modulation is exclusive to fast-spiking interneurons and is exclusively D1-mediated, in slices from older animals a D2-mediated modulation appears to develop that is synergistic with the D1-mediated effect and extends to other interneurons rather than just fast-spiking ones (Tseng et al. 2007). In contrast, a reversal of the D1 mediated depolarization of interneurons was observed following subsequent application of a D2 agonist in slices from young rats (Gorelova et al 2002). In summary, DA in PFC increases the excitability of pyramidal neurons through D1-receptors and diminishes it via D2-class receptors by acting on multiple voltage-gated somatic and dendritic ion channels. In addition, DA via D1 receptors and possibly D2 receptors enhances the excitability of at least some interneurons.

In vitro physiology: Excitatory synaptic currents

In striatal neurons, reports of modulation of mixed glutamate receptor mediated synaptic responses have been contradictory. In dorsal striatal neurons, DA depresses (Umemiya & Raymond 1997) or has no effect (Nicola & Malenka 1998) on compound postsynaptic potentials. However, in other studies the non-NMDA response was shown to be augmented by activation of either DA or protein kinase A (PKA) (Colwell & Levine 1995; Levine & Cépeda 1998a,b). Across many brain regions, most studies show a decrease in the evoked AMPA EPSP/Cs by DA (Cépeda et al. 1993; 1998a,b; Seamans et al. 2001a, Zheng et al. 1999; Urban et al. 2002; Law-Tho et al. 1994 and Gao et al. 2001).

In rodent PFC, DA or a D1 agonist decreases evoked non-NMDA EPSP/Cs, without altering the post-synaptic inward AMPA current induced by focal application of AMPA (Law-Tho et al. 1994; Gao et al. 2001; Seamans et al., 2001a; Zheng et al., 1999). This suggests that the D1-mediated reduction of non-NMDA EPSP/Cs occurs presynaptically. Accordingly, the paired-pulse ratio evoked by single axon inputs between layer III PFC pyramidal cell-pairs and mini EPSCs (in TTX), were both reduced by focally applied DA and D1 agonists in ferret PFC slices (Gao et al 2001; Gao & Goldman-Rakic 2003a). However, this effect on paired-cell EPSPs may be species specific because in primate dorsolateral PFC slices Urban et al. (2002) found no such reduction in paired-cell recordings from layer III PFC neurons but did report that EPSCs evoked by a stimulating electrode were reduced by DA via D1, and possibly D2, receptors. In rat PFC neurons, D1 agonists also reduced the evoked EPSC, mEPSC frequency and slowed the synaptic activity-dependent MK801 blocking function (Seamans et al. 2001a), again suggesting that activation of presynaptic D1 sites on glutamate axonal terminals in the PFC of primates and rats reduce glutamate release.

A few studies have reported a DA-mediated increase in EPSP/Cs in PFC neurons (Wang et al. 2002a; Gonzalez-Islas and Hablitz, 2003 Marek and Aghajanian, 1999). However, in two of these latter studies (Wang et al. 2002a; Marek and Aghajanian, 1999) the effect was due to an increase in the frequency of spontaneous EPSCs that may reflect changes in pyramidal cell excitability rather than a direct D1 receptor mediated increase in presynaptic glutamate release. In contrast, another group showed that in layer II-III PFC neurons there is a DA mediated reduction in sEPSCs (Zhou and Hablitz 1999) although DA was later shown to enhance both AMPA and NMDA EPSCs (Gonzalez-Islas and Hablitz, 2003). Collectively these data imply that the magnitude of the modulation by DA of non-NMDA EPSCs may be species and layer specific.

The potentiation of evoked NMDA responses was first reported by Cépeda and colleagues (for review see Cépeda and Levine, 1998b) and most subsequent studies have reported that DA via D1 receptors increase NMDA currents or potentials in striatal (Cepeda et al. 1992; 1999; Cepeda & Levine 1998; Flores-Hernandez et al. 2002), hippocampal (Yang 2001; Huang & Kandel 1995) and cortical neurons (Zheng et al. 1999; Seamans et al. 2001a; Wang & O’Donnell 2001; Tseng & O’Donnell 2004). There appears to be a clear dose-dependency to the DA modulation of NMDA currents. The NMDA EPSC evoked by synaptic stimulation of layer V or focal NMDA pressure-puff was potentiated by low doses of DA or a D1 agonist (<10uM) (Seamans et al., 2001a; Zheng et al., 1999). However at higher doses of DA (> 50uM), attenuation of the NMDA current resulted. The low dose mediated potentiation of the NMDA EPSC was D1 receptor-dependent while the attenuation of NMDA EPSC at higher doses of DA required D2 receptors (Zheng et al., 1999; Seamans et al., 2001a) or D4 receptors (Wang et al. 2003).

One common feature of the D1 modulation of NMDA responses in vitro is its delayed onset and prolonged duration. This effect was shown by Huang & Kandel (1995) who termed the effect “late potentiation”. A single application of a D1 agonist can slowly increase the field EPSP response in hippocampal CA1 neurons to 140% of their baseline levels for > 3 hrs. This effect was largely eliminated in the presence of an NMDA antagonist, indicating that much of the potentiation was due to an increase in the NMDA component. Similar results were observed using patch-clamp recordings of hippocampal neurons (Yang 1999). Moreover, activation of D1 receptors or its downstream targets have been shown to induce similarly delayed and long-lasting effects on various synaptic currents evoked in hippocampal neurons (Greengard et al. 1991; Yang 2000) neostriatal neurons (Colwell & Levine 1995; Umemiya & Raymond 1997) retinal horizontal cells (Pereda et al. 1992), cerebellar parallel fibers (Salin et al. 1996; Mitoma & Konishi 1996) midbrain DA neurons (Cameron & Williams 1993) and PFC neurons (Seamans et al 2001a,b; Chen and Yang, 2002; Urban et al. 2002).

