Ethanol-induced modulation of synaptic output from the dorsolateral striatum in rat is regulated by cholinergic interneurons

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Abstract

The striatum is the largest input nucleus to the basal ganglia and associated with reward-based behavior. We assessed whether acute ethanol (EtOH) exposure could modulate synaptic efficacy in the dorsolateral striatum of juvenile Wistar rats. Since acute EtOH administration can both increase and decrease the probability of release of different neurotransmitters from synaptic terminals, we used field potential recordings to evaluate the net effect of EtOH on striatal output. We showed that 50 mM EtOH but not 20, 80 or 100 mM, depresses population spike (PS) amplitude in the dorsolateral striatum. This depression of synaptic output is insensitive to the N-methyl-d-aspartic acid (NMDA) receptor inhibitor DL-2-amino-5-phosphonopentanoic acid (AP-5, 50 μM), but is blocked in slices treated with glycine receptor antagonists (strychnine, 1 μM; PMBA, 50 μM), nicotinic acetylcholine receptor antagonists (mecamylamine, 10 μM; methyllycaconitine citrate (MLA), 40 nM), or GABAA receptor inhibitors (picrotoxin, 100 μM; bicuculline, 2 μM, 20 μM). A long-term facilitation of synaptic output, which is more pronounced in slices from adult Wistar rats, is detected following EtOH washout (50, 80, 100 mM). This long-term enhancement of PS amplitude is regulated by cholinergic interneurons and completely blocked by mecamylamine, MLA or the non-selective muscarinic antagonist scopolamine (10 μM). Administration of 100 mM EtOH significantly depresses PS amplitude in scopolamine-treated slices, suggesting that EtOH exerts dual actions on striatal output that are initiated instantly upon drug wash-on. In conclusion, EtOH modulates striatal microcircuitry and neurotransmission in a way that could be of importance for understanding the intoxicating properties as well as the acute reward sensation of EtOH.

Highlights

► Ethanol exerts dual actions on striatal output that are initiated simultaneously. ► Acute ethanol-treatment induces a GABAAR-sensitive short-term depression. ► Ethanol washout induces a long-term facilitation of striatal output. ► Ethanol-induced facilitation is regulated by cholinergic interneurons. ► This study provide important clues for understanding acute ethanol intoxication.

Introduction

The striatum is the largest input nucleus to the basal ganglia and is highly associated with reward-based behavior (Carelli, 2002, Löf et al., 2007, Söderpalm et al., 2009, Yin et al., 2008). Even though the mesoaccumbens pathway, arising from dopaminergic neurons in the ventral tegmental area and projecting to the ventral striatum, is involved in the behaviorally activating and reinforcing effects of stimulants, ethanol (EtOH) and opiates (Carelli, 2002, Ericson et al., 2003, Wise and Bozarth, 1985), reward-guided learning also involves dopaminergic inputs from the substantia nigra projecting to the dorsal striatum and seems to be an integrative function of basal ganglia networks (Yin et al., 2008). The dorsal striatum has also been shown to be involved in craving and the motivation to procure the drug in addicted humans (Volkow et al., 2006). This part of the striatum, and especially the dorsolateral striatum, might thus be recruited in advanced stages of addiction when drug use progresses towards a compulsive habitual pathology (Gerdeman et al., 2003).

The majority of synapses (∼80%) in the striatum are asymmetric glutamatergic synapses originating from the cortex and thalamus, while the majority of neurons (>90%) are GABAergic medium spiny neurons (MSNs) (Wilson, 2007). GABAergic neurotransmission thus has a strong influence on striatal output, and inhibition of gamma-aminobutyric acid type-A (GABAA) receptors significantly enhances recorded population spike (PS) amplitudes (Adermark and Lovinger, 2009). The striatum also contains cholinergic interneurons (1–2%), and acetylcholine has been implicated in controlling both glutamatergic and GABAergic transmission onto projecting MSNs (Pakhotin and Bracci, 2007, Sullivan et al., 2008, Zhou et al., 2002).

