Effect of Pain in the Development of Alcohol Use Disorders: Ethanol-evoked Dopamine Release Alterations in the Rat Nucleus Accumbens

doi:10.21203/rs.3.rs-4547464/v1

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Effect of Pain in the Development of Alcohol Use Disorders: Ethanol-evoked Dopamine Release Alterations in the Rat Nucleus Accumbens

https://doi.org/10.21203/rs.3.rs-4547464/v1

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Purpose

Alcohol use disorders (AUDs) are influenced by factors that can initiate, maintain, or induce relapse. Chronic pain has been linked to AUD as both a risk factor and a consequence of prolonged alcohol exposure. Pain share common neurological pathways with AUDs, and, in fact, alters the functioning of the mesolimbic dopaminergic system suggesting a plausible interaction. This study aims to investigate the effect of inflammatory pain on long-term alcohol intake in rats without prior alcohol consumption and observe changes in mesolimbic dopaminergic transmission.

Methods

Inflammatory pain was induced in eight-week-old Sprague Dawley rats using complete Freund adjuvant (CFA), while controls received saline. Two protocols were followed: one group had continuous access to 20% ethanol for one month (n = 10 per sex), and the second group for three months (n = 8 per sex) in a two-bottle choice paradigm. Mechanical nociception was assessed weekly using the Von Frey test. Dopamine levels in the nucleus accumbens core were measured through microdialysis during the final 1.5 months of ethanol exposure in the second cohort.

Results

After a month of alcohol exposure, rats showed no differences in alcohol consumption. However, from the second month until the end, rats exhibited a non-sex-dependent decrease in alcohol intake, significantly lower in CFA-animals. This reduction was accompanied by a blunted ethanol-evoked dopamine release in the nucleus accumbens.

Conclusion

These findings provide insights into the effect of pain on alcohol-elicited neurochemical responses and drinking behaviour, showing how pain alters dopamine response to alcohol, affecting drinking patterns and prolonging nociception from CFA.

Alcohol

Inflammatory pain

Dopamine

and Nucleus accumbens

Clinical studies lay bare a connection between pain suffering and alcohol use disorders (AUDs); (Apkarian et al., 2013; Jakubczyk et al., 2016) probably because pain induces alterations in the function of overlapping brain areas (Schrepf et al., 2016; Liu et al., 2022; Jiang et al., 2023). Diverse types of pain conditions alter basal ganglia structure and anatomy, and negatively impact motivation and reward processing, which triggers stress and negative affect states (Schwartz et al., 2014; LeBlanc et al., 2015; Markovic et al., 2021; Baldwin et al., 2022; Norris et al., 2024). In the basal ganglia, the Ventral Tegmental Area – Nucleus Accumbens connexion (VTA – NAc), a pathway with numerous dopaminergic neurons, plays a pivotal role in AUDs (Deehan et al., 2013). As reviewed by Dahchour and Ward (2022), many researchers have shown the alteration in dopamine (DA) extracellular levels within the NAc induced by ethanol. They bring to light how ethanol-induced DA levels vary along the different phases of alcohol exposure acquiring relevance in the neurobiological bases that sustain alcohol drinking-related behaviours. Overall, acute ethanol exposure increases DA release, chronic exposure barely induces changes in DA levels, and DA released is reduced during withdrawal. Interestingly, pain inhibits DA transmission in the mesocorticolimbic system (MCLS) (Yamazaki et al., 2002), similarly to chronic exposure or withdrawal to alcohol. Indeed, we have previously demonstrated that inflammatory pain acts as a risk factor to alcohol relapse after a forced withdrawal period (Lorente et al., 2022). Moreover, previous data has also shown that inflammatory pain also impacted acquisition (Yu et al. 2019) and maintenance of alcohol intake (Campos-Jurado and Morón 2023). All these studies found a very strong sex-dependent factor in their experiments. Interestingly, males in pain were more prone to have high initial alcohol intake rates and to maintain alcohol consumption patterns at high ethanol doses, whereas females in pain had greater risk to relapse. Nonetheless, these studies did not explore DA transmission under its conditions. Thus, here we assess DA release within the NAc in animals with a history of alcohol exposure while observing how long-term inflammatory pain modulates DA transmission.

