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, 110 (Pt A), 386-395

Voluntary Adolescent Drinking Enhances Excitation by Low Levels of Alcohol in a Subset of Dopaminergic Neurons in the Ventral Tegmental Area

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Voluntary Adolescent Drinking Enhances Excitation by Low Levels of Alcohol in a Subset of Dopaminergic Neurons in the Ventral Tegmental Area

Elizabeth M Avegno et al. Neuropharmacology.

Abstract

Enhanced dopamine (DA) neurotransmission from the ventral tegmental area (VTA) to the ventral striatum is thought to drive drug self-administration and mediate positive reinforcement. We examined neuronal firing rates in slices of mouse midbrain following adolescent binge-like alcohol drinking and find that prior alcohol experience greatly enhanced the sensitivity to excitation by ethanol itself (10-50 mM) in a subset of ventral midbrain DA neurons located in the medial VTA. This enhanced response after drinking was not associated with alterations of firing rate or other measures of intrinsic excitability. In addition, the phenomenon appears to be specific to adolescent drinking, as mice that established a drinking preference only after the onset of adulthood showed no change in alcohol sensitivity. Here we demonstrate not only that drinking during adolescence induces enhanced alcohol sensitivity, but also that this DA neuronal response occurs over a range of alcohol concentrations associated with social drinking in humans.

Keywords: Adolescence; Dopamine; Electrophysiology; Ethanol self-administration; Ventral tegmental area.

Figures

Fig. 1
Fig. 1. Intermittent access (IA) model produces escalated binge-like alcohol intake in adolescent mice
(a) Timeline for the adolescent alcohol exposure. The IA procedure begins at age p30 and runs for 15 drinking sessions. Mice demonstrated an escalated average ethanol intake per session (b) and preference for ethanol over water (c). Data is from a group of 42 mice. (d) Blood alcohol concentration (BAC) values for 30 mice, measured 6 h after EtOH presentation during the 11th drinking session. Dashed line indicates 80 mg/dL, the threshold for binge alcohol consumption. (e) HIC scores were not significantly different between drinking and naïve mice (n = 6 mice per group) measured 8 and 12 h after peak BAC (corresponding to 2 and 6 h after removing EtOH) at the end of the 15th drinking session (p = 0.2 at 8 h; p = 0.5 at 12 h; two-tailed t-test). Dashed line indicates the minimum HIC score indicative of convulsive activity. (f) Total number of open arm entries and time spent in the open arms (g) did not differ in an elevated plus maze (f, p = 0.9; g, p = 0.6; two-tailed t-test). Error bars show SEM.
Fig. 2
Fig. 2. Adolescent drinking experience enhances the ethanol sensitivity of VTA DA neurons
(a) Sample cell-attached recording of TH-GFP+ neuron. Each 10 s trace is representative of the firing activity of the neuron after 5 min of baseline recording or drug exposure. Scale bar, 100 pA, 1 s. (b) Midbrain coronal section of TH-GFP mouse. Scale bar, 1 mm. (c) Mean baseline firing rate of VTA DA neurons from drinkers (3.0 ± 0.2 Hz, n = 42 cells from 27 mice) does not differ from those of age-matched controls that only drank water (3.0 ± 0.4 Hz, n = 41 cells from 20 mice; p = 0.96, two-tailed t-test). (d) Percentage changes in firing rate of VTA DA neurons in alcohol drinking and water-drinking mice. Two-tailed t-tests reveal a significant difference in excitation induced by 10, 20, and 50 mM EtOH in DA neurons from drinking mice compared to naïve controls (see Table 1). Error bars show SEM.
Fig. 3
Fig. 3. Adolescent drinking experience selectively enhances ethanol sensitivity of medial VTA DA neurons
Each panel contains representative image (adapted from Allen Brain Atlas) indicating approximate positions of neurons recorded in midbrain section (bregma −3.3 mm), as well as percentage change in firing rate of DA neurons from drinking mice compared to age-matched water-only controls. (a) Data from medial VTA DA neurons. Two-tailed t-tests reveal a significant difference in the response to 10, 20, and 50 mM EtOH of medial VTA DA neurons of drinking mice compared to controls (see Table 1). (b) Data from lateral VTA DA neurons. No significant difference is observed in response to EtOH of lateral VTA DA neurons of drinking mice compared to controls (Table 1). (c) Data from SN DA neurons indicates no significant difference in response to EtOH (Table 1). Error bars show SEM.
Fig. 4
Fig. 4. Drinking during early adulthood does not result in enhanced sensitivity of VTA DA neurons to ethanol
(a) Average ethanol intake per session for a group of 4 adult mice. (b) Preference for ethanol over water develops during the procedure. (c) Left panel, percentage changes in firing rate of VTA DA neurons in alcohol drinking and water drinking mice. Two-tailed t-tests reveal no significant difference in excitation induced by EtOH in DA neurons from alcohol drinking mice compared with naïve controls (Table 3). Right panel, data from adolescent mice (Fig. 2d) is shown for comparison. (d) Mean baseline firing rate of VTA DA neurons from drinkers (2.8 ± 0.4 Hz, n = 11 cells from 4 mice) does not significantly differ from those of age-matched controls that drank only water (2.5 ± 0.3 Hz, n = 7 cells from 4 mice; p = 0.6, two-tailed t-test). Error bars show SEM.
Fig. 5
Fig. 5. Adolescent drinking experience enhances the ethanol sensitivity of medial shell-projecting VTA DA neurons
(a) 40 × image of a coronal brain slice. Left panel is a bright field image. Middle panel shows the same field of view, showing GFP-expressing (TH-containing) neurons. Right panel, same field of view showing retrobead-containing (NAc medial shell-projecting) neurons. (b) Coronal section of retrobead injected mouse. Nuclei are stained with DAPI and appear blue. Scale bar, 1 mm. (c) Mean baseline firing rate of VTA DA neurons from drinkers (4.1 ± 1 Hz, n = 8 cells from 5 mice) does not significantly differ from those of age-matched controls that drank only water (3.1 ± 0.5 Hz, n = 7 cells from 4 mice; t(13) = 0.86, p = 0.41, two-tailed t-test). (d) Percentage changes in firing rate of VTA DA neurons in alcohol drinking and water drinking mice. A two-tailed t-test reveals a significant difference in excitation induced by 50 mM EtOH in DA neurons from alcohol drinking mice (31.3 ± 8.6%) compared to naïve controls (6.2 ± 4.1%; t(13) = 2.5, p = 0.026, two-tailed t-test). Error bars in c and d show SEM. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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