Psychopharmacology (2004) 174:211–219 DOI 10.1007/s00213-003-1743-0 ORIGINAL INVESTIGATION Maciej Gasior · Rafal Kaminski · Jeffrey M. Witkin Pharmacological modulation of GABA B receptors affects cocaine-induced seizures in mice Received: 28 July 2003 / Accepted: 19 November 2003 / Published online: 20 February 2004  Springer-Verlag 2004 Abstract Rationale: Previous data have demonstrated that the convulsant effects of cocaine can be modulated by compounds that increase levels of endogenous g- aminobutyric acid (GABA) or that directly stimulate GABA A receptors. Objectives: To determine whether the convulsant effects of cocaine can be modulated by ligands selective for GABA B receptors in mice. Methods: Effects of the GABA B receptor agonist ((€)-baclofen), antagonist (phaclofen), and their combination were tested against clonic seizures induced by cocaine (75 mg/kg). Enan- tiomers of baclofen were used to confirm stereospecificity of (€)-baclofen’s effects. Pharmacological specificity of (€)-baclofen’s effects was tested by comparison against seizures induced by GBR 12909 (monoamine transporter inhibitor), pentylenetetrazole (GABA A antagonist), N- methyl-d-aspartate (NMDA agonist), and aminophylline (A 1 /A 2 adenosine antagonist). Additionally, effects of (€)- baclofen on kindled seizures induced by repeated admin- istration of cocaine (60 mg/kg every 24 h for 6 days) were evaluated. The inverted screen test was used to assess behavioral side effects of baclofen. Results: (€)-Baclofen dose-dependently inhibited acute (ED 50 =4.1 mg/kg) and kindled (6.4 mg/kg) seizures induced by cocaine at doses somewhat lower than those producing behavioral side effects (11.5 mg/kg), and these effects were stereo- specific. (€)-Baclofen suppressed seizures induced by GBR 12909 but not by pentylenetetrazole, NMDA, and aminophylline, suggesting selectivity of its anticonvulsant effects for monoamine-related mechanisms. Finally, pha- clofen dose-dependently enhanced the convulsant effects of a threshold dose of cocaine (60 mg/kg). Conclusions: Modulation of GABA B receptors can affect seizures induced by cocaine. This molecular mechanism may be involved in seizures induced by cocaine or, alternatively, may function as an independent inhibitory mechanism against seizures arising from blockade of monoamine uptake. Keywords Cocaine · Baclofen · GABA · Seizures · Kindling · Anticonvulsant Introduction A plethora of evidence has accumulated to document a principal role of g-aminobutyric acid (GABA)-mediated neurotransmission in the neuropathology of seizures in humans and experimental animals (Snodgrass 1992; Bradford 1995). Accordingly, the anticonvulsant effects of many antiepileptic drugs are attributed to their ability to augment GABA A -mediated inhibition (Rogawski and Porter 1990). A role of GABA B receptors in seizure disorders appears to be more complex as agonists and antagonists of the receptor can produce both anticonvul- sant and convulsant effects depending on the type of convulsant stimulus. For example, the prototypical GABA B agonist (€)-baclofen has been reported to induce seizures per se after intraventricular injections in rodents and after therapeutic doses in humans (Rush and Gibberd 1990; Snodgrass 1992). Further, (€)-baclofen potenti- ated the convulsant effects of acutely administered pentylenetetrazole but attenuated the development of pentylenetetrazole-kindled seizures in rodents (Snodgrass 1992; Snead 1996; De Sarro et al. 2000). Like baclofen, M. Gasior · R. Kaminski · J. M. Witkin Drug Development Group, Behavioral Neuroscience Branch, National Institute on Drug Abuse, National Institutes of Health, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA M. Gasior ( ) ) · R. Kaminski Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 10 Center Drive, MSC 1408, Building 10, Room 5N250, Bethesda, MD 20892-4457, USA e-mail: GasiorM@ninds.nih.gov Tel.: +1-301-4023500 Fax: +1-301-4022871 J. M. Witkin Neuroscience Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Building 48-DC 0510, Indianapolis, IN 46285-0510, USA