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Chronic Benzodiazepine Administration Concurrent

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Chronic Benzodiazepine Administration Concurrent NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO. 3 267 Chronic Benzodiazepine Administration XI. Concurrent Administration of PKll195 Attenuates Lorazepam Discontinuation Effects John]. Byrnes, B.A., Lawrence G. Miller, M.D., Karen Perkins, M.D., DavidJ. Greenblatt, M.D., and Richard 1. Shader, M.D. Btnzodiazepine discontinuation is associated with after lorazepam discontinuation; this effect was attenuated I1lerations in motor activity and gamma-aminobutyric by coadministration of PK11195 at 5 mglkg per day. rid-A receptor upregulation in a mouse model. Prior Lorazepam discontinuation effects were not altered by studies indicate that concurrent administration of the PK11195 at 1 mglkg per day, whereas the lO-mglkg dose compound N-methyl-N-(methyl-l-propyl)chloro-2-phenyl­ was not different from 5 mglkg per day. The competitive l-isoquinoline-3-carboxamide (PK1195), a "peripheral" ligand R05-4864 at 10 mglkg per day, blocked the effects site benzodiazepine antagonist, can attenuate the effects of of PKI1195 on lorazepam discontinuation. Benzodiazepine Iorazepam on tolerance and receptor alterations. To receptor binding in vivo was increased in the cortex and nwluate the effects of PK11195 administration on hippocampus at 4 days postlorazepam discontinuation. btnzodiazepine discontinuation, we administered This effect was attenuated in the hippocampus but not in Iorazepam (2 mglkg per day), PK 11195 (1 to 10 mglkg the cortex by concurrent administration of PK1195. ptrday) or the combination to mice for 7 days, and then These data indicate that concurrent administration of nwluated pentylenetetrazole-induced seizure threshold PK11195 may attenuate discontinuation effects of l11libenzodiazepine binding at days 1, 4, and 7 after lorazepam. [Neuropsychopharmacology 8:267-273, discontinuation. Seizure theshold was reduced at 4 days 1993J KEY WORDS: Lorazepam; PK11195; Benzodiazepine; cases even seizures and mortality (Greenblatt et al. Gamma-aminobutyric acid 1990). We have previously described a mouse model of benzodiazepine discontinuation that demonstrates The abrupt discontinuation of benzodiazepine com­ both behavioral and neurochemical alterations (Miller pounds may evoke a variety of discontinuation syn­ et al. 1988b). In particular, hyperactivity and a reduced dromes,characterized by anxiety, insomnia, and in rare seizure threshold are associated with upregulation at the gamma-aminobutyric acid-A (GABAA) receptor complex. Generally similar results have been obtained Fromthe Departments of Pharmacology and Experimental Thera­ with the benzodiazepines lorazepam, alprazolam, and peuticsand Psychiatry, Tufts University School of Medicine; and the clonazepam (Lopez et al. 1990; Galpern et al. 1990, Division of Clinical Pharmacology, New England Medical Center, 1991a). Boston, Massachusetts. Addresscorrespondence to: Dr.Lawrence G. Miller, Box 1007,New Several interventions have been proposed to pre­ England Medical Center, 750 Washington Street, Boston, Massa­ vent or limit the effectsof benzodiazepine discontinu­ chusetts 02111. ation, includingtapering doses, use of "partial agonist" ReceivedJune 18,1992;revised October 21,1992; accepted October 26. 1992. benzodiazepines, and treatment with anticonvulsants C 1993American College of Neuropsychopharmacology Published by Elsevier Science Publishing Co., Inc. 655Avenue of the Americas, New York, NY 10010 0893-133XI93/$6.00 268 J.J. Byrnes et al. NEUROPSYCHOPHARMACOLOGY 1993- VOL. 8, NO.l or benzodiazepine antagonists (Miller et al. 1992). In and 7 after lorazepam discontinuation. As previously the mouse model, treatment with the anticonvulsant reported, concurrent administration of PKl1195 does carbamazepine attenuates the effects of alprazolam not alter lorazepam concentrations in brain (Miller et discontinuation (Galpern et al. 1991b). We have re­ al. 1992). Also as previously reported (Miller et aI. cently reported that administration of the "peripheral" 1988a), lorazepam isundetectable in cortex at day 1 post· benzodiazepine antagonist N-methyl-N-(methyl-1- discontinuation and subsequently thereafter. propyl)chloro-2-phenyl-1-isoquinoline-3-carboxamide (PK11195) limits the development of tolerance to loraze­ Pentylenetetrazole-Induced Seizures pam (Miller et al. 1992), as was previously reported in a model of diazepam tolerance in the rat (Massotti et As previously described (Schatzki et al. 1989), unre­ al. 1990). strained mice were infused intravenously with a solu· In view of the postulated relationship between tion of penytlenetetrazole, 7.5 mg/ml (5.43 mmol/mI), tolerance and withdrawal, the present study was de­ at 0.30 ml/min. Infusion was terminated at the onset signed to evaluate the