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US 20060069086A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0069086 A1 Michallow (43) Pub. Date: Mar. 30, 2006 (54) METHODS FOR REGULATING Publication Classification NEUROTRANSMITTER SYSTEMIS BY INDUCING COUNTERADAPTATIONS (51) Int. Cl. A6II 3/55 (2006.01) (76) Inventor: Alexander Michalow, Bourbonnais, IL A6II 3/405 (2006.01) (US) A6II 3/343 (2006.01) A6II 3L/37 (2006.01) Correspondence Address: (52) U.S. Cl. ......................... 514/220; 514/469: 514/649; MCDONNELL BOEHNEN HULBERT & 5147419 BERGHOFF LLP 3OO S. WACKER DRIVE (57) ABSTRACT 32ND FLOOR CHICAGO, IL 60606 (US) The present invention relates to methods for regulating neurotransmitter systems by inducing a counteradaptation (21) Appl. No.: 11/234,850 response. According to one embodiment of the invention, a method for regulating a neurotransmitter includes the step of (22) Filed: Sep. 23, 2005 repeatedly administering a ligand for a receptor in the neurotransmitter system, with a ratio of administration half Related U.S. Application Data life to period between administrations of no greater than 1/2. The methods of the present invention may be used to address (60) Provisional application No. 60/612,155, filed on Sep. a whole host of undesirable mental and neurological condi 23, 2004. tions. Patent Application Publication Mar. 30, 2006 Sheet 1 of 4 US 2006/0069086 A1 a) first time second period time period -1- tax % max base line N-administration half-life administration next administration Period between administrations time b) first time Second period time period i bad N-administration half-life administration next administration Period between administrations F.G. 1 time Patent Application Publication Mar. 30, 2006 Sheet 2 of 4 US 2006/0069086 A1 good bad admin admin admin admins admin4 admins admins time FIG. 2 O ? C () () C 8 O 9 SS .S. time FIG. 3 time FIG. 4 Patent Application Publication Mar. 30, 2006 Sheet 3 of 4 US 2006/0069086 A1 4-1 Patch removed time F.G. 5 Patent Application Publication Mar. 30, 2006 Sheet 4 of 4 US 2006/0069086 A1 a) induction of maintenance through repeated Counteradaptation administration of ligand H1N- -1- time b) induction of maintenance through repeated Counteradaptation administration of ligand good O O E bad time F.G. 6 US 2006/0069086 A1 Mar. 30, 2006 METHODS FOR REGULATING gain. Further, patients can adapt or build up a resistance to NEUROTRANSMITTER SYSTEMIS BY INDUCING conventional therapeutic agents with repeated use, making COUNTERADAPTATIONS them lose efficacy over time. CROSS-REFERENCE TO RELATED SUMMARY OF THE INVENTION APPLICATIONS 0008 One embodiment of the present invention relates to 0001) This application claims the benefit under 35 U.S.C. a method of regulating a neurotransmitter system by induc S 119(e) of U.S. Provisional Patent Application Ser. No. ing a counteradaptation in a patient, the neurotransmitter 60/612,155 entitled “COUNTER-ADAPTATION system including a type of receptor linked to an undesirable THERAPY FOR TREATMENT OF DEPRESSION AND mental or neurological condition. The method comprises the OTHER MENTAL CONDITIONS, and filed on Sep. 23, step of repeatedly administering to the patient a ligand for 2004. The above-referenced provisional application is the type of receptor, each administration having an admin hereby incorporated herein by reference in its entirety. istration half-life, thereby causing the ligand to bind recep tors of that type during a first time period associated with BACKGROUND OF THE INVENTION each administration, thereby inducing a counteradaptation, 0002) 1. Field of the Invention wherein the counteradaptation causes the regulation of the neurotransmitter system, and wherein the ratio of the admin 0003. The present invention relates generally to neu istration half-life to the period between administrations is no rotransmitter systems associated with undesirable mental greater than 1/2. and neurological conditions. The present invention relates more particularly to methods for regulating these neu 0009. In another embodiment of the invention, a method rotransmitter systems by inducing counteradaptative is provided for inducing a regulation of a neurotransmitter responses. system in a patient, the neurotransmitter system including a type of receptor linked to an undesirable mental or neuro 0004 2. Technical Background logical condition. The method comprising the steps of 0005 Mood, mood disorders and related conditions are a inducing a counteradaptation by giving the patient a ligand result of a complex web of central nervous system events for the type of receptor; then repeatedly administering to the that interrelate many neurotransmitter systems. A most com patient a ligand for the type of receptor, each administration mon mood disorder is depression. Depression is a clinical having an administration half-life, thereby causing the diagnosis with numerous somatic and mental symptoms, ligand to bind receptors of that type during a first time period which is due to an alteration of numerous neurotransmitter associated with each administration, thereby maintaining or systems. While the neurotransmitter systems most com improving the counteradaptation, wherein the counteradap monly related with depression are the norepinephrine and tation causes the regulation of the neurotransmitter system, serotonin systems, current research indicates that other sys and wherein the ratio of the administration half-life to the tems, such as the Substance P system, the dynorphin system period between administrations is no greater than 1/2. (kappa receptors), and the endogenous endorphin System 0010. In one aspect of the invention, the neurotransmitter (mu and delta opiate receptors) are also involved in depres system is the SP system; the type of receptor is SP receptors; Sion. Further, these neurotransmitter systems are also related the ligand is an SP receptor agonist; the undesirable mental to a whole host of other undesirable mental and neurological or neurological condition is positively linked to the recep conditions, including bipolar disorders, obsessive-compul tors; and the counteradaption causes a down-regulation of sive disorders, anxiety, phobias, stress disorders, Substance the SP system. abuse, sexual disorders, eating disorders, motivational dis orders and pain disorders. 