Hippocampal serotonin depletion unmasks differences in the hyperlocomotor effects of phencyclidine and MK-801: quantitative versus qualitative analyses

Abstract

Antagonism of N-methyl-D-aspartate (NMDA) receptors by phencyclidine (PCP) is thought to underlie its ability to induce a schizophrenia-like syndrome in humans, yet evidence indicates it has a broader pharmacological profile. Our previous lesion studies highlighted a role for serotonergic projections from the median, but not dorsal, raphe nucleus in mediating the hyperlocomotor effects of PCP, without changing the action of the more selective NMDA receptor antagonist, MK-801. Here we compared locomotor responses to PCP and MK-801 in rats that were administered 5,7-dihydroxytryptamine (5,7-DHT) into either the dorsal or ventral hippocampus, which are preferentially innervated by median and dorsal raphe, respectively. Dorsal hippocampus lesions potentiated PCP-induced hyperlocomotion (0.5, 2.5 mg/kg), but not the effect of MK-801 (0.1 mg/kg). Ventral hippocampus lesions did not alter the hyperlocomotion elicited by either compound. Given that PCP and MK-801 may induce different spatiotemporal patterns of locomotor behavior, together with the known role of the dorsal hippocampus in spatial processing, we also assessed whether the 5,7-DHT-lesions caused any qualitative differences in locomotor responses. Treatment with PCP or MK-801 increased the smoothness of the path traveled (reduced spatial d) and decreased the predictability of locomotor patterns within the chambers (increased entropy). 5,7-DHT-lesions of the dorsal hippocampus did not alter the effects of PCP on spatial d or entropy – despite potentiating total distance moved – but caused a slight reduction in levels of MK-801-induced entropy. Taken together, serotonergic lesions targeting the dorsal hippocampus unmask a functional differentiation of the hyperlocomotor effects of PCP and MK-801. These findings have implications for studies utilizing NMDA receptor antagonists in modeling glutamatergic dysfunction in schizophrenia.

The novel ketamine analog methoxetamine produces dissociative-like behavioral effects in rodents

“…Locomotor hyperactivity is a prominent component of the behavioral syndrome induced by competitive and uncompetitive NMDAR antagonists with psychotomimetic effects (Sturgeon et al, 1979; Mattia et al, 1986; Lehmann-Masten and Geyer, 1991; Danysz et al, 1994; Bakshi et al, 1999; Imre et al, 2006; Adams et al, 2013). Importantly, although many stimulant drugs increase locomotor activity, multivariate assessments in the BPM have shown that the effects of PCP and MK-801 on unconditioned motor activity are qualitatively distinct from those produced by other stimulant classes (Lehmann-Masten and Geyer, 1991; Krebs-Thomson et al, 1998).…”

“…Interestingly, those investigators also reported that MXE does not alter locomotor activity when administered to Sprague-Dawley rats at doses up to 5 mg/kg. The lack of an effect of MXE is surprising because locomotor hyperactivity is a prominent component of the behavioral syndrome induced by NMDAR antagonists in rodents (Sturgeon et al, 1979; Mattia et al, 1986; Lehmann-Masten and Geyer, 1991; Danysz et al, 1994; Imre et al, 2006; Adams et al, 2013). The locomotor stimulation produced by NMDAR antagonists is often used as a preclinical measure of their psychotomimetic effects.…”

BDNF-Deficient Mice Show Reduced Psychosis-Related Behaviors Following Chronic Methamphetamine

“…After injection, the mice were allowed to explore the arena for a further 2 hours, with distance travelled data automatically calculated in 5-minute bins. Raw 50-msec-resolution data files were used for analysis of patterns of exploration ( Paulus and Geyer, 1991 ; Perry et al, 2009 ; Adams et al, 2013 ). Sequential patterns of exploration were defined by the measure entropy, which describes whether movements are repetitive (low entropy) or random (high entropy).…”

Temporal dissociation of phencyclidine: Induced locomotor and social alterations in rats using an automated homecage monitoring system – implications for the 3Rs and preclinical drug discovery

“…Using conventional manual scoring, we verified PCP -induced asociality whereby rats exhibited significant reductions in time spent allogrooming, pouncing and pinning compared to those treated with saline ( (Adams et al, 2013) and between 5 and 75 min (Sturgeon et al, 1979). Unlike conventional outof-cage locomotor assays, homecage analysis permitted a 24 h profile of PCP.…”