Differences in Nicotine Encoding Dopamine Release between the Striatum and Shell Portion of the Nucleus Accumbens

Abstract

The aim of this work was to determine the effect of nicotine desensitization on dopamine (DA) release in the dorsal striatum and shell of the nucleus accumbens (NAc) from brain slices. In vitro fast-scan cyclic voltammetry analysis was used to evaluate dopamine release in the dorsal striatum and the NAc shell of Sprague-Dawley rats after infusion of nicotine, a nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Mec), and an α4β2 cholinergic receptor antagonist (DHβe). DA release related to nicotine desensitization in the striatum and NAc shell was compared. In both structures, tonic release was suppressed by inhibition of the nicotine receptor (via Mec) and the α4β2 receptor (via DHβe). Paired-pulse ratio (PPR) was facilitated in both structures after nicotine and Mec infusion, and this facilitation was suppressed by increasing the stimulation interval. After variable frequency stimulation (simulating phasic burst), nicotine infusion induced significant augmentation of DA release in the striatum that was not seen in the absence of nicotine. In contrast, nicotine reduced phasic DA release in NAc, although frequency augmentation was seen both with and without nicotine. Evaluation of DA release evoked by various trains (high-frequency stimulation (HFS) 100 Hz) of high-frequency stimulation revealed significant enhancement after a train of three or more pulses in the striatum and NAc. The concentration differences between tonic and phasic release related to nicotine desensitization were more pronounced in the NAc shell. Nicotine desensitization is associated with suppression of tonic release of DA in both the striatum and NAc shell that may occur via the α4β2 subtype of nAChR, whereas phasic frequency-dependent augmentation and HFS-related gating release is more pronounced in the striatum than in the NAc shell. Differences between phasic and tonic release associated with nicotine desensitization may underlie processing of reward signals in the NAc shell, and this may have major implications for addictive behavior.

Keywords: Nicotine desensitization; dopamine; nucleus accumbens; striatum.

Fig. 1.

(A) Nicotine infusion induces a desensitizing suppression of tonic DA release (by single pulse 1p/25 Hz) not only in the striatum but also in the NAc shell. The suppression of tonic DA release in the striatum was similar to the NAc shell under 0.5 μM. (B) Suppression effects were also found using the nAChR antagonist mecamylamine (Mec) 1 μM infusion and (C) DHβe 0.1 μM infusion. (y-axis [DA]₀ (normalized to control p1): evoked a signal in the striatal or NAc shell / P1 in the control striatal or NAc shell; P1: the mean control concentration was evoked by one pulse.) *p < 0.05, **p < 0.01 and ***p < 0.001 striatum versus NAc shell. ^### p < 0.001 striatum versus baseline in 30 mins. ^$$$ p < 0.001 NAc versus baseline in 30 min. (D) Brain slice showing sites of striatal and NAc recordings. DA: dopamine; Dhβe: α4β2 cholinergic receptor antagonist; Mec: mecamylamine; NAc: nucleus accumbens; nAChR: nicotinic acetylcholine receptor.

Fig. 2.

Nicotine effects on input/output curves for tonic and phasic dopamine release in the striatum and shell portion of the NAc under different stimulation intensities (from 1 to 10 volts) were altered by nicotine infusion. (A) In the striatum, tonic release was significantly suppressed by nicotine infusion. (B) The phasic release in the striatum was enhanced by nicotine infusion. (C) In the NAc shell portion, tonic release was significantly suppressed by nicotine infusion, which was similar to the striatum. (D) The phasic dopamine release in the NAc shell portion was also suppressed by nicotine infusion; this suppression was more significant at higher stimulation intensities. (E) Nicotine desensitization induced a dose-dependent suppression of dopamine tonic release (1p/25 Hz) in the NAc shell. (F) Nicotine desensitization induced suppression of phasic release in the NAc shell but enhanced phasic release in the striatum. *p < 0.05, **p < 0.01 and ***p < 0.001. NAc: nucleus accumbens

Fig. 3.

