References on the Administration of Benzodiazepines Using ALZET® Osmotic Pumps

1. Adinazolam

P0433 Turmel,A., de Montigny,C. Sensitization of rat forebrain neurons to serotonin by adinazolam, an antidepressant triazolobenzodiazepine. Eur.J.Pharmacol. 1984; 99(--):241-244. >>> Adinazolam; Diazepam; Benzyl alcohol; Ethanol; Propylene glycol; Sodium benzoate; Water; IP; rat; 2002; 5 and 14 days; comparison of Adin. iv injec vs. mp infusion; comparison of agents effects; Adin. used with water vehicle, Diaz. with combination vehicle.

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2. Alprazolam

P3498 Tanay,V.A.-M.I., Glencorse,T.A., Greenshaw,A.J., Baker,G.B., Bateson,A.N. Chronic administration of antipanic drugs alters rat brainstem GABA-A receptor subunit mRNA levels. Neuropharmacology 1996; 35(-9/10-):1475-1482. >>> Phenelzine; alprazolam; imipramine; buspirone; Water, sterile; DMSO; propylene glycol; SC; rat; 21 days; Antidepressant; controls received mp w/ vehicle; pumps were turned in subcutaneous pocket to avoid fibrous tissue outgrowth.

P3673 Byrnes,J.J., Miller,L.G., Greenblatt,D.J., Shader,R.I. Chronic benzodiazepine administration. Psychopharmacology 1993; 111(--):91-95. >>> Alprazolam; Lorazepam; PEG 400; SC; mice; 2001; 2002; 7, 8, or 14 days; controls received vehicle; tolerance.

P2332 Kaplan,G.B., Cotreau,M.M., Greenblatt,D.J. Effects of benzodiazepine administration on A1 adenosine receptor binding in-vivo and ex-vivo. J.Pharm.Pharmacol. 1992; 44(--):700-703. >>> Alprazolam; Lorazepam; PEG 400; IP; mice; 2001; 6 days; controls received mp w/ vehicle.

P3033 Moreau,J.-L., Jenck,F., Pieri,L., Schoch,P., Martin,J.R., Haefely,W.E. Physical dependence induced in DBA/2J mice by benzodiazepine receptor full agonists, but not by the partial agonist Ro 16-6028. Eur.J.Pharmacol. 1990; 190(--):269-273. >>> Triazolam; Alprazolam; Diazepam; Propylene glycol; SC; mice; 2001; 7 days; controls received mp with vehicle; functionality of mp verified by receptor binding study; comparison of oral alprozolam vs. mp; ". . .the use of implantable minipumps. . .permitted. . .development of behavioral tolerance associated with downregulation of benzodiazepine receptor binding and GABA receptor function. . ."; dependence.

P1779 Miller,L.G., Woolverton,S., Greenblatt,D.J., Lopez,F., Roy,R.B., Shader,R.I. Chronic benzodiazepine administration. IV. Rapid development of tolerance and receptor downregulation associated with alprazolam administration. Biochem.Pharmacol. 1989; 38(-21-):3773-3777. >>> Alprazolam; PEG 400; SC; mice; 2001; 2002; 14 days; functionality of mp verified by measuring plasma levels; tolerance.

P1396 Bell,J., Bickford-Wimer,P.C., de la Garza,R., Egan,M., Freedman,R. Increased central nonadrenergic activity during benzodiazepine withdrawal: an electrophysiological study. Neuropharmacology 1988; 27(-11-):1187-1190. >>> Alprazolam; Lorazepam; Ethanol; Propylene glycol; Saline; SC; rat; 2ML2; 12 days; no comment posted.

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3. Chlordiazepoxide

P7318 Andre,J., Zeau,B., Pohl,M., Cesselin,F., Benoliel,J.J., Becker,C. Involvement of cholecystokininergic systems in anxiety-induced hyperalgesia in male rats: Behavioral and biochemical studies. Journal of Neuroscience 2005; 25(-35-):7896-7904. >>> Chlordiazepoxide; Water, distilled; SC; Rat; 2ML1; 4-7 days; Controls received mp w/ saline.