2.1. Animal model

8-week-old Sprague Dawley rats (18 animals/sex) were used (Envigo®, Barcelona, Spain). Animals were kept individually housed in standard plastic cages (42 × 27 × 18 cm³) in light/dark (12/12 h) controlled cycles, temperature 23 ± 1°C, and 60% humidity with food and tap water provided ad libitum. Half of the animals were injected with the complete Freund adjuvant (CFA) to induce inflammatory pain and the other half with saline (control) (Hipólito et al., 2015; Campos-Jurado et al., 2020; Cuitavi et al., 2021; Lorente et al., 2022; 2023). Mechanical nociception was monitored by the Von Frey test as previously described (Bonin et al., 2014). The first session was performed just before the intraplantar injection to obtain the basal mechanical nociception. Afterwards, weekly Von Frey sessions were carried out. Protocols were approved by the Animal Care Committee of University of Valencia following EEC Council Directive (63/2010) and Spanish law (RD 53/2013).

2.3. Experimental design

Two experiments were run. Animals in the first one (n=10/sex) followed the ethanol continuous access for a month, whereas the second one (n=8/sex) followed the protocol for 3 months. In both experiments animals were given continuous access to tap water and to a 20% ethanol solution in their home cages. Bottles were daily weighed, and its position was changed to avoid location preferences. Animals were sacrificed by isoflurane overdose 24h after the last ethanol exposure.

To further investigate the underlying mechanisms of the CFA effect on ethanol-induced DA release in the NAc in rats with a long-term exposure to alcohol, microdialysis experiments were carried out in the second experiment along the last one and a half month of alcohol consumption. Rats from each sex and group were altern to avoid differences related to time. Probes were implanted into the NAc core (NAcC; Males - anteroposterior: 1.4 mm, mediolateral: 1.5 mm and dorsoventral: 7.8 mm from bregma; Females - anteroposterior: 1.2 mm, mediolateral: 1.4 mm and dorsoventral: 7.6 mm from bregma; Paxinos and Watson, 2006) as previously described (Campos-Jurado et al., 2020). After a stabilisation period of 100 minutes, samples were collected every 20 minutes and extracellular DA levels were determined by using offline high performance liquid chromatography (HPLC) with electrochemical detection (Campos-Jurado et al., 2020). Once DA baseline level was established (defined as 3 last consecutive samples presenting a maximum 10% variation in DA content), 2 mL of saline were subcutaneously (s.c.) administered and DA levels were analysed every 20 minutes for 100 minutes as a control for the possible effect of the s.c. injection itself. Right after, a single s.c. ethanol dose (1.5 g/kg diluted in 2 mL of saline) was administered and DA levels in the dialysates were analysed for 160 minutes more. After animal sacrifice, we obtained brain 40 μm-thick coronal slices, which were stained with a cresyl violet protocol to verify probe placement.

2.5. Statistical analysis

Results are shown as mean ± standard error of the mean. To perform the statistical analysis, the 26.0 version of the SPSS program was used. The Kolmogorov–Smirnov test and Levene’s test were performed to assess the normality and the homogeneity of the variance of the data. For the Von Frey test, alcohol intake, DA levels and AUC of DA levels, a two-way repeated measures ANOVA was applied. The Bonferroni multiple comparisons post-hoc test was used when appropriate in all the stated measurements but for the DA levels. In this case, the Dunnett post-hoc test was applied. A T-test for independent samples was used to analyse the differences in the widths of the paws. In all cases a 95% confidence level was set.

