Homberg J R, Arends B, Wardeh G, Raasø H S, Schoffelmeer A N M, de Vries T J
Graduate School Neuroscience Amsterdam, Research Institute Neurosciences Vrije Universiteit, Drug Abuse Program, Department of Medical Pharmacology, VU Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands.
Neuroscience. 2004;128(1):121-30. doi: 10.1016/j.neuroscience.2004.05.048.
Numerous clinical studies have indicated that lifetime anxiety is highly prevalent in drug addicts. In the treatment of drug abuse, dually diagnosed drug addicts may benefit from pharmacological intervention strategies that alleviate the psychiatric symptomatology. We have previously shown that rats with different coping strategies in a stressful environment show strong differences in the motivation to self-administer cocaine. That is, cocaine self-administration under a progressive ratio (PR) schedule of reinforcement was enhanced in high grooming (HG) rats as compared with low grooming (LG) rats. To identify the pharmacological basis of these differences, we tested the acute effects of several anxiolytic drugs on cocaine self-administration in HG and LG rats under a PR schedule of reinforcement. Chlordiazepoxide increased PR responding in both the HG and LG rats, while the selective corticotrophin releasing hormone 1 receptor antagonist R121919 had no effect on cocaine self-administration under the PR schedule. Interestingly, buspirone and fluoxetine decreased PR responding in HG rats only and thereby abolished the individual differences in PR responding between HG and LG rats. In support of the differential effects of the serotonergic drugs on PR responding in HG and LG rats, we found that the in vitro electrically evoked release of [3H]serotonin from mesocorticolimbic brain slices was reduced in the medial prefrontal cortex, substantia nigra and nucleus accumbens core, and increased in the nucleus accumbens shell of HG rats relative to LG rats. These findings show that serotonergic anxiolytics abolish the pre-existing individual differences in cocaine self-administration between HG and LG rats, which show differences in the reactivity of serotonergic neurons. This suggests that the effectiveness of pharmacological interference may depend on the neurochemical and motivational state of the individual.
众多临床研究表明，终生焦虑在吸毒成瘾者中极为普遍。在药物滥用治疗中，同时患有精神疾病的吸毒成瘾者可能会从减轻精神症状的药物干预策略中受益。我们之前已经表明，在应激环境中具有不同应对策略的大鼠在自我给药可卡因的动机上表现出很大差异。也就是说，与低梳理（LG）大鼠相比，高梳理（HG）大鼠在渐进比率（PR）强化程序下的可卡因自我给药有所增强。为了确定这些差异的药理学基础，我们在PR强化程序下测试了几种抗焦虑药物对HG和LG大鼠可卡因自我给药的急性影响。氯氮卓增加了HG和LG大鼠的PR反应，而选择性促肾上腺皮质激素释放激素1受体拮抗剂R121919在PR程序下对可卡因自我给药没有影响。有趣的是，丁螺环酮和氟西汀仅降低了HG大鼠的PR反应，从而消除了HG和LG大鼠在PR反应上的个体差异。为了支持血清素能药物对HG和LG大鼠PR反应的不同影响，我们发现，相对于LG大鼠，HG大鼠内侧前额叶皮质、黑质和伏隔核核心中[3H]血清素的体外电诱发释放减少，而伏隔核壳中的释放增加。这些发现表明，血清素能抗焦虑药物消除了HG和LG大鼠之间预先存在的可卡因自我给药个体差异，这两种大鼠在血清素能神经元的反应性上存在差异。这表明药物干预的有效性可能取决于个体的神经化学和动机状态。
