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Clinical Trial
. 2018 May;43(6):1235-1246.
doi: 10.1038/npp.2017.257. Epub 2017 Nov 1.

Oxytocin Reduces Alcohol Cue-Reactivity in Alcohol-Dependent Rats and Humans

Anita C Hansson  1 , Anne Koopmann  2 , Stefanie Uhrig  1 , Sina Bühler  2 , Esi Domi  3 , Eva Kiessling  1 , Roberto Ciccocioppo  3 , Robert C Froemke  4 , Valery Grinevich  5 , Falk Kiefer  2 , Wolfgang H Sommer  1   2 , Sabine Vollstädt-Klein  2 , Rainer Spanagel  1
Affiliations
Clinical Trial

Oxytocin Reduces Alcohol Cue-Reactivity in Alcohol-Dependent Rats and Humans

Anita C Hansson et al. Neuropsychopharmacology. 2018 May.

Abstract

Approved pharmacological treatments for alcohol use disorder are limited in their effectiveness, and new drugs that can easily be translated into the clinic are warranted. One of those candidates is oxytocin because of its interaction with several alcohol-induced effects. Alcohol-dependent rats as well as post-mortem brains of human alcoholics and controls were analyzed for the expression of the oxytocin system by qRT-PCR, in situ hybridization, receptor autoradiography ([125I]OVTA binding), and immunohistochemistry. Alcohol self-administration and cue-induced reinstatement behavior was measured after intracerebroventricular injection of 10 nM oxytocin in dependent rats. Here we show a pronounced upregulation of oxytocin receptors in brain tissues of alcohol-dependent rats and deceased alcoholics, primarily in frontal and striatal areas. This upregulation stems most likely from reduced oxytocin expression in hypothalamic nuclei. Pharmacological validation showed that oxytocin reduced cue-induced reinstatement response in dependent rats-an effect that was not observed in non-dependent rats. Finally, a clinical pilot study (German clinical trial number DRKS00009253) using functional magnetic resonance imaging in heavy social male drinkers showed that intranasal oxytocin (24 IU) decreased neural cue-reactivity in brain networks similar to those detected in dependent rats and humans with increased oxytocin receptor expression. These studies suggest that oxytocin might be used as an anticraving medication and thus may positively affect treatment outcomes in alcoholics.

