Research report[3H]DPDPE binding to δ opioid receptors in the rat mesocorticolimbic and nigrostriatal pathways is transiently increased by acute ethanol administration
Introduction
Activation of dopaminergic (DAergic) pathways in brain by drugs of abuse plays a critical role in the development of addictive behaviour. Biochemical and pharmacological evidence reveal that the DAergic mesolimbic pathway plays a key role in mediating the reinforcing properties of ethanol and other drugs of abuse [42], [86]. In addition, brain sensitivity to ethanol has been suggested to be an important indicator of the liability for ethanol addiction, since a low level of response to the drug in humans has been associated with a greater likelihood of future alcoholism [68]. The DAergic activity in the nigrostriatal pathway has been postulated to play a major role in brain sensitivity to ethanol and to represent an important component in addictive processes [89], despite the fact that this pathway has not been implicated in ethanol reward circuits.
Ethanol reinforcement and high alcohol drinking behaviour have been postulated to be partially mediated by a neurobiological mechanism involving the ethanol-induced activation of the endogenous opioid system [22], [35], [80]. This activation may in turn enhance the hedonic value and the reinforcing properties of ethanol. Several studies support this hypothesis and suggest that ethanol may alter opioid transmission at different levels, including the processing, release and/or receptor binding of opioid peptides. Ethanol administration increases opioid peptide gene expression [23], [45] and brain enkephalin [69] and β-endorphin [64] content, and a correlation has been observed between the increase in β-endorphin and the risk of alcoholism in humans [28]. Ethanol also increases the release of β-endorphin from the nucleus accumbens (NAcc) [51], [57]. Selective and non-selective opiate receptor antagonists suppress voluntary ethanol consumption in rodents [22], [38], [43], [44], [45], [72], monkeys [56] and humans [82], whereas the inhibition of enkephalin degradation increases voluntary ethanol intake [24]. These data suggest that occupation of both μ and δ opioid receptors and activation of the endogenous enkephalinergic and β-endorphinergic systems play a key role in high alcohol drinking behaviour.
Brain sensitivity to ethanol has been suggested to involve DAergic activation of the nigrostriatal pathway. The number and activity of postsynaptic DAergic receptors may be relevant in ethanol sensitivity, since an increased number of striatal DAergic receptors is correlated to an enhanced brain resistance to ethanol-induced narcosis [88], [89]. Some studies have shown that ethanol and pentobarbital-induced narcosis are of shorter duration in drug-treated animals than in their corresponding controls [88], [89]. This response, measured as a reduction in drug-induced sleep time, has been interpreted as a decreased sensitivity (increased resistance) of the brain to the narcotic effects of both drugs. Besides DAergic innervations, opioid peptides may be also implicated as determinants of brain sensitivity to ethanol [13].
Opioid peptides and ethanol alter DAergic transmission in the brain. For instance, ethanol and morphine increase the firing rate of DAergic neurons in the ventral tegmental area (VTA) and the substantia nigra pars compacta (SNc) [26], [33], [55], as well as dopamine (DA) release and metabolism in the NAcc and striatum [16], [20], [85]. Opioid receptors have been localized on DAergic cell bodies in the VTA and the SNc and in terminals in the NAcc and striatum [47], [61], [62], [78], as well as on non-DAergic afferent terminals or processes in intrinsic neurons in the VTA and the substantia nigra pars reticulata (SNr) and SNc [25], [47], [58]. In addition, since the ethanol-induced release of DA from terminals in the NAcc and the striatum is blocked by both δ-selective and non-selective opiate receptor antagonists [2], [5], [31], [85], endogenous opioids, through activation of opioid receptors, may regulate DAergic transmission in the mesolimbic and nigrostriatal pathways in response to ethanol. Therefore, opioid receptors may play a role in modulating DAergic activity and contribute to ethanol reinforcement mechanisms and brain sensitivity to the drug.
Numerous studies have shown that ethanol differentially alters opioid receptor binding in brain tissue and neuroblastoma cell lines depending on the conditions of study. Acute ethanol treatment inhibits the binding of opioid peptides to the δ receptor in neuroblastoma cell lines [10], [30] and rat brain membranes [6], with a decrease in ligand binding affinity [10], [36]. However, low doses of ethanol have been reported to enhance, while high concentrations inhibit the binding of D-Ala2,D-Leu5-enkephalin (DADLE) to δ opioid receptors in striatal membranes [75]. Chronic ethanol exposure has been reported to increase the number of δ opioid binding sites in NG108-15 cells [10], [11], [12] and δ ligand binding affinity of rodent striatal homogenates and brain membranes, with no effect on the number of δ receptors [60], [63]. On the other hand, ligand binding to δ receptors in brain sections is not altered in the NAcc or the striatum by chronic ethanol treatment [79]. The discrepancies in ethanol responses reported in these studies may be explained by differences in ethanol doses and route of administration, time of exposure to the drug, time elapsed after ethanol administration at the moment the experiment was carried out, and receptor ligand used. In addition, the time course of the in vivo ethanol effects in different brain regions has not been reported. Therefore, in order to investigate the role of δ opioid receptors in the biological responses elicited by a single acute dose of ethanol, we studied the time course effects of the drug on mesocorticolimbic and nigrostriatal δ opioid receptors.
Section snippets
Animals and treatments
Adult male Wistar rats (250–300 g) fed ad libitum (Purina Chow) and maintained in a 12-h light–dark period received a single acute dose of ethanol (2.5 g/kg) (experimental group) or distilled water (control group) by oral administration with an intra-gastric cannula, as previously reported [52], [53]. Animals were habituated to the cannula by one daily oral administration of distilled water (5 ml/kg) for the previous 7 days in order to diminish stress. Animals were sacrificed by decapitation 30
Results
Quantitative receptor autoradiographic assays in control animals, using [3H]DPDPE as radioligand, revealed δ opioid receptor densities similar to previously reported data [7], [18], [32], [37], [65], [91]. Highest δ receptor densities were found in the CP (Fig. 1C, E and G), followed by the NAcc (Fig. 1C) and the frontal and prefrontal cortices (Fig. 1A), whereas lowest levels were detected in the SNr (Fig. 1I). Delta receptor labelling in the anterior-medial region of the CP was higher than in
Discussion
The endogenous opioid system has been proposed to play a key role in mediating the reinforcing actions of ethanol and alcohol drinking behaviour [22], [35], [80]. Numerous studies suggest that activation of μ and δ opioid receptors is involved in these processes. Voluntary ethanol consumption in rodents has been shown to be blocked both by non-selective (naloxone) and μ (β-funaltrexamine, CTOP: D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) and δ (naltrindole, naltriben and ICI 174864) selective
Acknowledgments
We thank L. Mayagoitia for assistance in statistical analyses, and J.C. Calva and S.R. Mejía-Mauries for technical assistance. This work was supported by Consejo Nacional de Ciencia y Tecnología (CONACyT) (34359-N).
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