Intermittent ethanol consumption depresses endocannabinoid-signaling in the dorsolateral striatum of rat
Highlights
► Long-term alcohol intake inhibits endocannabinoid signaling at inhibitory synapses. ► Long-term alcohol intake inhibits endocannabinoid signaling at excitatory synapses. ► Long-term alcohol intake inhibits short-term depression induced by CB1R activation. ► Alcohol intake affects presynaptic mechanisms that synergize with CB1R activation. ► Long-term alcohol intake reduces GABAAR-mediated inhibition of striatal output.
Introduction
Reward-guided behaviors are often attributed to the cortico-basal ganglia networks coursing through the striatum (Yin et al., 2008). The nucleus accumbens (nAc) and its reciprocal connection with the ventral tegmental area (VTA) represent a primary component of the mesolimbic reward pathway (Söderpalm et al., 2009, Spanagel and Weiss, 1999), but reward-guided learning also involves the dorsal striatum and dopaminergic inputs from the substantia nigra (Yin et al., 2008). In addition, the dorsal striatum is involved in the motivation to procure the drug in addicted humans (Volkow et al., 2007), suggesting that this part of the striatum could be recruited in advanced stages of addiction when drug use progresses towards a compulsive habit pathology (Gerdeman et al., 2003).
Recent research suggests that adaptations elicited by drugs of abuse share common features with traditional learning models, and that drugs of abuse cause long-term changes in behavior by altering synaptic function and plasticity (Gerdeman et al., 2003, Kauer and Malenka, 2007). Addiction can in that respect be considered a pathological process of learning and memory and increased knowledge about how drugs of abuse can modulate synaptic physiology and plasticity therefore holds promise for elucidating the neurological underpinnings of addictive behavior. Endocannabinoid (eCB) signaling is necessary for behavioral adaptations of motor behavior to change reward-position contingencies in the striatum (Balleine et al., 2007), and the eCB-system also appears to be involved in the neuronal circuitry regulating ethanol (EtOH) preference in rodents (Lallemand and De Witte, 2006, Vinod et al., 2008). Furthermore, the levels of the cannabinoid 1 receptor (CB1R) and CB1 receptor-mediated G-protein signaling have been shown to be significantly lower in the ventral striatum of alcohol-dependent subjects in a post mortem study (Vinod et al., 2010). The eCB system is thus a possible candidate linking neuronal adaptations elicited by drugs of abuse with behavioral consequences of that adaptation.
The components of the eCB system are highly expressed at different levels in the basal ganglia neural circuit where they interact bi-directionally with excitatory and inhibitory signaling systems, and balances neuronal circuits (Adermark and Lovinger, 2009, Adermark et al., 2009, Herkenham et al., 1990). The activation points required for eCB signaling and the induction of long-term depression (LTD) are similar at excitatory and inhibitory synapses, but inhibitory synapses are more sensitive to eCB signaling and CB1R activation (Adermark and Lovinger, 2009, Adermark et al., 2009). Due to this, stimulation protocols that induce short-lasting CB1R-dependent depression at excitatory synapses can be sufficient to induce LTD at inhibitory synapses, resulting in a frequency-dependent control of net striatal output by eCB-dependent plasticity (Adermark et al., 2009). Interestingly, striatal inhibitory synapses have been shown to be especially sensitive to acute EtOH administration and concentrations as low as 20 mM is sufficient to impair eCB signaling at these synapses (Clarke and Adermark, 2010).
Based on the possible recruitment of the dorsal striatum in addicted subjects and the role of the eCB system in regulating EtOH preference, the aim of this study was to evaluate possible alterations in eCB signaling and synaptic plasticity in the dorsolateral striatum in alcohol-consuming rats. Male Wistar rats had free access to a 20% EtOH solution for three 24 h sessions a week during seven weeks. Coronal brain slices containing the striatum were acutely isolated from EtOH-consuming rats, isolated controls and age-matched controls. Synaptic plasticity was studied by field potential recordings.
Section snippets
Intermittent drinking schedule
Male Wistar rats (Taconic, Ejby, Denmark) weighing 130–170 g at the time of arrival were housed in individual cages (41 × 21 × 18 cm) at constant room temperature (22 °C) and humidity (65%). The animals were kept under regular light–dark conditions (lights on at 7:00 am and off at 7:00 pm) and had free access to ‘rat standard feed’ (Lantmännen, Kimstad, Sweden) and tap water. The animals were allowed to adapt to the novel environment for one week before any experiments were initiated. EtOH-consuming
Alcohol intake
Rats received EtOH for 7 weeks (21 sessions). EtOH consumption did not increase over time and mean EtOH-intake for the last three sessions was 3.40 ± 0.63 g/kg/session (n = 10) (Fig. 1A). Total fluid intake did not vary significantly between EtOH-consuming rats (77 ± 7.1 ml/kg/session) and isolated control rats (70 ± 8.1 ml/kg/session) (unpaired t-test, t = 1.13, p > 0.05). The weight gain over time was not significantly different in EtOH-consuming rats as compared to isolated control rats (Fig. 1B). Mean
Discussion
The data presented here suggests that intermittent alcohol intake in isolated rats for seven weeks impairs eCB signaling at a level that is downstream from CB1R activation. Our data also indicates that the inhibitory control of striatal output displayed by GABAA receptors is reduced. Importantly, isolation per-se appears to depress eCB signaling and a trend (p = 0.09) for reduced GABAergic tone on GABAA receptors was indicated when compared to age-matched controls.
The intermittent-access paradigm
Acknowledgements
We are thankful for the assistance provided by Julia Tersmeden. This work was supported by the Swedish Medical Research Council (Diary numbers 2009-2289, 2006-6385, 2009-4477), Swedish Brain Foundation, the Swedish Society of Medicine (2009-22263), Åke Wibergs Stiftelse (711145539), Tore Nilsson foundation, Magnus Bergvall’s foundation, Fredrik and Ingrid Thuring’s foundation, Lars Hiertas minne, PE Lindahls stiftelse, Bror Gadelius Minnesfond, Stiftelsen Sigurd och Elsa Goljes minne, Gunnar
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