Impaired discrimination of a subanesthetic dose of ketamine in a maternal immune activation model of schizophrenia risk

Abstract

Background: Animal models of psychiatric diseases suffer from a lack of reliable methods for accurate assessment of subjective internal states in nonhumans. This gap makes translation of results from animal models to patients particularly challenging. Aims/methods: Here, we used the drug-discrimination paradigm to allow rats that model a risk factor for schizophrenia (maternal immune activation, MIA) to report on the subjective internal state produced by a subanesthetic dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. Results/outcomes: The MIA rats’ discrimination of ketamine was impaired relative to controls, both in the total number of rats that acquired and the asymptotic level of discrimination accuracy. This deficit was not due to a general inability to learn to discriminate an internal drug cue or internal state generally, as MIA rats were unimpaired in the learning and acquisition of a morphine drug discrimination and were as sensitive to the internal state of satiety as controls. Furthermore, the deficit was not due to a decreased sensitivity to the physiological effects of ketamine, as MIA rats showed increased ketamine-induced locomotor activity. Finally, impaired discrimination of ketamine was only seen at subanesthetic doses which functionally correspond to psychotomimetic doses in humans. Conclusion: These data link changes in NMDA responses to the MIA model. Furthermore, they confirm the utility of the drug-discrimination paradigm for future inquiries into the subjective internal state produced in models of schizophrenia and other developmental diseases.

Hippocampal phase precession is preserved under ketamine, but the range of precession across a theta cycle is reduced

“…Ketamine hydrochloride 100 mg/ml (Pheonix Pharm, Auckland, NZ) was diluted to a concentration of either 25 mg/ml or 7.5 mg/ml in 0.9% physiological saline, and administered to animals at a dose of 7.5 mg/kg via intraperitoneal injection. The dose was chosen based on data from our previous study Meighan et al (2021) , which indicated that animals could discriminate a dose within the range of 3 and 10 mg/kg from saline, but that this was not the case for lower (1 mg/kg) or higher (30 mg/kg) doses. Furthermore, data from the same study indicated that doses of 3 and 10 mg/kg had no effect on control animal locomotion, whereas the effect of 30 mg/kg was marked.…”

“…In the present study we used an ABA protocol to examine the effects of saline (A) or acute ketamine (7.5 mg/kg; B) administration on hippocampal phase precession in adult male rats (see Figure 1a ). It has previously been shown that animals can successfully discriminate this dose of ketamine from saline injections in an operant chamber ( Meighan et al, 2021 ). Single cell and LFP activity from CA1 were recorded as pre-trained animals navigated clockwise around a rectangular running track for a food reward.…”

The instrumental role of operant paradigms in translational psychiatric research: Insights from a maternal immune activation model of schizophrenia risk

“…We recently combined the MIA model of schizophrenia risk with a classic operant paradigm to try an innovative new approach to this problem (Meighan et al, 2021). We took advantage of the drug-discrimination paradigm, a method that trains rats to respond on one lever in the presence of saline, and another lever in the presence of a drug (Stolerman et al, 2011).…”

Antipsychotics, the heartland of clinical psychopharmacology?

“…Clinicians should conduct routine evaluations of weight gain in patients and examine their metabolic profile throughout follow up. Meighan et al (2021) used the drug-discrimination paradigm in rats that models a risk factor for schizophrenia (maternal immune activation; MIA) to examine the subjective internal state produced by a subanaesthetic dose of the NMDA receptor antagonist ketamine. Their data indicates that the MIA manipulation not only induces a variety of behavioural, neuroanatomical, neurophysiological and neurochemical changes often associated with disorders such as schizophrenia, but also may induce subjective experiential changes in rats that have features similar to drug-induced psychosis (Meighan et al, 2021).…”

“…Meighan et al (2021) used the drug-discrimination paradigm in rats that models a risk factor for schizophrenia (maternal immune activation; MIA) to examine the subjective internal state produced by a subanaesthetic dose of the NMDA receptor antagonist ketamine. Their data indicates that the MIA manipulation not only induces a variety of behavioural, neuroanatomical, neurophysiological and neurochemical changes often associated with disorders such as schizophrenia, but also may induce subjective experiential changes in rats that have features similar to drug-induced psychosis (Meighan et al, 2021). They suggest that the drug-discrimination paradigm should be utilised to further explore the neurobiological underpinnings of psychiatric symptoms which manifest as changes in subjective states in nonhuman models.…”