title: The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine.
abstract: The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone.
  
  
  
  The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of cocaine (0.19, 0.38, 0.75mg/kg/infusion), and following LY379268 (0.03 or 0.30mg/kg; i.p.), phenmetrazine (25mg/kg/day; osmotic minipump), and a combination of the two drugs.
  
  
  
  LY379268 and phenmetrazine alone reduced breakpoints for all doses of cocaine. The combination of the two drugs showed a concerted effect in reducing breakpoints for all doses of cocaine, with the lowest dose of cocaine reduced by as much as 70%.
  
  
  
  These data support combination therapy of dopamine and glutamate systems as an effective means to reduce the motivation to take cocaine since a combination of drugs can address neurobiological dysfunction in multiple neurotransmitter systems compared to therapies using single drugs.
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston- Salem, NC 27157, USA.
authors.forename: Anushree N
authors.initials: AN
authors.lastname: Karkhanis
authors.affiliation: Clinical Sciences, Medical Affairs, Ferring Pharmaceuticals Inc., 100 Interpace Parkway, Parsippany, NJ 07054, USA.
authors.forename: Thomas J R
authors.initials: TJ
authors.lastname: Beveridge
authors.affiliation: Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston- Salem, NC 27157, USA.
authors.forename: Sara R
authors.initials: SR
authors.lastname: Jones
authors.affiliation: Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston- Salem, NC 27157, USA. Electronic address: mferris@wakehealth.edu.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ferris
mesh_terms: D000596:Amino Acids / Q000008:administration & dosage*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage*; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000523:psychology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D008297:Male; D009042:Motivation / Q000187:drug effects* / Q000502:physiology; D010633:Phenmetrazine / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012054:Reinforcement, Psychology; D012646:Self Administration
chemical_list: D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C118218:LY 379268; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D003042:Cocaine; D010633:Phenmetrazine
keywords: Cocaine self administration; Combination therapy; Dopamine releaser; LY379268; Phenmetrazine; mGluR2/3 agonist