Controls of tonic and phasic dopamine transmission in the dorsal and ventral striatum - PubMed (original) (raw)

Controls of tonic and phasic dopamine transmission in the dorsal and ventral striatum

Lifen Zhang et al. Mol Pharmacol. 2009 Aug.

Abstract

Dopamine (DA) release varies within subregions and local environments of the striatum, suggesting that controls intrinsic and extrinsic to the DA fibers and terminals regulate release. While applying fast-scan cyclic voltammetry and using tonic and phasic stimulus trains, we investigated the regulation of DA release in the dorsolateral to ventral striatum. The ratio of phasic-to-tonic-evoked DA signals varied with the average ongoing firing frequency, and the ratio was generally higher in the nucleus accumbens (NAc) compared with the dorsolateral striatum. At the normal average firing frequency, burst stimulation produces a larger increase in the DA response in the NAc than the dorsolateral striatum. This finding was comparable whether the DA measurements were made using in vitro brain slices or were recorded in vivo from freely moving rodents. Blockade of the dopamine transporters and dopamine D(2) receptors particularly enhanced the tonic DA signals. Conversely, blockade of nicotinic acetylcholine receptors (nAChRs) containing the beta(2) subunit (beta(2)(*)) predominantly suppressed tonic DA signals. The suppression of tonic DA release increased the contrast between phasic and tonic DA signals, and that made the frequency-dependent DA dynamics between the dorsolateral striatum and NAc more similar. The results indicate that intrinsic differences in the DA fibers that innervate specific regions of the striatum combine with (at least) DA transporters, DA receptors, and nAChRs to regulate the frequency dependence of DA release. A combination of mechanisms provides specific local control of DA release that underlies pathway-specific information associated with motor and reward-related functions.

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Figures

Fig. 1.

Fig. 1.

DA signals elicited by a signal pulse (1p) or by 5p or 20p given at 20 Hz. a, example traces of DA signals measured using fast-scan cyclic voltammetry in the dorsolateral striatum. Bottom, comparison of the DA signal evoked by 1p (broken line) and by a 20p train at 20 Hz (solid gray line). The two sets of different scale bars represent 0.5 μM DA and 2 s.b, example traces of DA signals measured in the NAc core. c, example traces of DA signals measured in the NAc shell. d, the average DA signal evoked by 1p, calculated as the area under the curve, is displayed for the three regions (n = 7-16,**, p < 0.01, compared with the dorsolateral striatum, DS). e, the average phasic/tonic ratio of the DA signal evoked by 20p over 1p ([DA]20p/[DA]1p) is displayed for the three regions (n = 7-16, **, p < 0.01, compared with DS).

Fig. 2.

Fig. 2.

The ratio of the phasic-to-slow-tonic DA signals within the dorsolateral striatum and the NAc shell. a, an example DA trace is shown in response to a tonic stimulation (three pulses at 0.2 Hz after achieving pseudo-steady state) followed by a phasic stimulation (5p at 20 Hz) within the dorsolateral striatum. b, an example DA trace is shown in response to the same tonic and phasic stimulation within the NAc shell. Scale bars, 0.2 μM DA and 5 s. c, The average ratio of the phasic-to-tonic DA signal ([DA]5p/[DA]1p) showed a greater contrast in the NAc shell compared with the dorsolateral striatum (n = 4, **,p < 0.01).

Fig. 3.

Fig. 3.

To mimic biologically realistic tonic and phasic DA neuron firing activity, we applied stimulus trains of 3.3 (tonic) and 20 Hz (phasic). a, an example DA trace is shown in response to a tonic stimulation (seven pulses at 3.3 Hz after achieving pseudo-steady state) followed by a phasic stimulation (5p at 20 Hz) within the dorsolateral striatum. b, an example DA trace is shown in response to the same tonic and phasic stimulation within the NAc core and within the NAc shell (c). d, DA signal (area under the curve) evoked by the phasic train was significantly larger in NAc shell and core than in the dorsolateral striatum (n = 11, 12, and 10, respectively;*, p < 0.05). e, in vivo fast-scan cyclic voltammetry showed that an unexpected food pellet elicited a DA signal in the dorsolateral striatum that was smaller than that in the NAc (n = 10, p < 0.01), consistent with the in vitro slice data above.

Fig. 4.

Fig. 4.