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Figures

Figure 1
Figure 1
Expression of the oxytocin (OXT) system in 3 weeks abstinent rats. (a) OXT receptor (Oxtr) mRNA and OXTR binding sites are increased in several forebrain regions of dependent rats. (Left panels) Schematic outline of analyzed regions in the rat brain according to Paxinos and Watson (1998) (left). OXTR expression pattern for mRNA (in situ hybridization, middle) and binding sites ([125I]OVTA receptor autoradiography, (right) corresponding to the schematic outline. (Right panels) Bar graphs showing Oxtr mRNA (left) and OXTR binding sites (right) in analyzed regions of alcohol-dependent (Alc-dep., orange bars) and -non-dependent (Non-dep., white bars) rats. Data are expressed as mean±SEM (nCi/g for mRNA or fmol/mg for binding sites). Statistical analysis was performed by region-wise one-way analysis of variance (ANOVA), N=4–8/group, p-values: *p<0.05; **p<0.01; ***p<0.001. For abbreviations and experimental procedures, see Materials and Methods. (b) Reduced hypothalamic OXT expression in dependent rats. (Left panels) Schematic outline of the hypothalamic rat brain region at Bregma level −1.8 mm according to Paxinos and Watson (1998) (left). OXT mRNA pattern (middle) and OXT immunoreactivity (ir, right) corresponding to the schematic outline in the PVN and the SON. (Right panels) Bar graphs showing Oxt mRNA (left) and OXT-ir cells (right) in the PVN and SON of alcohol-dependent (Alc-dep., orange bars) and -non-dependent rats (Non-dep., white bars), displayed as mean±SEM (Oxt mRNA: nCi/g, OXT-ir: mean grey value). OXT-ir mean grey values of non-dependent rats (PVN: mean grey value=74.2±1.1; SON: mean grey value=63.0±1.0) are defined as 0% and changes in density show decreased density in OXT-ir in alcohol-dependent rats (dark-orange bars). Statistical analysis was performed by region-wise one-way ANOVA, N=7–8 rats/group for in situ hybridization and n=3–4 rats/group for immunoreactivity measurements, p values: *p<0.05; **p<0.01; ***p<0.001. AcbC, nucleus accumbens core; AcbS, nucleus accumbens shell; BLA, basolateral amygdaloid nucleus; BMA, basomedial amygdaloid nucleus; CeA, central amygdaloid nucleus; Cg, cingulate cortex; CPu, caudate putamen; dCA1, dorsal hippocampal cornus ammon 1 subregion; dCA3, dorsal hippocampal cornus ammon 3 subregion; dDG, dorsal dentate gyrus; IC, insular cortex; IL, infralimbic region; MeA, medial amygdaloid nucleus; OFC, orbitofrontal cortex; PreL, prelimbic cortex; PVN, hypothalamic paraventricular nucleus; SON, supraoptic nucleus; vHippo, ventral hippocampus; VMH, ventromedial hypothalamic nucleus. Scale bars 1 mm.
Figure 2
Figure 2
Oxytocin mRNA (Oxtr mRNA) is reduced in the nucleus accumbens by acute alcohol and during early withdrawal, while increased after prolonged abstinence. (a, left) Schematic outline of the nucleus accumbens core (AcbC) and the nucleus accumbens shell (AcbS) according to Paxinos and Watson (1998), and Oxtr mRNA pattern in the Acb region (right). (b) Transcriptional changes in Oxtr mRNA level during various stages of abstinence in the AcbC and (c) in the AcbS of dependent rats (Alc-dep., light-orange bars) and non-dependent rats (Non-dep., white bars). Bar graphs show the percentage of regulation relative to non-dependent rats. Absolute values are listed in Supplementary Table S3. Statistical analysis was performed by two-way analysis of variance (ANOVA), followed by Fisher’s least significant difference (LSD) test, N=6–8/group, p-values: *p<0.05, **p<0.01, ***p<0.001. Scale bar 1 mm.
Figure 3
Figure 3
Cue-induced reinstatement of alcohol-seeking is decreased after intracerebroventricular (icv) administration of oxytocin (OXT) in alcohol-dependent rats. (Left) Training of alcohol self-administration of rats later made dependent by alcohol vapor exposure (upper left) and non-dependent rats (lower left); displayed are active and inactive lever presses as well as number of received rewards of dependent (dark-orange color) and non-dependent rats (white color) (mean±SEM). (Right) Extinction (EXT) and cue-reinstatement (Cue-RI) of alcohol seeking after icv injection of 10 nM OXT (black bar) or vehicle (Veh) in alcohol-dependent (upper right, Veh=aCSF, dark-orange bar) and -non-dependent rats (lower right, Veh=aCSF, white bar). Data are expressed as mean±SEM. Statistical analysis was performed by general linear model variant analysis, followed by Newman–Keuls test if appropriate, p-values: **p<0.01, N=7–11/group. Cue-reinstatement values were significantly different compared with extinction values in all tested groups (not shown in graph), p-values between groups: **p<0.01.
Figure 4
Figure 4
Increased oxytocin mRNA (OXTR mRNA) and OXTR binding sites in post-mortem samples of alcoholics compared with control samples. (a) Schematic outline of analyzed regions in the human brain according to von Hagens et al (1990). (b) OXTR mRNA expression and (c) [125I]OVTA binding; bar graphs illustrate quantitative analysis in post-mortem samples of alcoholics (OXTR mRNA: light orange bars; OXTR binding sites: dark-orange bars) and age-matched controls (white bars). Data are shown as mean±SEM (ddCt for mRNA expression, dCt values for controls are as follows: anterior cingulate cortex (ACC): 11.13±0.2; Brodmann area 9 (BA9): 11.14±0.3; nucleus caudatus (NC): 9.80±0.2; ventral striatum (VS): 9.28±0.3; fmol/mg for binding sites). Statistical analysis was performed by region-wise general linear models (GLMs), accounting for the possible influence of age, brain pH, post-mortem interval (PMI), and smoking; N=9–15/group, p-values: *p<0.05; **p<0.01; ***p<0.001, see also Supplementary Table S6.
Figure 5
Figure 5
Oxytocin (OXT) reduces neural reactivity to alcohol-related cues in heavy social drinkers. (a) Cue-reactivity task (alcohol, neutral pictures). (b) Decrease in blood oxygenation level-dependent (BOLD) response to alcohol compared with neutral cues by oxytocin compared to placebo in heavy social drinkers, N=12, p<0.05 family-wise error rate (FWE)-corrected (Monte Carlo-based simulations), (x,y,z)=(40,−12,16), effect size in sphere of 1 cm diameter: 0.37. The neutral pictures were taken from the International Affective Picture System (IAPS; Lang et al, 2008).
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