Acute EtOH administration can both increase and decrease the release probability of different neurotransmitters from synaptic terminals, which in turn can be correlated with important behavioral or developmental effects of alcohol (Spanagel, 2009). In particular, ligand-gated ion-channels like GABAA receptors, nicotinic acetylcholine receptors (nAChRs), ionotropic glutamate receptors and glycine receptors are sensitive to acute EtOH treatment (Lovinger, 1997, Molander and Söderpalm, 2005, Wang et al., 2010). These receptors are all expressed by neurons in the striatum and EtOH-treatment might thus acutely affect synaptic transmission and signal processing through multiple pathways. EtOH could thus modulate the neurocircuitry regulating striatal output and the flow of cortical information through the basal ganglia, possibly leading to neuronal and cognitive impairments associated with intoxication.

The acute effects displayed by EtOH are vast and complex, and the over all impact is often dependent on the agonist concentrations applied and the model system used (Crews et al., 1996, Grupp, 1980, Holdstock and de Wit, 1998, Lovinger, 1997, Lovinger and Homanics, 2007, Rossetti et al., 1992, Stancampiano et al., 2004). Furthermore, the dendrites of striatal MSNs are not uniformly orientated and dendritic arbors are not subregionally separated. Due to this, the net effect of EtOH on striatal output is difficult to estimate based on single-channel recordings or whole cell recordings. To further address the acute effects caused by EtOH administration on striatal neurotransmission we thus conducted field potential recordings, which display changes in net activity for a whole population of cells. Recordings were carried out in acutely isolated brain slices from P19-P25 Wistar rats. Population spikes were evoked in the dorsolateral striatum, a key brain region for habit formation (Yin and Knowlton, 2006).

Section snippets

Brain slice preparation

Experiments were carried out in accordance with the guidelines laid down by the Swedish Council regarding the care and use of animals for experimental procedures and were approved by the Local Ethics Committee of Gothenburg. Striatal slices were prepared from male and female 19–25-day-old Wistar rats (Breeding performed at University of Gothenburg; rats originating from Charles River, Germany). Animals were deeply anesthetized with Isofluran Baxter (Baxter Medical AB, Kista, Sweden) and

Ethanol induces short-term depression of striatal output

Acute EtOH treatment induced a dose-dependent depression of PS amplitudes evoked in the dorsolateral striatum. No change was seen after 15–20 min treatment with 20 mM EtOH (PS amplitude = 98 ± 9.2% of baseline, t = 0.38, n = 12, p > 0.05) (Fig. 1A), while 50 mM induced a small but robust depression of striatal output (92 ± 4.4% of baseline, t = 3.46, n = 12, p < 0.01) (Fig. 1). Treatment with higher EtOH concentrations (80 mM or 100 mM) did not depress PS amplitude (80 mM: 101 ± 4.8% of baseline, t = 0.23, n = 13, p > 0.05;

Discussion

The data presented here show that acute exposure to EtOH has both acute and long-term effects on striatal output, which are modulated by antagonists targeting glycine receptors, cholinergic receptors and GABAA receptors. Although the order of events can not be firmly determined by the methodology used or the experiments performed in the present study it is possible that EtOH interacts with glycine receptors primary located on cholinergic interneurons, thereby enhancing cholinergic activity,

Conclusion

The striatum is highly associated with reward-based behavior and is involved in modulating the reinforcing properties of drugs of abuse. Thus, the acute effects of EtOH on baseline synaptic transmission presented here provide new insights concerning the acute intoxicating properties of this drug. Our data suggest that glycine receptors could be important players in the acute phase of EtOH exposure, and should be considered when studying the neurological underpinnings of addictive behavior.

Acknowledgements

This work was supported by the Swedish Brain Foundation, Swedish Medical Research Council (Diary numbers 2009–2289, 2009–4477, and 2006–6385), the Swedish Society of Medicine (2009–22263, 2009–22179), Kungliga Vetenskapsakademin PE Lindahls stiftelse, Åke Wibergs stiftelse, Tore Nilsson Foundation, Thuring's Foundation, Magnus Bergvall's Foundation, Goljes minne, Stiftelsen Lars Hiertas minne, Gunnar och Märta Bergendahls minne and governmental support under the LUA/ALF agreement.

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