In summary, in PFC and many other brain regions DA enhances NMDA synaptic currents via D1- and reduces them via D2-receptors. The effects on non-NMDA excitatory currents are mainly a D1-mediated reduction in presynaptic release probability, however, seem to be more specific to species, brain region, and cell layer. The combined DA effects on NMDA currents and release probability could make DA-modulation of synaptic input trains frequency- and duration-dependent: D1 agonists decreased single EPSPs that occurred early in a train or series of EPSPs at low input frequency (mainly AMPA-mediated), yet enhanced the late depolarization and high-frequency inputs (Bamford et al. 2004; Seamans et al. 2001a; Gonzales-Burgos et al. 2005). A similar frequency dependent gating effect of DA has also been shown for inputs to the PFC from the hippocampus or amygdala (Floresco & Grace 2003; Floresco & Tse 2007). Thus DA may favor sustained high frequency as opposed to brief and/or low-frequency inputs with potentially profound functional implications (Durstewitz & Seamans 2002). This idea of selective filtering of different input frequencies by DA is not new as DeFrance et al. (1985) showed in nucleus accumbens neurons recorded extracellularly, DA reduced the fimbria-induced synaptic field response at 0.5 Hz but enhanced the response evoked at 6 Hz stimulation. When combined these changes in synaptic currents may enhance or reduce the spatio-temporal extent of evoked activity as assessed by voltage-sensitive dye bulk imaging in PFC slices, depending on the magnitude of inhibition and its state of modulation (Bandyopadhyay et al. 2005; Bandyopadhyay & Hablitz 2007).

In vitro physiology: Inhibitory synaptic currents

In striatal GABAergic projection neurons, DA via D2 receptors reduced evoked IPSC amplitude and spontaneous IPSC frequency, suggesting a presynaptic mode of action (Delgado et al. 2000). Likewise, the IPSC in pallidal neurons produced by stimulation of the efferents of the striatum, was also reduced by DA via D2 receptors. Again, changes in mini IPSC frequency and paired-pulses ratios suggested a presynaptic mode of action (Cooper & Stanford 2001). DA or D2 agonists reduced evoked IPSCs in striatal medium spiny neurons in wild type, but not D2 knock out mice. Furthermore, the depression of evoked IPSCs was also observed following release of DA by amphetamine, and this amphetamine-induced depression of IPSCs was blocked by a D2 antagonist (Centonze et al. 2002). In striatal cholinergic interneurons, DA via D2 receptors reduced evoked IPSCs and mini IPSC frequency through a presynaptic action that was mediated by inhibition of presynaptic N-type Ca2+ channels (Momiyama & Koga 2001). In these cholinergic interneurons, Pisani et al. (2001) also showed that D2 agonists decreased evoked IPSCs via a presynaptic mechanism, while D1 agonists depolarized these interneurons without affecting evoked IPSC amplitude directly. In contrast, Yan & Surmeier (1997) reported that D5 receptor stimulation enhanced a zinc-sensitive GABA current postsynaptically in dissociated striatal cholingergic interneurons. D1 agonists directly depolarized fast-spiking striatal GABAergic interneurons, while a D2 agonist decreased evoked IPSCs through a presumably presynaptic action (Bracci et al. 2002).

In PFC DA appears to act through diverse cellular mechanisms to modulate inhibition. Penit-Soria et al. (1987) first showed that a high concentration (400 mM) of DA increased spontaneous IPSP frequency in layer V-VI neurons in PFC slices, suggesting that DA could increase action potential dependent release of GABA. But subsequently Law-Tho et al. (1994) showed that DA depressed pharmacologically isolated IPSPs evoked by an extracellular stimulating electrode. In contrast, in layer I-II PFC neurons, Zhou & Hablitz (1999) observed that DA increases spontaneous sIPSC frequency and amplitude. In spite of the increase in sIPSC amplitude, a subsequent study by this group (Gonzales-Islas & Hablitz 2001) and others (layer V-VI, Seamans et al. 2001b) showed that DA reduced evoked IPSC amplitude. The latter effect was also observed by Gao & Goldman-Rakic (2003b) using interneuron-pyramidal cell pair recordings from ferret PFC neurons. The modulation of IPSCs was appeared to be bi-directional as the initial decrease in amplitude was followed by a D1-mediated late increase in IPSC amplitude (Seamans et al. 2001b). A D2 agonist applied at the peak of the D1 mediated increase in IPSCs could reverse the increase and produce a decrease in IPSC amplitude in pyramidal neurons (Seamans et al. 2001b). In pyramidal neurons the D2 effect on IPSC amplitude appeared to be largely postsynaptic and occurred through a novel signaling cascade for DA receptors (Trantham-Davidson et al. 2004). In addition, D4 receptors were also shown to reduce GABA currents through a PKA/PP1 pathway (Wang et al. 2002).

In summary, DA in striatum and PFC appears to mainly enhance GABAergic currents via D1-class receptors and reduce them via D2-class receptors. At the same time, DA modulates excitability of GABAergic interneurons through various mechanisms that may account for some of the apparently inconsistent results. The computational consequences of the overall effect of DA modulation of these diverse intrinsic and synaptic currents (Durstewitz et al. 1999, 2000; Durstewitz & Seamans 2002) will be discussed elsewhere.


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Internal references

  • Valentino Braitenberg (2007) Brain. Scholarpedia, 2(11):2918.
  • John Dowling (2007) Retina. Scholarpedia, 2(12):3487.
  • Wolfram Schultz (2007) Reward. Scholarpedia, 2(3):1652.

See Also

Dopamine, Dopamine Anatomy, Reward, Reward Signals

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