Jacobson Laura H, Sweeney Fabian F, Kaupmann Klemens, O'Leary Olivia F, Gassmann Martin, Bettler Bernhard, Cryan John F
Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland.
Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
Behav Brain Res. 2016 Feb 1;298(Pt B):12-6. doi: 10.1016/j.bbr.2015.10.039. Epub 2015 Oct 27.
GABAB receptors are crucial modulators of the behavioural effects of drug abuse, and agonists and positive allosteric modulators show promise as pharmacological strategies for anti-addiction therapeutics. GABAB receptors are functional heterodimers of GABAB1 and GABAB2 subunits. The predominant neuronal GABAB1 subunit isoforms are GABAB1a and GABAB1b. Selective ablation of these isoforms in mice revealed differential behavioural responses in fear, cognition and stress sensitivity. However, the influence of the two GABAB1 isoforms on responses to drugs of abuse is unclear. Therefore we examined the responses of GABAB1 subunit isoform null mice to cocaine in acute locomotor activity and conditioned place preference (CPP) paradigms. During habituation for the acute locomotor activity assay, GABAB1b(-/-) mice showed higher levels of locomotor activity relative to wild-type (WT) and GABAB1a(-/-) mice, in accordance with previous studies. Acute cocaine (10 mg/kg) increased locomotor activity in habituated mice of all three genotypes, with GABAB1a(-/-) mice showing sustained hyperlocomotor responses 30 min after cocaine relative to WT and GABAB1b(-/-) mice. No genotypes demonstrated a cocaine-induced place preference, however, GABAB1a(-/-) mice demonstrated enhanced locomotor sensitisation to chronic cocaine in the CPP paradigm in comparison to WT mice, whereas GABAB1b(-/-) mice failed to develop locomotor sensitisation, despite higher levels of basal locomotor activity. These findings indicate that GABAB1a and GABAB1b isoforms differentially regulate behavioural responses to cocaine, with deletion of GABAB1a enhancing cocaine-induced locomotor activity and deletion of GABAB1b protecting from cocaine-induced sensitisation.
GABAB受体是药物滥用行为效应的关键调节因子，激动剂和正变构调节剂作为抗成瘾治疗的药理学策略显示出前景。GABAB受体是GABAB1和GABAB2亚基的功能性异二聚体。主要的神经元GABAB1亚基异构体是GABAB1a和GABAB1b。在小鼠中选择性敲除这些异构体揭示了在恐惧、认知和应激敏感性方面的不同行为反应。然而，两种GABAB1异构体对滥用药物反应的影响尚不清楚。因此，我们在急性运动活动和条件性位置偏爱（CPP）范式中检查了GABAB1亚基异构体敲除小鼠对可卡因的反应。在急性运动活动测定的适应过程中，与野生型（WT）和GABAB1a敲除小鼠相比，GABAB1b敲除小鼠表现出更高水平的运动活动，这与先前的研究一致。急性给予可卡因（10mg/kg）增加了所有三种基因型适应小鼠的运动活动，与WT和GABAB1b敲除小鼠相比，GABAB1a敲除小鼠在给予可卡因后30分钟表现出持续的运动亢进反应。没有基因型表现出可卡因诱导的位置偏爱，然而，与WT小鼠相比，GABAB1a敲除小鼠在CPP范式中对慢性可卡因表现出增强的运动敏化，而GABAB1b敲除小鼠尽管基础运动活动水平较高，但未能产生运动敏化。这些发现表明，GABAB1a和GABAB1b异构体对可卡因的行为反应有不同的调节作用，敲除GABAB1a增强可卡因诱导的运动活动，敲除GABAB1b可防止可卡因诱导的敏化。