0011. In another aspect of the invention, the neurotrans mitter system is the endogenous endorphin System; the type 0006 Conventional strategies for treating neurotransmit of receptor is mu and/or delta opiate receptors; the ligand is ter-linked conditions are centered on improving abnormally a mu and/or delta opiate receptor agonist; the undesirable high or low levels of synaptic neurotransmitters. Conven mental or neurological condition is negatively linked to the tional therapeutic agents work to directly regulate the func receptors; and the counteradaption causes an up-regulation tioning of the neurotransmitter systems. Such agents may be of the endogenous endorphin system. anxiolytic agents, hypnotic agents, or selective reuptake inhibitors, and include benzodiazepines (e.g., diazepam, 0012. In yet another aspect of the invention, the neu lorazepam, alprazolam, temazepam, flurazepam, and chlo rotransmitter system is the dynorphin system; the type of diazepoxide), TCAS, MAOIs, SSRIs (e.g., fluoxetine hydro receptor is kappa receptors; the ligand is a kappa receptor chloride), NRIs, SNRIs, CRF modulating agents, serotonin agonist; the undesirable mental or neurological condition is pre-synaptic autoreceptor antagonists, 5HT agonist, positively linked to the receptors; and the counteradaption GABA-A modulating agents, serotonin 5H and/or 5H causes a down-regulation of the dynorphin system. modulating agents, beta-3 adrenoceptor agonists, NMDA 0013 In still yet another aspect of the invention, the antagonists, V1B antagonists, GPCR modulating agents, neurotransmitter system is the serotonin system; and the dynorphin antagonists, and Substance Pantagonists. counteradaption causes an up-regulation of the serotonin 0007 Conventional therapeutic agents and methods, system. Thus, in one embodiment of this aspect of the while somewhat effective, suffer from a few disadvantages. invention, the type of receptor is serotonin pre-synaptic For example, use of many conventional therapeutic agents is autoreceptors; the ligand is a serotonin pre-synaptic autore attended by side effects, such as sexual dysfunction, nausea ceptor agonist; and the undesirable mental or neurological nervousness, fatigue, dry mouth, blurred vision and weight condition is positively linked to the receptors. In another US 2006/0069086 A1 Mar. 30, 2006 embodiment of this aspect of the invention the type of BRIEF DESCRIPTION OF THE DRAWINGS receptor is serotonin post-synaptic receptors; the ligand is a serotonin post-synaptic autoreceptor antagonist; and the 0020 FIG. 1 is a graph of in vivo ligand concentration undesirable mental or neurological condition is negatively (part a) and mood vs. time (part b) according to one linked to the serotonin post-synaptic autoreceptors. embodiment of the invention; 0014. In still yet another aspect of the invention, the 0021 FIG. 2 is a graph of mood vs. time for several neurotransmitter system is the norepinephrine system; and administrations of a ligand according to another embodi the counteradaption causes an up-regulation of the norepi ment of the invention; nephrine system. Thus, in one embodiment of this aspect of 0022 FIG. 3 is a graph of in vivo ligand concentration
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  • Selective Blockade of NK2 Or NK3 Receptors Produces Anxiolytic- and Antidepressant-Like Effects in Gerbils ⁎ N

    Selective Blockade of NK2 Or NK3 Receptors Produces Anxiolytic- and Antidepressant-Like Effects in Gerbils ⁎ N

    Pharmacology, Biochemistry and Behavior 83 (2006) 533–539 www.elsevier.com/locate/pharmbiochembeh Selective blockade of NK2 or NK3 receptors produces anxiolytic- and antidepressant-like effects in gerbils ⁎ N. Salomé, J. Stemmelin, C. Cohen , G. Griebel Sanofi-Aventis, Department of Psychopharmacology, 31 av Paul Vaillant-Couturier, 92220 Bagneux, France Received 17 October 2005; received in revised form 1 March 2006; accepted 9 March 2006 Available online 19 April 2006 Abstract There is a growing interest in the potential anxiolytic- and antidepressant-like effects of compounds that target neurokinin receptors. Since the structure and the pharmacology of the human neurokinin receptor resembles that of gerbils, rather than that of mice or rats, we decided to investigate the anxiolytic- and /or antidepressant-like effects of NK1 (SSR240600), NK2 (saredutant) and NK3 (osanetant) receptor antagonists in gerbils. It was found that saredutant (3–10 mg/kg, p.o.) and osanetant (3–10 mg/kg, p.o.) produced anxiolytic-like effects in the gerbil social interaction test. These effects were similar to those obtained with the V1b receptor antagonist SSR149415 (3–10 mg/kg, p.o.), diazepam (1 mg/kg, p.o.) and buspirone (10 mg/kg, p.o.). Fluoxetine and SSR240600 were devoid of effects in this test. In the tonic immobility test in gerbils, saredutant (5–10 mg/kg, i.p.) and osanetant (5–10 mg/kg, i.p.) produced similar effects to those observed with fluoxetine (7.5–15 mg/kg, i.p.), SSR149415 (10–30 mg/kg, p.o.) and buspirone (3 mg/kg, i.p.). Diazepam and SSR240600 were inactive in this paradigm.