The frequency-dependence of DA signals in the dorsolateral striatum in response to inhibition of DATs, dopamine D2-type receptors, and β2* nAChRs. a, example DA traces evoked by 1p or by 5p trains at stimulus frequencies of 5, 20, or 80 Hz. The DA signal was evoked under the following conditions: no inhibition (control), inhibition of DATs with GBR 12909 (GBR, 2 μM), inhibition of D2-type receptors with sulpiride (2 μM), inhibition of nAChRs with DHβE (0.1 μM), and in the presence of all three antagonists (GBR + sul + DHβE). Scale bars, 1 μM DA and 5 s, except in GBR, where the y scale represents 2 μM DA. b, GBR (⋄) and sulpiride (▵) enhanced the relative DA signal (normalized to the DA signal evoked by 1p) at low frequencies compared with the control (▪). c, DHβE (○) elicited robust facilitation of the DA signal at higher frequencies compared with control. d, combining GBR, sulpiride, and DHβE led to an increased DA signal that was comparable in size across stimulus frequencies using either 3p (□) or 5p (plus-box) compared with control (n = 4-12).

Fig. 5.

Fig. 5.

The dorsolateral striatum and the NAc shell respond differently to stimulus trains of 5p or 10p given at 20 Hz. Comparisons of the DA signals evoked by phasic stimulus trains were obtained in the absence (control) or presence of DAT, D2 receptor, and β2* nAChR antagonists. The DA signals were normalized to the response evoked by 1p stimulation under each experimental condition. a, in the absence of antagonists (control), the DA signal in the NAc shell was more responsive to phasic stimulus trains. b, with DATs inhibited by GBR (2 μM, n = 6), the relationship of the two regions remained similar to control. c, with D2-type receptors inhibited by sulpiride (2 μM, n = 6), the relationship of the two regions remained similar to control. d, with nAChRs inhibited by DHβE (0.1 μM, n = 6), the frequency dependence of both regions increased, but the increase was greater in the dorsolateral striatum. Consequently, the frequency dependence of the two regions became more similar after nAChR inhibition.

Fig. 6.

Fig. 6.

Inhibition of β2* nAChRs with DHβE (0.1 μM) altered DA signals. a, example DA signals evoked by 1p and by a 5p train given at 20 Hz within the dorsolateral striatum in the absence (control) or presence of DHβE. Scale bars, 0.5 μM DA and 0.5 s. b, the average DA signal evoked by 1p and 5p at 20 Hz in the presence of DHβH normalized to the control response as 100%. c, the DA signal evoked by 1p in the dorsolateral striatum and NAc shell in the absence (control) or presence of DHβE. The DA signals are normalized to 1p using different_y_-scale bars: 0.5 μM DA for the dorsolateral striatum, and 0.1 μM DA for the NAc shell and 0.5 s. d, the average DA signal evoked by 1p in the dorsolateral striatum and by the NAc shell in the presence of DHβH normalized to the control response as 100%.

Fig. 7.

Fig. 7.

DA signals evoked by 1p in the absence or presence of antagonists for DATs, D2-type receptors, or β2* nAChRs. a, representative DA signals evoked by 1p from the dorsolateral striatum (gray traces) and the NAc shell (dashed traces). The DA signals were controls (ctrl) or with DATs (GBR, 2 μM), D2-type receptors (sulpiride, 2 μM), or β2* nAChRs (DHβH, 0.1 μM) inhibited. Scale bars, 1 μM DA and 2 s. b, the ratio of the DA signal evoked by 1p in the dorsolateral striatum over that in the NAc shell with and without antagonists as labeled (n = 5-11). c, the average magnitude of DA signal evoked by 1p in the dorsolateral striatum with and without antagonists as labeled (n = 6-19). The bar labeled “β2” represents data from mutant mice lacking the nAChR β2-subunit. The control response in the NAc shell is shown for comparison (last bar, light gray). d, the average ratio of the DA signal evoked by 5p at 20 Hz over that evoked by 1p, [DA]5p/[DA]1p, in the dorsolateral striatum with and without antagonists as labeled (n = 6-19). The control response in the NAc shell is shown for comparison (last bar, light gray). Significance is given as *, p < 0.05; **, p < 0.01 compared with control.

Fig. 8.

Fig. 8.

The frequency-dependence of DA signals from wild-type and nAChR β2-subunit-null mice. a, representative DA signals evoked by 1p and 5p at 20 Hz from wild-type littermates [β2(+/+)] and mutant null mice [β2(-/-)] in the dorsolateral striatum. b, representative DA signals from wild-type [β2(+/+)] and null mice [β2(-/-)] in the NAc shell. c, normalized to the DA signal evoked by 1p in the dorsolateral striatum, the average DA signal is shown for 5p delivered at frequencies ranging from 10 to 80 Hz in null mice [β2(-/-), □] and wild-type mice [β2(+/+), ▪](_n_ = 11 and 15, respectively). d, normalized to the DA signal evoked by 1p in the NAc shell, the average DA signal is shown for 5p at 10 to 80 Hz in null mice [β2(-/-), ○] and wild-type mice [β2(+/+), •]) (n = 11 and 12, respectively).

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