P4378 Cash,D.J., Serfozo,P., Allan,A.M. Desensitization of a g-aminobutyric acid type A receptor in rat is increased by chronic treatment with chlordiazepoxide: a molecular mechanism of dependence.. Journal of Pharmacology and Experimental Therapeutics 1997; 283(-2-):704-711. >>> Chlordiazepoxide;; SC;; rat;; 15 days;; controls received mp with vehicle; tolerance; dependence; chlordiazepoxide is a tranquilizer; rats were 6-8 weeks old;.

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4. Clonazepam

P3556 Arnot,M.I., Bateson,A.N., Martin,I.L. Dimethyl sulfoxide/propylene glycol is a suitable solvent for the delivery of diazepam from osmotic minipumps. J.Pharm.&Tox.Meth. 1996; 36(--):29-31. >>> Diazepam; Clonazepam; flumazenil; DMSO; Propylene glycol; Tetraglycol; 3H tracer; Radio-isotopes; in vitro; 2ML4; no duration posted; no comment posted.

P3305 Lima,L., Trejo,E., Urbina,M. Serotonin turnover rate, [3H] paroxetine binding sites, and 5-HT1A receptors in the hippocampus of rats subchronically treated with clonazepam. Neuropharmacology 1995; 34(-10-):1327-1333. >>> Clonazepam; PEG; CSF/CNS (dorsal raphe nucleus); rat; 10 days; comparison of IP injections vs. mp.

P2654 Brodin,K., Ogren,S.-O., Brodin,E. Clomipramine and clonazepam increase cholecystokinin levels in rat ventral tegmental area and limbic regions. Eur.J.Pharmacol. 1994; 263(--):175-180. >>> Nortriptyline; Amitriptyline; Clomipramine; Alaproclate; Clonazepam; Alcohol; Saline; SC; rat; 2ML2; 14 days; antidepressant; controls received mp w/ vehicle; functionality of mp verified by plasma levels; dose-response (Table 1; pg. 177); enzyme inhibitor; clonazepam is a benzodiazepene; the others are monoamine uptake inhibitors.

P1650 Miller,L.G., Galpern,W.R., Greenblatt,D.J., Lumpkin,M., Shader,R.I. Chronic benzodiazepine administration. VI. a partial agonist produces behavioral effects without tolerance or receptor alterations. J.Pharmacol.Exp.Ther. 1990; 254(-1-):33-36. >>> Clonazepam; RO-16-6028; PEG 400; SC; mice; 14 days; functionality of mp verified by tissue levels; dose-response (graph); tolerance/dependence.

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5. Diazepam

P5972 Hensch,T.K., Stryker,M.P. Columnar architecture sculpted by GABA circuits in developing cat visual cortex. Science 2004; 303(-5664-):1678-1681. >>> Diazepam; Propylene Glycol; CSF/CNS (visual cortex); Cat (kitten); 2004; 2ML4; 4 weeks; Diazepam is a benzodiazepine agonist.

P5275 Fagiolini,M., Hensch,T.K. Inhibitory threshold for critical-period activation in primary visual cortex. Nature 2000/3/9; 404(-6774-):183-186. >>> Diazepam; Propylene glycol; CSF/CNS (visual cortex); Mice; 1007D; 4 days; Controls received mp w/ vehicle; comparison of icv injections vs. mp; 50% propylene glycol used.

P3118 Torchin,C.D., Kapetanovic,I.M., Kupferberg,H.J. A system for testing the development and reversal of anticonvulsant tolerance to benzodiazepines in mice. Epilepsy Res. 1993; 16(--):27-35. >>> Diazepam; flumazenil; flunitrazepam; ZK-93426; Tetraglycol; SC; mice; 2001; no duration posted; controls received mp with vehicle; tolerance; tetraglycol chosen as solvent because PEG, propylene glycol, tween, DMSO, saline, molecusol, and methyl cellulose did not maintain benzodiazepines in solution or proconvulsant activity was seen (see pg. 30); flumazenil is RO-15-1788; infusion delayed in some animals by using saline-filled catheter tubing; some animals received benzodiazepine + antagonist concomitantly.