3.1. Experiment 1: effect of CFA on a one-month alcohol intake.

The two-bottle choice procedure was used to evaluate the effect of pain on acquisition of alcohol intake in male and female rats. The alcohol drinking behaviour during the acquisition was evaluated on every consumption day (Fig. 1A). The ANOVA for repeated measures did not detect differences in the sex factor (F(1,36)=0.785, p=0.381), the group factor (CFA or saline-treated rats; F(1,36)=0.327, p=0.571) or in the intersection between sex and group (F(1,36)=1.519, p=0.226). The alcohol intake levels were also analysed in weeks, by calculating the average of the 7 days of alcohol drinking for each individual (Fig. 1B). In a similar manner, the ANOVA for repeated measures did not detect differences in the sex factor (F(1,36)=0.716, p=0.403), the group factor (CFA or saline-treated rats; F(1,36)=0.348, p=0.559) or in the intersection between sex and group (F(1,36)=1.558, p=0.220). Interestingly, mechanical nociceptive thresholds were lower in CFA-treated male and female rats than in saline-treated animals until the end of the experimental procedure (Fig. 1C). The ANOVA for repeated measures detected a main effect of group (CFA or saline-treated rats; F(1,36)=111.318, p<0.001), but it did not detect differences in the sex factor (F(1,36)=2.857, p=0.100) or in the intersection between group and sex (F(1,36)=4.101, p=0.500). After, the Bonferroni post hoc analysis for multiple comparisons revealed a significant difference between saline and CFA treated animals in days 3, 10, 17 and 24 (p<0.001). Moreover, the analysis showed a within-subject effect of time (F(4,144)=15.012, p<0.001), and an effect in the interaction of time and group (F(4,144)=15.340, p<0.001). The Bonferroni post hoc analysis for multiple comparisons revealed significant differences from baseline in all post-CFA measurements in male and female rats (p<0.005).

3.2. Experiment 2: effect of CFA on three-month alcohol intake and in the ethanol-induced DA release in the NAc.

Rats were continuously exposed to ethanol for three months from two days after a s.c. saline or a CFA injection in the plantar surface of the hind paw. Sex did not elicit any significant differences. Therefore, Fig. 2A shows the average of the daily alcohol intake rate (g/kg/day) for the saline and the CFA groups in each month of the procedure. The repeated-measures ANOVA performed indicated statistically significant differences along time (F(1,14) = 40.842, p < 0.0001) and in between saline- and CFA-animals (F(1,14) = 5.367, p = 0.036). Interestingly, the post-hoc test used showed a statistically significant decrease of the alcohol intake levels during the second and the third months when compared to the first month of alcohol consumption. Furthermore, during the third month CFA-animals showed statistically significant lower alcohol consumption levels than saline-animals.

We further investigate DA signalling alterations in NAcC in a sample from these rats exposed to three-months alcohol intake. 16 rats were used, nonetheless only completed experiments from NAcC located probes were included in the analysis (n= 10 control experiments and 8 CFA-experiments).

Our data showed that inflammatory pain blunts ethanol induced NAcC DA release after long-term alcohol exposure (Fig. 2C). Repeated-measures ANOVA revealed that there are statistically significant differences between saline- and CFA-animals (F(1,16) = 3.999, p < 0.0001). The post-hoc test showed a statistically significant increase of DA levels at various times after the s.c. ethanol injection when compared to basal levels only in saline-animals. In fact, results from Fig. 2D, which shows a comparison of AUCs from the DA levels after the s.c. saline injection and the s.c. ethanol injection, confirm this effect. Repeated-measures ANOVA showed statistically significant differences in interaction between the existence of a pain condition and time (F(1,16) = 4.591, p = 0.048). However, the post-hoc test revealed that only saline-animals significantly increased the AUC of DA levels after the ethanol injection when compared to the AUC of DA levels after the saline injection.

Very interestingly the long-term exposure to alcohol lead to inflammation and increased nociception (Fig. 2E). In fact, the repeated-measures ANOVA show statistically significant differences in the interaction between the existence of a pain condition and time (F(1,8) = 4.388, p < 0.0001) and the post-hoc analysis revealed that, every week after the plantar injection, CFA-animals had a statistically significant lower nociception threshold when compared to their basal levels and saline-animals the same week. Moreover, in these conditions, CFA-animals preserved the inflammation until the end of the experimental procedure (Fig. 2F, p < 0.0001).