effectsof chronic administration of a tonic-clonic seizure as determined by two ob­ of PKl1195 on benzodiazepine discontinuation in the servers. mouse model. Mice received chronic lorazepam, with or without PK11195 or the competitive ligand R05-4864, Benzodiazepine Binding for 1 week, and then induced seizure thresholds and benzodiazepine binding were evaluated. Benzodiazepine binding in vivo was performed as pre­ viously described (Miller et al. 1988a). Briefly, micewere injected intravenously with 3 /.lCi PH]Ro15-1788. Af· ter 20 minutes, animals were sacrifIcedand brains rap­ METHODS idly removed and dissected on ice. After weighing, Materials brain regions were dissolved in Solvable (40°C for 24 hours) and then counted by scintillation spectrometry. Male CD1 mice,6 to 8 weeks of age (Charles River, Wil­ For nonspecifIcbinding, mice were treated with clonaze­ mington, MA)were maintainedon a 12-hour light/dark pam, 5 mg/kg (16.13 mmol/kg) intraperitoneally 30 cycle and given food and water ad libitum. Osmotic minutes prior to radioligand injection and samples were pumps were obtained from Alza (Palo Alto, CA). PEG processed as above. 400 was obtained from J.T. Baker (St. Louis, MO). For benzodiazepine binding in vitro, synaptosomal pH]flunitrazepam (specifIc activity 70 Ci/mmol), membranes from mouse cerebral cortex were prepared [3H]Ro15-1788 (flumazenil; specifIc activity 81 Ci/ and binding was performed as previously described mmol), and Solvable were purchased from New En­ (Miller et al. 1988a). Briefly, PHjFNTZ at 0.1 to 10 gland Nuclear (Boston, MA). Flunitrazepam and nmollL was added to duplicate or triplicate samples. clonazepam were gifts from Hoffmann-LaRoche (Nut­ Flunitrazepam at 10-5 mollL was added to an identi· ley, NJ). Lorazepam was a gift from Wyeth (Radnor, cal set of samples. After incubation at 4°C for 45 PA). PKl1195 and R05-4864 were obtained from Re­ minutes, samples were fIltered using a Brandel M48R search Biochemicals (Natick, MA). All other reagents (Gaithersburg, MD) onto Whatman GF/B fIlters.Filters were obtained from standard commercial sources. were washed three times with cold bufferand counted by scintillation spectrometry. Drug Administration Lorazepam (2 mg/kg per day; 6.23 mmollkg per day), Data Analysis PK11195 (1 to 10 mg/kg per day; 2.79 to 27.9 mmollkg Binding data were analyzed using the EBDA programs per day) and R05-4864 (10 mg/kg per day; 32.8 mmollkg (McPherson 1983). Data were compared using analy­ per day) were administered by subcutaneously im­ sis of variance with Dunnett's test or Student's t-test. planted osmotic pumps as previously reported (Miller et al. 1988a). The doses of lorazepam and PK11195 were based on prior studies (Miller et al. 1992). The study RESULTS groups were lorazepam alone, PK11195 alone, R05-4864 Pentylenetetrazole-Induced Seizures alone, lorazepam plus PKl1195, lorazepam plus R05- 4864, and all three compounds. For lorazepam and At 1 day postdiscontinuation, there was no difference PK11195 and for all three compounds, drugs were ad­ between mice treated with lorazepam or the combina­ ministered via the same pump. In allcases, pumps were tion of lorazepam and PKl1195 (Fig. 1). However, at removed after 7 days of administration. All drugs were day 4 postdiscontinuation, seizure threshold was dissolved in PEG 400. Mice were studied at days 1, 4, markedly decreased in mice treated with lorazepam NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO. 3 Discontinuation after PKI1195/Lorazepam 269 2.5 1.2 �• LRZ/PK 1.0 2.0 i a ! g 0.8 • Ilol .. ... 0 1.5 0 'N N C C It II: 0.6 � to- • Ilol � to- • 1.0 Ilol Z Z • Ilol .. ... 0.4 ,. > � to- Z Z • Ilol � 0.5 11- 0.2 0.0 0.0 4 7 PK11195 DOSE + LRZ DAYS AFTER DISCONTINUATION Figure1. Pentylenetetrazole-induced seizures after loraze­ Figure 2. Dose effects of PK1195 (PK) in combination with pam(LRZ) and PK11195 (PK). Mice treatedwith LRZ (2 mg/kg lorazepam (LRZ). Mice treated with LRZ (2 mg/kg per day) per day)or LRZplus (5 mg/kg per day) for 7 days were evalu­ or LRZ plus PK (1 to 10 mg/kg per day) for 7 days were evalu­ liedat days 1, 4, and 7 postdiscontinuation. Umestrained ated at day 4 postdiscontinuation. Umestrained mice were mi:ewere injected intravenously with pentylenetetrazole, 7.5 injected intravenously with pentylenetetrazole, 7.5 mg/ml at mg/mlat 0.30ml/min. Infusion was discontinued at the on­ 0.30 ml/min. Infusion was discontinued at the onset of a setof a tonic-clonic seizure. Pentylenetetrazole = quantity tonic-clonic seizure. Results are mean ± SEM, n = 6 to 13. requiredto induce a seizure. Results are mean ± SEM, n = * P < .05 for PK 5 and 10 mg/kg compared to LRZ. 6109.·p< .05 compared to LRZ at days 1 and 7; ** P < .05 comparedto LRZ/PK at days 1 and 7, and to LRZ at day 4. concurrently with Ro5-4864, which competes with aloneas previously reported (Schatzki et al. 1989).
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