The individual and combined effects of phenmetrazine and mgluR2/3 agonist LY379268 on the motivation to self-administer cocaine

Abstract

Background 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. Methods 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, 0.75 mg/kg/infusion), and following LY379268 (0.03 or 0.30 mg/kg; i.p.), phenmetrazine (25 mg/kg/day; osmotic minipump), and a combination of the two drugs. Results 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%. Conclusions 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.

Presynaptic G Protein-Coupled Receptors: Gatekeepers of Addiction?

“…In rats, mGlu 2/3 activation reduces motivation to self-administer cocaine as determined by a reduced breakpoint under a progressive ratio reinforcement schedule (Hao et al, 2010; Karkhanis et al, 2016). Studies evaluating self-administration of many drugs of abuse in rats have demonstrated that mGlu 2/3 activation by LY379268 reduces intake of amphetamine (Kim et al, 2005), methamphetamine (Crawford et al, 2013), alcohol (Sidhpura et al, 2010), and nicotine (Liechti et al, 2007).…”

Metabotropic glutamate 2,3 receptor stimulation desensitizes agonist activation of G‐protein signaling and alters transcription regulators in mesocorticolimbic brain regions

“…After a 12‐hr latency, each pump (208 μl fill volume) released 1.0 μl/hr, providing a 7‐day dosage of 3.0 mg kg −1 day −1 LY379268. This dose was chosen to represent the range of doses used in previous studies showing efficacy of LY379268 in reducing cocaine and methamphetamine self‐administration in (Baptista et al., 2004; Crawford et al., 2013; Hao et al., 2010; Karkhanis et al., 2016). Rats in the 14‐day treatment group underwent the implantation procedure twice consecutively to give 14 days of continuous drug exposure.…”

DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants

“…112–116 Accordingly, systemic administration of mGluR2/3 agonists can attenuate cocaine and methamphetamine self-administration as well as reinstatement behaviors. 117–121 Moreover, the glutamate carboxypeptidase II (GCPII) inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), which is an indirect mGluR2/3 agonist, attenuates cocaine place preference, 122 cocaine self-administration, and cocaine relapse. 123,124…”

“…Targeting presynaptic metabotropic glutamate 2 and 3 receptors (mGluR2/3s) also appears as a promising pharmacotherapeutic strategy to manage psychostimulant addiction (for review, see). Animal studies show enduring neuroadaptations in mGluR2/3 receptors following repeated psychostimulant exposure, which contributes to synaptic plasticity in glutamate and DA levels that drives drug-taking and drug-seeking behavior. − Accordingly, systemic administration of mGluR2/3 agonists can attenuate cocaine and methamphetamine self-administration as well as reinstatement behaviors. − Moreover, the glutamate carboxypeptidase II (GCPII) inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), which is an indirect mGluR2/3 agonist, attenuates cocaine place preference, cocaine self-administration, and cocaine relapse. , …”