The effect of pain on alcohol drinking behaviour in rodents remains controversial and critically affected by several factors including strain, alcohol exposure protocols and AUD phase modelling. Our results here show for the first time how the temporal evolution of inflammatory pain together with acquisition in alcohol intake is essential to understand the changes observed in alcohol consumption, since differences between pain and no-pain rats can only be appreciated after the first month of protocol is over. Indeed, long-term inflammatory pain reduces voluntary alcohol consumption at 20% ethanol concentration after 3 months of free continuous access paradigm both in male and female rats. However, there is evidence that C57BL/6J mice experimented an increase in alcohol intake rates following the very same CFA inflammatory pain model and same continuous access to ethanol as we did in our research, albeit they only measured alcohol intake for three weeks (Yu et al., 2019). Of note, various articles highlight that mice and rats show different drinking behaviour patterns depending on the alcohol paradigm used (Hopf and Lesscher, 2014; Vengeline et al., 2014) and process pain differently (Mogil, 2019). Thereby, more comparative studies are warranted to better understand how inflammatory pain modulates alcohol drinking behaviours in each rodent species and each AUD phase modelled.

Interestingly, and supporting our alcohol drinking results, inflammatory pain blunted acute ethanol-evoked DA release in the NAcC in these long-term alcohol exposed rats, thus suggesting alterations in alcohol reward processing. Although long-term alcohol exposure has traditionally been related to low levels of DA in the MCLS (Dahchour and Ward, 2022), a recent study that used fast scan cyclic voltammetry showed how high alcohol drinking mice still increase their DA levels in NAcC after a stimulation (Liu et al., 2020), as we have observed with our control rats. Thus, these alterations of DA release after long-term exposure to alcohol in pain conditions, might underlie the decrease in alcohol drinking observed in our experiments. Moreover, Campos-Jurado et al. (2020) showed that CFA-injected males presented altered DA release after a single dose of ethanol in acute conditions, correlating with dose-dependent alterations in ethanol conditioned place preference. In this sense, pain-induced alterations in the VTA-NAc DA neurons ability to respond to reward stimuli (Markovic et al. 2021) might regulate alcohol consumption in a dose-dependent manner. In fact, in rats with a history of alcohol consumption prior CFA injection, pain did not alter alcohol consumption patterns when 20% concentration was used, although it impaired the reduction in alcohol consumption when animals were challenged with 50% ethanol (Campos-Jurado and Morón 2023).

Finally, we present unknown evidence that the inflammatory pain model based on a single CFA, concomitant to the exposure to alcohol, lasts for longer periods of times than previously data in rats without exposure to alcohol. The CFA model is usually used for a maximum of 3 weeks (Coderre and Laferrière, 2020; Kremer et al., 2021), because CFA elicits a prompt inflammation, and this time is enough to study chronic pain conditions. Indeed, no previous study reported the use of the CFA model for longer than a month (Narita et al., 2006; Parent et al., 2012). We consider this finding to be highly revealing in the context of AUD and expect to improve in future long-term studies.

In conclusion, our results contribute to the understanding of pain alterations in DA response to alcohol which in turn affect alcohol drinking patterns and prolong the duration of the nociception derived from the CFA administration.

AUTHOR CONTRIBUTION STATEMENT

Conceptualisation: LH; Methodology: JC, YC-J, JDL, and LH; Formal analysis: JC, AR-C, YC-J, JDL, and LH; Investigation: JC, AR-C, YC-J, JDL, and LH; Writing—original draft: JC.; Resources: LH; Supervision: AP, and LH; Writing—review and editing: JC, AP, and LH. All authors contributed to the article and approved the submitted version.

ACKNOWLEDGEMENTS

We would like to thank Ms. Pilar Laso and the staff from the “Servei d’Investigació-UV” for grant management. We would also thank the personnel of the Animal facilities (SCSIE) at the University of Valencia for their help and effort in assuring animal welfare.

Availability of the data

Data will be available upon request.

Funding

This work was supported by MCIU/AEI/10.13039/501100011033/FEDER,UE [PID2019-109823RB-I00 and PID2022-137803NB-I00]; Spanish Ministerio de Sanidad, Delegación del Gobierno para el Plan Nacional sobre Drogas [PNSD2019I038]; and by the University of Valencia [UV-INV-PREDOC-1327981].

Competing interests

The authors have no conflicts of interest to declare.

Autor contributions

Ethics approval

Protocols were approved by the Animal Care Committee of University of Valencia following EEC Council Directive (63/2010) and Spanish law (RD 53/2013).

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No competing interests reported.

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Effect of Pain in the Development of Alcohol Use Disorders: Ethanol-evoked Dopamine Release Alterations in the Rat Nucleus Accumbens

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