Dissociable effects of the noncompetitive NMDA receptor antagonists ketamine and MK-801 on intracranial self-stimulation in rats

Abstract

Rationale The noncompetitive NMDA antagonist ketamine produces rapid antidepressant effects in treatment-resistant patients suffering from major depressive and bipolar disorders. However, abuse liability is a concern. Objectives This study examined abuse-related effects of keta-mine using intracranial self-stimulation (ICSS) in rats. The higher-affinity NMDA antagonist MK-801 and the monoamine reuptake inhibitor cocaine were examined for comparison. Methods Male Sprague Dawley rats were implanted with electrodes targeting the medial forebrain bundle and trained to respond to brain stimulation under a frequency–rate ICSS procedure. The first experiment compared the potency and time course of ketamine (3.2–10.0 mg/kg) and MK-801 (0.032–0.32 mg/kg). The second experiment examined effects of repeated dosing with ketamine (3.2–20.0 mg/kg/day) and acute cocaine (10.0 mg/kg). Results Following acute administration, ketamine (3.2–10 mg/kg) produced only dose- and time-dependent depressions of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. In contrast, MK-801 (0.032–0.32 mg/kg) produced a mixed profile of rate-increasing and rate-decreasing effects; ICSS facilitation was especially prominent at an intermediate dose of 0.18 mg/kg. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine (10.0 and 18.0 mg/kg) but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. As reported previously, 10.0 mg/kg cocaine facilitated ICSS. Conclusions The dissociable effects of ketamine and MK-801 suggest differences in the pharmacology of these nominally similar NMDA antagonists. Failure of ketamine to facilitate ICSS contrasts with other evidence for the abuse liability of ketamine.

Intracranial Self-Stimulation to Evaluate Abuse Potential of Drugs

“…13E shows facilitation of ICSS by 0.18 mg/kg i.p. MK801 in rats responding under a frequency-rate ICSS procedure (Hillhouse et al, 2014). Notably, both MK801 and PCP produced modest facilitation of ICSS at low doses, whereas higher doses recruited abuselimiting rate-decreasing effects.…”

“…Ketamine was also reported to weakly facilitate ICSS in one study that used a free-operant ICSS procedure (Herberg and Rose, 1989); however, Fig. 13F shows that ketamine failed to facilitate ICSS in a hybrid frequency-rate procedure that was sensitive to rateincreasing effects of MK801, and additional studies showed that repeated ketamine produced tolerance to its rate-decreasing effects but still failed to unmask abuserelated rate-increasing effects (Hillhouse et al, 2014) (Table 5). Taken together, these ICSS results suggest a hierarchy of abuse potential for NMDA antagonists with MK801 = PCP .…”

“…Filled points show drug effects significantly different from vehicle as determined by two-way ANOVA and the Holm-Sidak post hoc test (P , 0.05). Data sets are published for diazepam and toluene (Tracy et al, 2014) and for MK801 and ketamine (Hillhouse et al, 2014). Results with nicotine and caffeine are unpublished but collected with identical procedures.…”

“…In contrast to these effects of orthosteric ligands, numerous studies have reported facilitation of ICSS by NMDA receptor channel blockers including PCP and the more selective ligand MK801 [(5S,10R)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate] (Kornetsky et al, 1979;Corbett, 1989;Herberg and Rose, 1989;Carlezon and Wise, 1993b;Sundstrom et al, 2002;Bespalov et al, 2006;Hillhouse et al, 2014) (see Table 5 for illustrative data). For example, Fig.…”

La ketamina come antidepressivo ad azione rapida: controversia e implicazioni [translation of “Ketamine as a rapid antidepressant: the debate and implications” by Dr. Giacomo Galli and Dr. Serena Saraceni]

“…Ci sono tuttavia evidenze che mettono in dubbio tale postulato. In primo luogo la ketamina ha dimostrato una bassa affinità per i recettori NMDA rispetto ad altri recettori, implicando che l'elevazione acuta del tono dell'umore debba essere dovuta ad altri meccanismi d'azione (Hillhouse 2014;Sanacora 2015). Questi potrebbero includere, nei mammiferi, l'effetto su target come i recettori per la rapamicina (mTOR; Li 2011b), il BDNF (Autry 2011), il sistema dopaminergico (Tan 2012), i recettori sigma (Robson 2012) e i recettori nicotinici dell'aceticolina (Nishitani 2014).…”