• Energy Research

The ability of drugs of abuse to increase mesolimbic levels of dopamine is a characteristic associated with their rewarding effects. Exactly how these effects are produced by different substances is not as well characterised. Our previous work in rats has demonstrated that accumbal glycine receptors (GlyRs) are involved in mediating the dopamine-activating effects of ethanol, and in modulating ethanol intake. In this study the investigation of GlyR involvement was extended to include several different drugs of abuse. By using microdialysis and electrophysiology we compared effects of addictive drugs, with and without the GlyR antagonist strychnine, on dopamine levels and neurotransmission in nucleus accumbens. The dopamine-increasing effect of systemic ethanol and the drug-induced change in neurotransmission in vitro, as measured by microdialysis and field potential recordings, were dependent on GlyRs in nAc. Accumbal GlyRs were also involved in the actions of tetrahydrocannabinol and nicotine, but not in those of cocaine or morphine. These data indicate that accumbal GlyRs play a key role in ethanol-induced dopamine activation and contribute also to that of cannabinoids and nicotine.

The ability of drugs of abuse to increase mesolimbic levels of dopamine is a characteristic associated with their rewarding effects. Exactly how these effects are produced by different substances is not as well characterised. Our previous work in rats has demonstrated that accumbal glycine receptors (GlyRs) are involved in mediating the dopamine-activating effects of ethanol, and in modulating ethanol intake. In this study the investigation of GlyR involvement was extended to include several different drugs of abuse. By using microdialysis and electrophysiology we compared effects of addictive drugs, with and without the GlyR antagonist strychnine, on dopamine levels and neurotransmission in nucleus accumbens. The dopamine-increasing effect of systemic ethanol and the drug-induced change in neurotransmission in vitro, as measured by microdialysis and field potential recordings, were dependent on GlyRs in nAc. Accumbal GlyRs were also involved in the actions of tetrahydrocannabinol and nicotine, but not in those of cocaine or morphine. These data indicate that accumbal GlyRs play a key role in ethanol-induced dopamine activation and contribute also to that of cannabinoids and nicotine.

The acute effect of hyperosmotic ethanol on gap junction permeability was examined in astroglial cells in primary culture from five different brain regions. Gap junction permeability was analyzed by measuring dye spreading from cell to cell with the low molecular weight dye Lucifer Yellow. Ethanol concentrations 25-300 mM significantly decreased dye spreading in cultures from the cerebral cortex in a dose-dependent but time-independent manner for up to 60 min. Besides cerebral cortex, exposure to 150 mM ethanol decreased dye spreading in astroglial cultures from the hippocampus and from the brain stem, while cultures from the olfactory bulb and from the hypothalamus were not significantly affected. The ethanol-induced decrease in dye spreading in cultures from the cerebral cortex was not mediated through changes in cell volume, osmolarity, protein kinase C (PKC) phosphorylation, intracellular pH, or intracellular calcium concentration ([Ca(2+)](i)). The decrease in dye spreading was abolished upon incubation in sodium-reduced buffer, and after blockage of the Na(+)/K(+)/2Cl(-) cotransporter with furosemide. The results presented here indicate that ethanol-mediated decrease in dye spreading is directly or indirectly dependent on sodium.

The acute effect of hyperosmotic ethanol on gap junction permeability was examined in astroglial cells in primary culture from five different brain regions. Gap junction permeability was analyzed by measuring dye spreading from cell to cell with the low molecular weight dye Lucifer Yellow. Ethanol concentrations 25-300 mM significantly decreased dye spreading in cultures from the cerebral cortex in a dose-dependent but time-independent manner for up to 60 min. Besides cerebral cortex, exposure to 150 mM ethanol decreased dye spreading in astroglial cultures from the hippocampus and from the brain stem, while cultures from the olfactory bulb and from the hypothalamus were not significantly affected. The ethanol-induced decrease in dye spreading in cultures from the cerebral cortex was not mediated through changes in cell volume, osmolarity, protein kinase C (PKC) phosphorylation, intracellular pH, or intracellular calcium concentration ([Ca(2+)](i)). The decrease in dye spreading was abolished upon incubation in sodium-reduced buffer, and after blockage of the Na(+)/K(+)/2Cl(-) cotransporter with furosemide. The results presented here indicate that ethanol-mediated decrease in dye spreading is directly or indirectly dependent on sodium.

AbstractThe striatum is a critical structure for the control of voluntary behaviour, and striatal synaptic plasticity has been implicated in instrumental learning. As ethanol consumption can cause impairments in cognition, learning, and action selection, it is important to understand the effects of this drug on striatal function. In this study we examined the effects of ethanol on long‐term synaptic plasticity in the dorsomedial striatum (DMS), a striatal subregion that plays a central role in the acquisition and selection of goal‐directed actions. Ethanol was found to impair N‐methyl‐d‐aspartic acid receptor (NMDAR)‐dependent long‐term potentiation (LTP) dose‐dependently in the DMS, and to promote long‐term depression (LTD) at the highest concentration (50 mm) used. These results suggest that ethanol, at a concentration usually associated with mild intoxication, could significantly change experience‐dependent modification of corticostriatal circuits underlying the learning of goal‐directed instrumental actions.

