Polysubstance addiction vulnerability in mental illness: Concurrent alcohol and nicotine self-administration in the neurodevelopmental hippocampal lesion rat model of schizophrenia.
Polysubstance addiction vulnerability in mental illness: Concurrent alcohol and nicotine self-administration in the neurodevelopmental hippocampal lesion rat model of schizophrenia.
复制标题
精神疾病中的多物质成瘾脆弱性：精神分裂症神经发育海马病变大鼠模型中同时酒精和尼古丁的自我给药。
DOI：
10.1111/adb.12704
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发表时间：
2020
影响因子：
3.4
通讯作者：
Chambers,RAndrew
中科院分区：
文献类型：
--
作者：
Sentir,AlenaM;Bell,RichardL;Engleman,EricA;Chambers,RAndrew
精神病患者经常出现多重成瘾。然而，关于这些合并症之间基于大脑的联系的基础研究非常有限。为了表征精神分裂症中多物质使用和成瘾易感性的第一个动物模型，患有新生儿腹侧海马病变（NVHL）的青少年大鼠和对照组在出生后19个工作日（PD 35 - 60）每天1小时自由接触酒精/蔗糖溶液（第10天从10%蔗糖逐渐减少到10%酒精/2%蔗糖）。从成年期（PD 63）开始，大鼠在15个阶段中获得了同时口服酒精（10%含2%蔗糖）和静脉注射尼古丁（0.015 mg/kg/注射）的杠杆按压。随后，10个操作性消退会议和3个恢复会议审查药物寻求后，扣留尼古丁，尼古丁和酒精，然后重新引入。青少年饮酒量在NVHL和对照组之间没有差异。然而，在成年期，NVHL在酒精和尼古丁水平上表现出更强的杠杆按压，在尼古丁水平上进展更强烈，即使两组的最大按压都是在酒精水平上。在灭绝中，两组都表现出预期的努力下降，因为药物被扣留，但NVHL坚持更大的压力在酒精和尼古丁的杠杆。在复吸中，酒精再进入增加了按压，NVHL总体上显示出更大的尼古丁杠杆活性。因此，产生精神疾病的发育性颞叶边缘异常可以产生成人多药成瘾脆弱性，作为一种独立于成瘾药物之间假定的交叉致敏效应的机制。对三阶（和更高）成瘾-精神疾病共病的进一步临床前建模可能会促进我们对这些复杂但常见的脑部疾病的理解和治疗。
Multiple addictions frequently occur in patients with mental illness. However, basic research on the brain‐based linkages between these comorbidities is extremely limited. Toward characterizing the first animal modeling of polysubstance use and addiction vulnerability in schizophrenia, adolescent rats with neonatal ventral hippocampal lesions (NVHLs) and controls had 19 weekdays of 1 hour/day free access to alcohol/sucrose solutions (fading from 10% sucrose to 10% alcohol/2% sucrose on day 10) during postnatal days (PD 35‐60). Starting in adulthood (PD 63), rats acquired lever pressing for concurrent oral alcohol (10% with 2% sucrose) and iv nicotine (0.015 mg/kg/injection) across 15 sessions. Subsequently, 10 operant extinction sessions and 3 reinstatement sessions examined drug seeking upon withholding of nicotine, then both nicotine and alcohol, then reintroduction. Adolescent alcohol consumption did not differ between NVHLs and controls. However, in adulthood, NVHLs showed increased lever pressing at alcohol and nicotine levers that progressed more strongly at the nicotine lever, even as most pressing by both groups was at the alcohol lever. In extinction, both groups showed expected declines in effort as drugs were withheld, but NVHLs persisted with greater pressing at both alcohol and nicotine levers. In reinstatement, alcohol reaccess increased pressing, with NVHLs showing greater nicotine lever activity overall. Developmental temporal‐limbic abnormalities that produce mental illness can thus generate adult polydrug addiction vulnerability as a mechanism independent from putative cross‐sensitization effects between addictive drugs. Further preclinical modeling of third‐order (and higher) addiction‐mental illness comorbidities may advance our understanding and treatment of these complex, yet common brain illnesses.