nAChR desensitization-related frequency-dependent augmentation of dopamine release is different in striatum and NAc shell. (All of the signals in each plot were compared with the control p1 signal.) (A) The suppression in tonic release reversed to an increment with high-frequency stimulation in the striatum under nicotine infusion, while this increment was not significant under control conditions (control: red solid, nicotine infusion: red open circles). In the NAc shell, the release of DA in the shell portion was suppressed significantly under nicotine infusion compared with the control group. The increment in DA release along with stimulation frequency was found under both control and nicotine infusion conditions (blue solid and open squares). (B)With infusion of mecamylamine, suppression of DA tonic release was seen in both the striatum and NAc shell, and DA release increased after high-frequency stimulation only in the striatum. These increments with increased frequency were found in the NAc shell with or without Mec infusion, but the DA level was significant lower only in the Mec infusion group. (C) Infusion of the α4β2 receptor inhibitor, DHβe, induced similar effects in NAc, which suggests that most receptors associated with the nicotine effects on DA release in NAc shell were of the α4β2 receptor subtype. (D) The difference between tonic and phasic release concentrations in the striatum significantly increased with increasing stimulation frequency (from 1 to 100 Hz) after nicotine infusion. In the NAc shell, these differences were seen both in controls and after nicotine infusion. The frequency-dependent augmentation after nicotine infusion was similar to the control. Similar effects were found with (E) Mec and (F) DHβe infusion. (G) The slope of the difference in the concentration equation indicates the release probability of DA in each group; the highest release probability was found in the striatum with nicotine infusion, and the slope was similar between control and nicotine infusion groups in the NAc shell portion. (H) Representative DA signals (IT) in the striatum under different stimulation frequencies with significant frequency augmentation are shown in nicotine, Mec, and DHβe infusion groups, compared with the control slices. (I) In the NAc shell, the frequency augmentation of DA release was found in the control slices and also after nicotine, Mec and DHβe infusion. The signals were reduced after nicotine, Mec and DHβe infusion compared with control signals. **p < 0.01 and ***p < 0.001; ^# p < 0.05, ^## p < 0.01 and ^### p < 0.001; ^$ p < 0.05 and ^$$$ p < 0.001. (y-axis [DA]₀ (normalized to control p1): evoked signal in striatal or shell / P1 in control striatal or shell; P1: mean control concentration evoked by one pulse). DA: dopamine; Dhβe: α4β2 cholinergic receptor antagonist; Mec: mecamylamine; NAc: nucleus accumbens; nAChR: nicotinic acetylcholine receptor.

Fig. 4.

Dopamine release related to HSF (100 Hz). (A) DA release did not increase with the number of HFS trains in the striatum but DA release increased with the number of HFS trains in the striatum after infusion with nicotine. DA release in the nicotine infusion group was lower than in control group in the NAc shell, but both groups showed an increase with trains of HFS. (B) Mec infusion suppressed DA release initially and the release increased along with the number of trains in the striatum (red open circles). In the NAc shell, DA release was suppressed with Mec infusion. In both the control and Mec infusion groups, DA release increased along with the number of trains. (C) DA release was suppressed initially with DHβe infusion in the NAc shell, and an increment in release with train number was found similar to the control group. (D) Linear regression for the difference between large trains of HFS phasic and tonic concentrations (normalized to control p1 concentration); the slope, referred to as the release probability of DA in the NAc shell, was steeper than in the striatum. (E) A similar situation was found with Mec infusion and (F) with DHβe infusion. (G) The slopes in the NAc shell portion, related to nicotine desensitization, were higher than in the control group and in the striatum. (H) Representative IT and CV curves in the striatum and (I) NAc shell with different numbers of HFS trains are shown. *p < 0.05, **p < 0.01 and ***p < 0.001; ^# p < 0.05 and ^### p < 0.001; ^$$ p < 0.01 and ^$$$ p < 0.001. (y-axis: evoked signal in striatal or shell / P1 in control striatal or shell; P1: mean control concentration evoked by one pulse). CV: cyclic voltammetry; DA: dopamine; Dhβe: α4β2 cholinergic receptor antagonist; HFS: high-frequency stimulation; IT: current time; Mec: mecamylamine; NAc: nucleus accumbens; nAChR: nicotinic acetylcholine receptor.

Fig. 5.

Nicotine-related short-term facilitation of DA release. PPRs (p2/p1) showed a characteristic short-term depression in the controls at all inter-pulse intervals at the striatum whereas the Paired pulse facilitation (PPF) could be found in the short interval (<50 msec) in the NAc shell portion and then the PPF became Paired pulse depression (PPD) while the interval was getting longer. (A) Both the striatum and the NAc shell area showed nicotine desensitization-related facilitation of DA release. This facilitation was dependent on frequency, with the largest at short stimulation intervals and suppressed at longer intervals. (B) Mec infusion induced a similar facilitation of DA release with short stimulation intervals and suppression at longer intervals. The suppression effects were more profound in the shell portion. (C) In the NAc shell, DHβe produced facilitation effects similar to those in the striatum. (D) The slopes of linear regression of the PPR related to the stimulation interval, and the slopes of the nicotine desensitization-related decline in the NAc shell portion, were higher than those in the striatum. A similar relationship could be found with (E) Mec and (F) DHβe infusion. (G) The voltammetric signals in the striatum with paired pulses at 10 ms intervals indicate synaptic facilitation by nicotine (blue line for the first response p1, red dotted line for the subtracted second response p2, and black line for the summation of p1+p2). This facilitation is suppressed by nicotine and Mec infusion with increased stimulation intervals, whereas there was no facilitation in the control groups. (H) The voltammetric responses in the NAc shell portion were similar to the striatum. ***p < 0.001; ^# p < 0.05, ^## p < 0.01 and ^### p < 0.001. DA: dopamine; Dhβe: α4β2 cholinergic receptor antagonist; Mec: mecamylamine; NAc: nucleus accumbens; PPD: Paired pulse depression; PPF: Paired pulse facilitation; PPR: paired-pulse ratio.