Cannabidiol Produces Distinct U-Shaped Dose-Response Effects on Cocaine-Induced Conditioned Place Preference and Associated Recruitment of Prelimbic Neurons in Male Rats.
Cannabidiol Produces Distinct U-Shaped Dose-Response Effects on Cocaine-Induced Conditioned Place Preference and Associated Recruitment of Prelimbic Neurons in Male Rats.
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DOI：
10.1016/j.bpsgos.2021.06.014
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Weiss F
中科院分区：
文献类型：
--
作者：
Nedelescu H;Wagner GE;De Ness GL;Carroll A;Kerr TM;Wang J;Zhang S;Chang S;Than AH;Emerson NE;Suto N;Weiss F
大麻二酚（CBD）已受到关注，用于治疗物质使用障碍。在复发的临床前模型中，CBD减弱了对包括可卡因在内的多种滥用药物的药物寻求。然而，在这些模式中，CBD并不总是有效的。CBD效应的这种不一致性可能与目前关于CBD剂量对药物相关行为的全方位影响的信息不足有关。我们解决这个问题，通过建立一个完整的剂量-反应曲线的CBD的行动，使用可卡因诱导的条件性位置偏爱的表达作为模型的药物动机的行为在雄性大鼠，并同时确定剂量依赖性的影响CBD对潜在的神经元激活和不同的神经元表型显示剂量依赖性激活的变化。此外，我们还确定了血浆和大脑样本中的CBD水平。CBD产生线性增加CBD脑/血浆浓度，但抑制条件性位置偏好在一个独特的U形方式。与其行为效应平行的是，CBD对前边缘系统而不是边缘下皮质或核内核的核心和外壳中的神经元激活产生U形抑制作用。RNAscope原位杂交鉴定了前边缘皮层中的GABA能和GABA能（γ-氨基丁酸能）信号转导的抑制，这是CBD减弱可卡因诱导的条件性位置偏爱的可能细胞机制。这些发现扩展了以前关于CBD在预防药物动机行为方面的潜力的证据。然而，CBD的剂量-反应曲线可能对未来的临床应用具有重要的剂量影响，并可能有助于理解文献中报道的CBD对药物寻求的差异影响。
Cannabidiol (CBD) has received attention for the treatment of substance use disorders. In preclinical models of relapse, CBD attenuates drug seeking across several drugs of abuse, including cocaine. However, in these models CBD has not been consistently effective. This inconsistency in CBD effects may be related to presently insufficient information on the full spectrum of CBD dose effects on drug-related behaviors. We address this issue by establishing a full dose-response profile of CBD’s actions using expression of cocaine-induced conditioned place preference as a model for drug-motivated behavior in male rats and by concurrently identifying dose-dependent effects of CBD on underlying neuronal activation and distinct neuronal phenotypes showing dose-dependent activation changes. Additionally, we established CBD levels in plasma and brain samples. CBD produced linear increases in CBD brain/plasma concentrations but suppressed conditioned place preference in a distinct U-shaped manner. In parallel with its behavioral effects, CBD produced U-shaped suppressant effects on neuronal activation in the prelimbic but not infralimbic cortex or nucleus accumbens core and shell. RNAscope in situ hybridization identified suppression of glutamatergic and GABAergic (gamma-aminobutyric acidergic) signaling in the prelimbic cortex as a possible cellular mechanism for the attenuation of cocaine-induced conditioned place preference by CBD. The findings extend previous evidence on the potential of CBD in preventing drug-motivated behavior. However, CBD’s dose-response profile may have important dosing implications for future clinical applications and may contribute to the understanding of discrepant CBD effects on drug seeking reported in the literature.
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影响因子：
2.9
作者：
Gaykema RP;Nguyen XM;Boehret JM;Lambeth PS;Joy-Gaba J;Warthen DM;Scott MM
通讯作者：
Scott MM
影响因子：
4.7
作者：
Angel Lujan, Miguel;Castro-Zavala, Adriana;Valverde, Olga
通讯作者：
Valverde, Olga
影响因子：
7.6
作者：
Gonzalez-Cuevas, Gustavo;Martin-Fardon, Remi;Weiss, Friedbert
通讯作者：
Weiss, Friedbert
影响因子：
17.7
作者：
Kalivas, PW;Volkow, ND
通讯作者：
Volkow, ND
影响因子：
4.1
作者：
Hay, Gracie L.;Baracz, Sarah J.;Cornish, Jennifer L.
通讯作者：
Cornish, Jennifer L.