P2618 Rasmussen,K., Helton,D.R., Berger,J.E., Scearce,E. The CCK-B antagonist LY288513 blocks effects of diazepam withdrawal on auditory startle. NeuroReport 1993; 5(-2-):154-156. >>> Diazepam; Water; Tween 80; SC; rat; 2ML2; 12 days; no comment posted.

P1392 Hawkins,M., Pan,W., Stefanovich,P., Radulovacki,M. Desensitization of adenosine A2 receptors in the striatum of the rat following chronic treatment with diazepam. Neuropharmacology 1988; 27(-11-):1131-1140. >>> Diazepam; Propylene glycol; Water;; SC; rat; 2ML1; 7 days; functionality of mp verified by sectioning; neuroscience.

P0886 Loscher,W. Development of tolerance to the anticonvulsant effect of GABAmimetic drugs in genetically epilepsy-prone gerbils. Pharmacol.Biochem.Behav. 1986; 24(--):1007-1013. >>> Aminobutyric acid, Y-acetylenic Y-; Aminooxyacetic acid; Diazepam; THIP; Valproic acid; Saline; SC; rat; 2ML2; 2 weeks; controls received mp w/saline; diazepam too unstable to be used in mp; epilepsy; functionality of mp verified after 14 day exper. period - all 50 mps worked accurately; stability of VPA, THIP, GAG and AOAA.

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6. Lorazepam

P8188 Fahey,J.M., Pritchard,G.A., Reddi,J.M., Pratt,J.S., Grassi,J.M., Shader,R.I., Greenblatt,D.J. The effect of chronic lorazepam administration in aging mice. Brain Research 2006; 1118(--):13-24. >>> Lorazepam; PEG 400; SC; Mice; 1, 14 days; Controls received mp w/ vehicle; functionality of mp verified by lorazepam plasma concentrations; tolerance; animal info (male, CD-1, 2-3 months old, 10-12 months old, 22-24 months old).

P4914 Fahey,J.M., Pritchard,G.A., Grassi,J.M., Pratt,J.S., Shader,R.I., Greenblatt,D.J. Pharmacodynamic and receptor binding changes during chronic lorazepam administration. Pharmacology Biochemistry and Behavior 2001; 69(--):1-8. >>> Lorazepam; PEG 400; SC; mice; 1 or 14 days; controls received mp w/ vehicle; plasma lorazepam levels; brains examined postmortem for membrane binding; lorazepam is a benzodiazepine with anxiolytic and anti-insomnia properties;.

P4593 Tehrani,M.H.J, Barnes,E.M. Sequestration of g-Aminobutyric acidA receptors on clathrin-coated vesicles during chronic benzodiazepine administration in vivo;. The Journal of Pharmacology and Experimental Therapeutics. 1997; 283(-1-):384-390. >>> Lorazepam;; PEG 400;; SC;; mice;; 2001;; 7 days;; controls received mp w/vehicle; tolerance;.

P3328 Mortensen,M., Suzdak,P.D., Thomsen,C. The effect of lorazepam tolerance and withdrawal on metabotropic glutamate receptor function. J.Pharmacol.Exp.Ther. 1995; 274(-1-):155-163. >>> Lorazepam; PEG 400; SC; mice; 2001; 7 days; tolerance.

P2610 Allan,A.M., Baier,L.D., Zhang,X. Effects of lorazepam tolerance and withdrawal on GABA receptor operated chloride channels in mice selected for differences in ethanol withdrawal severity. Life Sci. 1992; 51(-12-):931-943. >>> Lorazepam; PEG 400; SC; mice; 7 days; controls received mp w/ vehicle; tolerance.

