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(12) Patent Application Publication (10) Pub. No.: US 2007/0270403 A1 Broderick (43) Pub US 20070270.403A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0270403 A1 Broderick (43) Pub. Date: Nov. 22, 2007 (54) CLOZAPINE AND COCAINE EFFECTS ON A6II 3L/496 (2006.01) DOPAMINE AND SEROTONN RELEASE IN A6II 3/554 (2006.01) NUCLEUS ACCUMBENS DURING A6IP 25/8 (2006.01) PSYCHOSTMULANT BE HAVOR AND A 6LX 3/553 (2006.01) WTHDRAWAL. A 6LX 3L/2197 (2006.01) A 6LX 3/57 (2006.01) (76) Inventor: Patricia A. Broderick, Bronx, NY (US) A 6LX 3/59 (2006.01) A6II 3/545 (2006.01) Correspondence Address: (52) U.S. Cl. ................. 514/211.13: 514/220; 514/225.5; MORGAN & FINNEGAN, L.L.P. 514/252.13: 514/253.07: 514/254.04; 3 WORLD FINANCIAL CENTER 514/259.41: 514/266.22; 514/278; NEW YORK, NY 10281-2101 (US) 514/315; 514/323: 514/428 (21) Appl. No.: 10/580,884 (57) ABSTRACT The present invention provides methods of treating cocaine (22) PCT Filed: Dec. 6, 2004 induced pyschosis by administering an atypical antipsy chotic compound in an amount Sufficient to increase sero (86). PCT No.: PCT/USO4/4O756 tonin SR in the nucleus accumbens of a mammal. According to the invention, atypical antipsychotic com (2),S 371(c)(1), (4) Date: May 4, 2007 pounds include, without limitation, clozapine, risperidone, olanzepine, quetiapine, Ziprasidone, sertindole, ketanserin, O O aripiprazole, and haloperidol, flupenthixol, thiroridazine, Related U.S. Application Data loxapine, fluspirilense, and sulpliride. The invention further (60) Provisional application No. 60/526,833, filed on Dec. provides methods for microvoltammetric imaging of 4, 2003. changes in neurotransmitter concentrations in vivo and in real time comprising contacting the cell, cells, tissue, tissues, Publication Classification or organ of interest with a BRODERICK PROBE® sensor, applying a potential to said BRODERICK (51) Int. Cl. PROBE® sensor, and monitoring a temporally and A6 IK 3/55 (2006.01) spacially resolved recording using neuromolecular imaging A6 IK 3/40 (2006.01) (NMI) and electrochemical circuits such as, for example, A6 IK 3/438 (2006.01) Voltammetry. In one embodiment of the invention, neuro A6 IK 3/445 (2006.01) molecular imaging may be performed before, during or after A6 IK 3L/454 (2006.01) cocaine administration and/or cocaine-induced psychosis. Patent Application Publication Nov. 22, 2007 Sheet 1 of 28 US 2007/0270403 A1 200 -O-COC-DA 1. 7S -0- Cloz/Coc-DA 5 O 1. 7525O O 5O 30-20-10 0 10 20 30 40 50 60 70 80 gO 100 110 120 q-p--C--O- Pre-Drug Post Drug Time in Minutes Figure 1A Patent Application Publication Nov. 22, 2007 Sheet 2 of 28 US 2007/0270.403 A1 40 -o- Coc-5-HT 350 -o- Coz/COC-5-HT 300 250 2 1 OO5 o 5O O -30 -20 -10 O 10 20 30 40 50 60 70 80 90 100 110 120 Pre-Drug Post Drug Time in Minutes Figure 1B Patent Application Publication Nov. 22, 2007 Sheet 3 of 28 US 2007/0270403 A1 800 700 -O- Coc-Anb -O- CloZ/COC-Amb 600 O 500 400 300 200 1OO C 5 C O O local - o -30-20-10 0 10 20 30 40 50 60 70 80 90 100 110 120 Pre-Drug Post Drug Time in Minutes Figure 1C Patent Application Publication Nov. 22, 2007 Sheet 4 of 28 US 2007/0270403 A1 2OO 1 7 5 -O-COC-DA -0- ClozCOC-DA - O -30 -20 -10 0 10 20 30 40 50 60 commo-Pre-Drug 24- Hrs Post Drug Time in Minutes Figure 2A Patent Application Publication Nov. 22, 2007 Sheet 5 of 28 US 2007/0270403 A1 300 -O-COC-5-HT 2 5 O -O- Cloz/Coc-5-HT 2 O O 5 O 30 -20 -10 O 10 20 30 40 50 60 -O-D -CH-O- Pre-Drug 24 Hrs Post Drug Time in Minutes Figure 2B Patent Application Publication Nov. 22, 2007 Sheet 6 of 28 US 2007/0270403 A1 800 g 2700 -o- Coc-Amb 29dig 600 -O-Cloz/Coc-Amb 3. is 400 25 GD 200 -dim-mb Pre-Drug 24 Hrs Post Drug Time in Minutes Figure 2C Patent Application Publication Nov. 22, 2007 Sheet 7 of 28 US 2007/0270403 A1 Patent Application Publication Nov. 22, 2007 Sheet 8 of 28 US 2007/0270.403 A1 Patent Application Publication Nov. 22, 2007 Sheet 9 of 28 US 2007/0270.403 A1 Patent Application Publication Nov. 22, 2007 Sheet 10 of 28 US 2007/0270403 A1 Patent Application Publication