Behavioral and Neurochemical Changes Induced by Repetitive Combined Treatments of Ketamine and Amphetamine in Mice

Abstract

The combined abuse of recreational drugs such as ketamine (Ket) and amphetamine (Amph) should be seriously considered important social and health issues. Numerous studies have documented the behavioral and neurochemical changes associated with polydrug administration; however, most studies have only examined the acute effects. The consequences following chronic repetitive polydrug use are less studied. In the present study, intraperitoneal injections of saline, Amph (5 mg/kg), low dose Ket (LK, 10 mg/kg), high dose Ket (HK, 50 mg/kg), or Amph plus LK or HK (ALK or AHK) were conducted twice a day for three consecutive days, and one final treatment was administered on day 4. After seven total treatments, animal behaviors, including locomotion, stereotypy and ataxia, were examined in a novel open field. The expression of GAD67 and dopamine (DA) levels were assessed in the striatum and motor-related cortices using immunohistochemistry and high-performance liquid chromatography. Drug-induced hyperactivities and Amph-mediated potentiation of Ket-triggered ataxia manifested after repeated drug treatments. A significant increase in the number of GAD67-positive puncta in the striatum and motor-related cortices was observed, suggesting a neural adaptive change in the GABAergic system. Four hours after the final treatment, while the behavioral hyperactivities had ceased, considerable changes were still evident in the motor-related cortices, suggesting modulation to the DAergic system. Together, our results show the interactive effects of these two drugs in behavioral and neurochemical aspects and neural adaptive changes in the GABAergic and DAergic systems.

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

“…A blockade of NMDARs located on GABA interneurons, when exerted by MK-801, phencyclidine, and ketamine, decreases GABAergic inhibition (Littlewood et al, 2006;Sakamoto et al, 2006;Homayoun and Moghaddam, 2007). The fact that NMDAR antagonists reduce GAD67 and parvalbumin expression, two of the main markers of GABAergic inhibitory function (Lai et al, 2014;Briones et al, 2015), would suggest an interaction between glutamatergic and dopaminergic systems.…”

“…The increased climbing behavior induced by ketamine could be related to the ability of NMDAR antagonists to increase dopaminergic activity in the striatum and NAc (Lai et al, 2014;El Iskandrani et al, 2015). A blockade of NMDARs located on GABA interneurons, when exerted by MK-801, phencyclidine, and ketamine, decreases GABAergic inhibition (Littlewood et al, 2006;Sakamoto et al, 2006;Homayoun and Moghaddam, 2007).…”

“…apomorphine) have been used in animal models to induce hyperlocomotion (Medvedev et al, 2013;Sukhanov et al, 2014) and several stereotyped behaviors. The latter include climbing, which can also be induced by some N-methyl-D-aspartate receptor (NMDAR) antagonists, such as phencyclidine, dizocilpine (MK-801), and ketamine (Olszewski et al, 2004;Davis-MacNevin et al, 2013;Lai et al, 2014).…”

Action sequencing in the spontaneous swimming behavior of zebrafish larvae - implications for drug development

“…Using this technology platform, we have here studied the swimming behavior in larvae at post fertilization day 10 (dpf 10) and show that the discretized locomotor behavior in fact has a higher order organization which is characterized by the sequencing of swimming bouts of certain types. We also show that pharmacological interventions that are known to alter the sequencing of motor behavior in mammals 17, 18 , in part through interference with basal ganglia circuits 19, 20 , have an analogous dose-dependent effect in zebrafish larvae.…”

Sex-specific sensitivity to methamphetamine-induced schizophrenia-relevant behaviours in neuregulin 1 type III overexpressing mice

“…Interactions between Nrg1 and METH-induced stereotypies have been reported previously – when type I NRG1 protein is administered to neonatal mice, this dose-dependently increases sensitivity to METH-induced stereotypic behaviours and increases expression of the NMDA subunit GluN2D and glutamate decarboxylase 67 (GAD67) expression in adulthood (Kato et al, 2015). While dopamine D 1 receptors are known to modulate stereotyped behaviour (Chartoff et al, 2001; Kuczenski and Segal, 1999), both GluN2D and GAD67 receptors can also modulate methamphetamine-induced stereotypies (Lai et al, 2014; Suryavanshi et al, 2014; Tomiyama et al, 2013). It is possible that NMDA receptor subunit expression is reduced in Nrg1 III tg mice, which may lower METH-induced stereotyped behaviours.…”