P2501 Miller,L.G., Galpern,W.R., Byrnes,J.J., Greenblatt,D.J., Shader,R.I. Chronic benzodiazepine administration. x. concurrent administration of the peripheral-type benzodiazepine ligand PK11195 attenuates chronic effects of lorazepam. J.Pharmacol.Exp.Ther. 1992; 261(-1-):285-289. >>> Lorazepam; PK 11195; SC; mice; no duration posted; controls received mp w/ vehicle; tolerance; Lorazepam and PK11195 infused separately and together; PK11195 is a peripheral-type site ligand; pumps chosen because they produce "constant plasma and brain concentrations"..

P2080 Allan,A.M., Baier,L.D., Zhang,X. Effects of lorazepam tolerance and withdrawal on GABA-A receptor-operated chloride channels. J.Pharmacol.Exp.Ther. 1992; 261(-2-):395-402. >>> Lorazepam; PEG 400; SC; mice; 7 days; tolerance.

P2362 Miller,LG., Chesley,S., Galpern,W.R., Greenblatt,D.J., Shader,R.I. Prenatal benzodiazepine administration, II. lorazepam exposure is associated with decreases in [35S]TBPS binding but not benzodiazepine binding. Pharmacol.Biochem.Behav. 1991; 40(--):429-432. >>> Lorazepam; PEG 400; SC; mice (pregnant); 2001; 7 days; teratology.

P1591 Schatzki,A., Lopez,F., Greenblatt,D.J., Shader,R.I., Miller,L.G. Lorazepam discontinuation promotes 'inverse agonist' effects of benzodiazepines. Br.J.Pharmacol. 1989; 98(--):451-454. >>> Lorazepam; PEG 400; SC; mice; 2001; 2002; 7 days; no comment posted.

P1319 Miller,L.G., Greenblatt,D.J., Barnhill,J.G., Shader,R.I. Chronic benzodiazepine administration. 1. tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminoburyric acid receptor function. J.Pharmacol.Exp.Ther. 1988; 246(-1-):170-176. >>> Lorazepam; PEG 400; SC; mice; 2001; 2002; 14 days; dose-response (graph, text); tolerance; functionality of mp verified by plasma levels.

P1290 Miller,L.G., Greenblatt,D.J., Roy,R.B., Summer,W.R., Shader,R.I. Chronic benzodiazepine administration II: discontinuation syndrome is associated with upregulation of gamma-aminobutyric acid receptor complex binding and function. J.Pharmacol.Exp.Ther. 1988; 246(-1-):177-182. >>> Lorazepam; PEG 400; SC; mice; 2001; 7 days; tolerance; functionality of mp verified by plasma, brain levels.

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7. Triazolam

P2656 Cohen,C., Sanger,D.J. Tolerance, cross-tolerance and dependence measured by operant responding in rats treated with triazolam via osmotic pumps. Psychopharmacology 1994; 115(--):86-94. >>> Triazolam; Propylene glycol; SC; rat; 2ML2; 14 days; controls received mp w/ vehicle; tolerance; dependence.

P2115 Zhou,L.-W., Zhang,S.-P., Welsh,S., Connell,T.A., Weiss,B. Triazolam blocks the initial rotational effects of quinpirole but permits the later developing reduction of dopamine D2-mediated rotational behavior and dopamine D2 receptors. Eur.J.Pharmacol. 1992; 218(--):219-227. >>> Quinpirole HCl; Sulpiride; Triazolam; Ascorbic acid; DMSO; SC; mice; 2001; 6 days; Quinpirole is a dopamine agonist; antidepressant; stability verified in vitro for 7 days.

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References on the Administration of Benzodiazepines Using ALZET® Osmotic Pumps

1. Adinazolam

2. Alprazolam

3. Chlordiazepoxide

4. Clonazepam

5. Diazepam

6. Lorazepam

7. Triazolam

Sterile Catheter Tubing for Infusion Studies