AbstractThe striatum is a critical structure for the control of voluntary behaviour, and striatal synaptic plasticity has been implicated in instrumental learning. As ethanol consumption can cause impairments in cognition, learning, and action selection, it is important to understand the effects of this drug on striatal function. In this study we examined the effects of ethanol on long‐term synaptic plasticity in the dorsomedial striatum (DMS), a striatal subregion that plays a central role in the acquisition and selection of goal‐directed actions. Ethanol was found to impair N‐methyl‐d‐aspartic acid receptor (NMDAR)‐dependent long‐term potentiation (LTP) dose‐dependently in the DMS, and to promote long‐term depression (LTD) at the highest concentration (50 mm) used. These results suggest that ethanol, at a concentration usually associated with mild intoxication, could significantly change experience‐dependent modification of corticostriatal circuits underlying the learning of goal‐directed instrumental actions.

AbstractGlucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex4), liraglutide and dulaglutide, regulate glucose homeostasis and are thus used to treat diabetes type II. GLP‐1 also contributes towards a variety of additional physiological functions, including suppression of reward and improvement of learning. Acute activation of GLP‐1R in the nucleus accumbens (NAc) shell, an area essential for motivation, reduces the motivation to consume sucrose or alcohol when assessed in a simple motor task. However, the effects of repeated administration of the different GLP‐1R agonists on behaviours in a more complex motor task are unknown. The aim was therefore to investigate the effects of repeated Ex4, liraglutide or dulaglutide on the motivation and learning of a complex motor tasks such as skilled reach foraging in the Montoya staircase test. To explore the neurophysiological correlates of the different GLP‐1R agonists on motivation,ex vivoelectrophysiological recordings were conducted. In rats with an acquired skilled reach performance, Ex4 or liraglutide but not dulaglutide reduced the motivation of skilled reach foraging. In trained rats, Ex4 infusion into NAc shell decreased this motivated behaviour, and both Ex4 and liraglutide supressed the evoked field potentials in NAc shell. In rats without prior Montoya experience, dulaglutide but not Ex4 or liraglutide enhanced the learning of skilled reach foraging. Taken together, these findings indicate that the tested GLP‐1R agonists have different behavioural outcomes depending on the context.

AbstractGlucagon‐like peptide‐1 receptor (GLP‐1R) agonists, such as exendin‐4 (Ex4), liraglutide and dulaglutide, regulate glucose homeostasis and are thus used to treat diabetes type II. GLP‐1 also contributes towards a variety of additional physiological functions, including suppression of reward and improvement of learning. Acute activation of GLP‐1R in the nucleus accumbens (NAc) shell, an area essential for motivation, reduces the motivation to consume sucrose or alcohol when assessed in a simple motor task. However, the effects of repeated administration of the different GLP‐1R agonists on behaviours in a more complex motor task are unknown. The aim was therefore to investigate the effects of repeated Ex4, liraglutide or dulaglutide on the motivation and learning of a complex motor tasks such as skilled reach foraging in the Montoya staircase test. To explore the neurophysiological correlates of the different GLP‐1R agonists on motivation,ex vivoelectrophysiological recordings were conducted. In rats with an acquired skilled reach performance, Ex4 or liraglutide but not dulaglutide reduced the motivation of skilled reach foraging. In trained rats, Ex4 infusion into NAc shell decreased this motivated behaviour, and both Ex4 and liraglutide supressed the evoked field potentials in NAc shell. In rats without prior Montoya experience, dulaglutide but not Ex4 or liraglutide enhanced the learning of skilled reach foraging. Taken together, these findings indicate that the tested GLP‐1R agonists have different behavioural outcomes depending on the context.

Elevated dopamine levels are believed to contribute to the rewarding sensation of ethanol (EtOH), and previous research has shown that strychnine-sensitive glycine receptors in the nucleus accumbens (nAc) are involved in regulating dopamine release and in mediating the reinforcing effects of EtOH. Furthermore, the osmoregulator taurine, which is released from astrocytes treated with EtOH, can act as an endogenous ligand for the glycine receptor, and increase extracellular dopamine levels. The aim of this study was to address if EtOH-induced swelling of astrocytes could contribute to elevated dopamine levels by increasing the extracellular concentration of taurine. Cell swelling was estimated by optical sectioning of fluorescently labeled astrocytes in primary cultures from rat, and showed that EtOH (25-150 mM) increased astrocyte cell volumes in a concentration- and ion-dependent manner. The EtOH-induced cell swelling was inhibited in cultures treated with the Na(+) /K(+) /2Cl⁻ cotransporter blocker furosemide (1 mM), Na(+) /K(+) -ATPase inhibitor ouabain (0.1 mM), potassium channel inhibitor BaCl₂ (50 µM) and in cultures containing low extracellular sodium concentration (3 mM). In vivo microdialysis performed in the nAc of awake and freely moving rats showed that local treatment with EtOH enhanced the concentrations of dopamine and taurine in the microdialysate, while glycine and β-alanine levels were not significantly modulated. EtOH-induced dopamine release was antagonized by local treatment with the glycine receptor antagonist strychnine (20 µM) or furosemide (100 µM or 1 mM). Furosemide also prevented EtOH-induced taurine release in the nAc. In conclusion, our data suggest that extracellular concentrations of dopamine and taurine are interconnected and that swelling of astrocytes contributes to the acute rewarding sensation of EtOH.