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.
Highlights
Phencyclidine (PCP) and MK-801 are often used interchangeably in the psychopharmacological literature as they are both non-competitive antagonists of the glutamatergic N -methyl-Daspartate (NMDA) receptor
SEROTONIN DEPLETION IN THE DORSAL AND VENTRAL HIPPOCAMPUS In Experiment 1, dorsal hippocampus-injected (DHI) rats showed a comparable level of serotonin depletion in the ventral hippocampus as ventral hippocampus-injected (VHI) rats, but a greater extent of depletion in the dorsal hippocampus (Table 1)
VHI rats in this cohort showed a slight, but significant, depletion of serotonin in the dorsal hippocampus. Like those in Experiment 1, DHI rats in Experiment 2 showed serotonin depletion in both the dorsal and ventral hippocampus compared to sham-operated controls (Table 1)
Summary
Phencyclidine (PCP) and MK-801 are often used interchangeably in the psychopharmacological literature as they are both non-competitive antagonists of the glutamatergic N -methyl-Daspartate (NMDA) receptor. While psychostimulants typically require chronic use to elicit psychotic states in healthy subjects, a single dose of a PCP or ketamine can induce schizophrenia-like behavioral disturbances (Abi-Saab et al, 1998; Moghaddam and Jackson, 2003; Stone and Pilowsky, 2006). Their pharmacological characterisation as NMDA receptor antagonists in the 1980s
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