Nov. 22, 2007 Sheet 11 of 28 US 2007/0270.403 A1 Figure 3E Patent Application Publication Nov. 22, 2007 Sheet 12 of 28 US 2007/0270.403 A1 a0. O. O. Figure Patent Application Publication Nov. 22, 2007 Sheet 13 of 28 US 2007/0270403 A1 s ES E. 3.3. : ES; Patent Application Publication Nov. 22, 2007 Sheet 14 of 28 US 2007/0270403 A1 Patent Application Publication Nov. 22, 2007 Sheet 15 of 28 US 2007/0270.403 A1 Patent Application Publication Nov. 22, 2007 Sheet 16 of 28 US 2007/0270.403 A1 too to 2034656 F gul re3J Patent Application Publication Nov. 22, 2007 Sheet 17 of 28 US 2007/0270.403 A1 Figure 3K Patent Application Publication Nov. 22, 2007 Sheet 18 of 28 US 2007/0270.403 A1 Figure Patent Application Publication Nov. 22, 2007 Sheet 19 of 28 US 2007/0270.403 A1 igure 3M Patent Application Publication Nov. 22, 2007 Sheet 20 of 28 US 2007/0270.403 A1 Patent Application Publication Nov. 22, 2007 Sheet 21 of 28 US 2007/0270403 A1 -o-Coc-DA -O-Risp-DA -O-Risp/Coc-DA 1 S75 12 O O 7 5 5 O -30 -20 -1D C 10 2D 30 40 50 60 70 80 90 100 110 120 1-al-D1-->Pre-Drug Post Drug Time in Minutes Figure 4A Patent Application Publication Nov. 22, 2007 Sheet 22 of 28 US 2007/0270403 A1 s 5D) -O- COC-5-HT 450 -- Risp-5-HT 400 -o-Risp/Coc-5-HT 350 G98 S9 300 2 S 250 st 200 1so & 100 No 50 O -30 -20 -1D C 10 2D 30 40 50 60 70 8O 90 1 OO 10 120 1CHO Pre- Drug Post Drug Time in Minutes Figure 4B Patent Application Publication Nov. 22. 2007 Sheet 23 of 28 US 2007/0270403 A1 800 -O-COC-Amb 955 700 -- Risp-Amb 6OD -O-Risp/Coc-Amb t Eas 500 sc 400 s 3OO 200 2 100 O 30 - Pre-Drug Post Drug Time in Minutes Figure 4C Patent Application Publication Nov. 22, 2007 Sheet 24 of 28 US 2007/0270403 A1 s 1OD- -0- Coc-Fine M -O-Risp-Fine M -O-Risp/Coc-Fine M 2 : 80 2 o g 60 2 O C O C t s 40 O R RP 9i O-O o s A C s 2O f t lo NASY notif 3D -20 -1D O 10 2D 30 40 50 60 70 BO 90 100 110 12D Pre-Drug Post Drug Time in Minutes Figure 4D Patent Application Publication Nov. 22, 2007 Sheet 25 of 28 US 2007/0270.403 A1 2 O O -O-COC-DA -- Risp-DA 7 5 -O-Risp/Coc-DA 2O5O O -30 -20 -10 0 10 20 30 4D 50 60 -Como Cl-o- Pre-Drug Post Drug Time in Minutes Figure 5A Patent Application Publication Nov. 22, 2007 Sheet 26 of 28 US 2007/0270403 A1 -O-COC-5-HT 350 -- Risp-5-HT -o-Risp/Coc-5-HT 250 2DO 1 O5OO s O O 3C 20 O O. 10 20 3D 40 50. 60 Pre-Drug Post Drug Time in Minutes Figure 5B Patent Application Publication Nov. 22, 2007 Sheet 27 of 28 US 2007/0270403 A1 800 95 700 - H. Risp-Amb i 600 -o- RisplCoc-Amb a 500 400 3 O O 2 OO 1 O O 3.266 , to 20 30 26 so 66 1CHDPre-Drug -CH---O-Post Drug Time in Minutes Figure 5C Patent Application Publication Nov. 22, 2007 Sheet 28 of 28 US 2007/0270.403 A1 -o- Coc-Fine M -O-Risp-Fine M Risp/Coc-Fine M 6O 40 2 O 30-20 -o () ?o 20 so 40 so 60 re-ep Drug ---O-Post Drug Time in Minutes Figure 5D US 2007/0270403 A1 Nov. 22, 2007 CLOZAPINE AND COCAINE EFFECTS ON cially since data from animal studies of stimulant psychosis DOPAMINE AND SEROTONN RELEASE IN and human Schizophrenic psychosis share the same neuro NUCLEUS ACCUMBENS DURING chemical and behavioral manifestations (Wise and Bozarth, PSYCHOSTMULANT BE HAVOR AND 1987: Gawin et al., 1989; Margolin et al., 1995; Wise, 1995). WTHDRAWAL. Also, because cocaine is self-administered, universally across species (Risner and Jones, 1980: Fischman, 1984), it 0001) This application claims the benefit of U.S. Provi is highly likely that similar universal underlying reward sional Patent Application Ser. No. 60/526,833, filed on Dec. mechanisms and mechanisms of consequent adverse symp 4, 2003. tomatology are similar from species to species. STATEMENT OF GOVERNMENT SUPPORT 0006 The animal model of psychomotor stimulant 0002 This invention was made, at least in part, with behavior for cocaine addiction and psychosis has been government support including Award No. SO 6 GM 081.68 validated by using this model to correlate antipsychotic from the National Institutes Of Health (NIH/NIGMS). medications and DA-ergic neuroanatomic pathways, e.g., Therefore, the U.S.
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