Sari Youssef, Toalston Jamie E, Rao P S S, Bell Richard L
University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, OH 43614, USA.
Department of Psychiatry and Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Neuroscience. 2016 Jun 21;326:117-125. doi: 10.1016/j.neuroscience.2016.04.004. Epub 2016 Apr 7.
Increased glutamatergic neurotransmission appears to mediate the reinforcing properties of drugs of abuse, including ethanol (EtOH). We have shown that administration of ceftriaxone (CEF), a β-lactam antibiotic, reduced EtOH intake and increased glutamate transporter 1 (GLT-1) expression in mesocorticolimbic regions of male and female alcohol-preferring (P) rats. In the present study, we tested whether CEF administration would reduce nicotine (NIC) and/or EtOH intake by adult female P rats. P rats were randomly assigned to 4 groups: (a) 5% sucrose (SUC) or 10% SUC [SUC], (b) 5% SUC+0.07mg/ml NIC and 10% SUC+0.14mg/ml NIC [NIC-SUC], 15% EtOH and 30% EtOH [EtOH] and (d) 15% EtOH+0.07mg/ml NIC and 30% EtOH+0.14mg/ml NIC [NIC-EtOH]. After achieving stable intakes (4weeks), the rats were administered 7 consecutive, daily i.p. injections of either saline or 200mg/kg CEF. The effects of CEF on intake were significant but differed across the reinforcers; such that ml/kg/day SUC was reduced by ∼30%, mg/kg/day NIC was reduced by ∼70% in the NIC-SUC group and ∼40% in the EtOH-NIC group, whereas g/kg/day EtOH was reduced by ∼40% in both the EtOH and EtOH-NIC group. The effects of CEF on GLT-1 expression were also studied. We found that CEF significantly increased GLT-1 expression in the prefrontal cortex and the nucleus accumbens of the NIC and NIC-EtOH rats as compared to NIC and NIC-EtOH saline-treated rats. These findings provide further support for GLT-1-associated mechanisms in EtOH and/or NIC abuse. The present results along with previous reports of CEF's efficacy in reducing cocaine self-administration in rats suggest that modulation of GLT-1 expression and/or activity is an important pharmacological target for treating polysubstance abuse and dependence.
谷氨酸能神经传递增强似乎介导了包括乙醇（EtOH）在内的滥用药物的强化特性。我们已经表明，给予β-内酰胺抗生素头孢曲松（CEF）可减少雄性和雌性嗜酒（P）大鼠中脑皮质边缘区域的乙醇摄入量，并增加谷氨酸转运体1（GLT-1）的表达。在本研究中，我们测试了给予CEF是否会减少成年雌性P大鼠的尼古丁（NIC）和/或乙醇摄入量。P大鼠被随机分为4组：（a）5%蔗糖（SUC）或10%蔗糖[SUC]，（b）5%蔗糖+0.07mg/ml尼古丁和10%蔗糖+0.14mg/ml尼古丁[NIC-SUC]，15%乙醇和30%乙醇[EtOH]，以及（d）15%乙醇+0.07mg/ml尼古丁和30%乙醇+0.14mg/ml尼古丁[NIC-EtOH]。在摄入量稳定（4周）后，大鼠连续7天每天腹腔注射生理盐水或200mg/kg CEF。CEF对摄入量的影响显著，但不同强化物的影响有所不同；在SUC组中，ml/kg/天的蔗糖减少了约30%，在NIC-SUC组中，mg/kg/天的尼古丁减少了约70%，在EtOH-NIC组中减少了约40%，而在EtOH组和EtOH-NIC组中，g/kg/天的乙醇均减少了约40%。我们还研究了CEF对GLT-1表达的影响。我们发现，与NIC和NIC-EtOH生理盐水处理的大鼠相比，CEF显著增加了NIC和NIC-EtOH大鼠前额叶皮质和伏隔核中GLT-1的表达。这些发现为乙醇和/或尼古丁滥用中与GLT-1相关的机制提供了进一步支持。目前的结果以及之前关于CEF在减少大鼠可卡因自我给药方面疗效的报道表明，调节GLT-1的表达和/或活性是治疗多物质滥用和依赖的重要药理学靶点。
