Thorsell A, Rimondini R, Heilig M
Neurotec, Karolinska Institutet, M46, Huddinge University Hospital, SE-141 86 Huddinge, Sweden.
Neurosci Lett. 2002 Oct 25;332(1):1-4. doi: 10.1016/s0304-3940(02)00904-7.
Activation of central neuropeptide Y (NPY) receptors is known to produce several behavioral effects, including feeding, modulation of memory and antagonism of behavioral effects of stress. In addition, experiments in knock-out and transgenic mice have suggested a possible role of NPY regulation of voluntary ethanol intake. NPY receptors involved in this action are not known. Here, we examined the effects of a selective NPY-Y2 receptor antagonist, BIIE0246, on operant responding for ethanol in a sweetened solution, or the sweetened solution without ethanol, during 30 min sessions of free choice between the two. BIIE0246 produced a robust suppression of responding for ethanol (40% reduction, P=0.013) at an intracerebroventricular dose of 1.0 nmol, but not 0.3 nmol. Responding for the saccharin solution was not significantly affected. The dose range examined was selected since preliminary experiments with doses of 3 nmol and higher indicated sedative effects, but such effects were absent up to 1.0 nmol, as shown by unaffected exploratory locomotor activity. In summary, antagonism at central NPY-Y2 receptors seems to selectively suppress operant self-administration of ethanol. This suggests that Y2 receptors might be candidate targets for developing novel pharmacological treatments of alcoholism.
已知中枢神经肽Y（NPY）受体的激活会产生多种行为效应，包括进食、记忆调节以及对应激行为效应的拮抗作用。此外，对基因敲除和转基因小鼠的实验表明，NPY对自愿乙醇摄入的调节可能具有一定作用。参与这一作用的NPY受体尚不明确。在此，我们研究了选择性NPY-Y2受体拮抗剂BIIE0246对在含乙醇甜味溶液或不含乙醇甜味溶液之间自由选择30分钟期间，对乙醇进行操作性反应的影响。BIIE0246在脑室内注射剂量为1.0 nmol时，对乙醇反应产生了强烈抑制（降低40%，P = 0.013），但0.3 nmol剂量时未出现这种情况。对糖精溶液的反应未受到显著影响。选择所研究的剂量范围是因为初步实验表明，3 nmol及更高剂量具有镇静作用，但高达1.0 nmol时未出现此类作用，这表现为探索性运动活动未受影响。总之，中枢NPY-Y2受体的拮抗作用似乎能选择性抑制乙醇的操作性自我给药。这表明Y2受体可能是开发新型酒精中毒药物治疗方法的候选靶点。
