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

Adams WK, Halberstadt AL, van den Buuse M - Front Pharmacol (2013)

Bottom Line: Ventral hippocampus lesions did not alter the hyperlocomotion elicited by either compound.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.

View Article: PubMed Central - PubMed

Affiliation: Behavioural Neuroscience Laboratory, Florey Institute for Neuroscience and Mental Health, University of Melbourne Melbourne, VIC, Australia ; Centre for Neuroscience, University of Melbourne Melbourne, VIC, Australia.

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.

No MeSH data available.


Related in: MedlinePlus

Effect of 5,7-DHT-lesions targeting the dorsal or ventral hippocampus on locomotor hyperactivity induced by 0.5 and 2.5 mg/kg PCP and 0.1 mg/kg MK-801. Panels show mean distance moved (cm) in 5 min intervals ± SEM for DHI (n = 16), VHI (n = 8) and sham-operated rats (n = 17) treated with (A) saline (B) 0.5 and (C) 2.5 mg/kg PCP and (D) 0.1 mg/kg MK-801. Total distance moved following 0.5 and 2.5 mg/kg PCP injection was significantly higher in DHI rats compared to controls (see text for details).
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Figure 1: Effect of 5,7-DHT-lesions targeting the dorsal or ventral hippocampus on locomotor hyperactivity induced by 0.5 and 2.5 mg/kg PCP and 0.1 mg/kg MK-801. Panels show mean distance moved (cm) in 5 min intervals ± SEM for DHI (n = 16), VHI (n = 8) and sham-operated rats (n = 17) treated with (A) saline (B) 0.5 and (C) 2.5 mg/kg PCP and (D) 0.1 mg/kg MK-801. Total distance moved following 0.5 and 2.5 mg/kg PCP injection was significantly higher in DHI rats compared to controls (see text for details).

Mentions: Analysis of variance of average pre-injection distance moved found no group differences, indicating that 5,7-DHT administration into the dorsal or ventral hippocampus did not affect levels of baseline activity (Figure 1). Locomotor activity diminished over this 30 min pre-injection habituation period similarly in all animals (main effect of time: F5,190 = 163.5, p < 0.001).


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

Adams WK, Halberstadt AL, van den Buuse M - Front Pharmacol (2013)

Effect of 5,7-DHT-lesions targeting the dorsal or ventral hippocampus on locomotor hyperactivity induced by 0.5 and 2.5 mg/kg PCP and 0.1 mg/kg MK-801. Panels show mean distance moved (cm) in 5 min intervals ± SEM for DHI (n = 16), VHI (n = 8) and sham-operated rats (n = 17) treated with (A) saline (B) 0.5 and (C) 2.5 mg/kg PCP and (D) 0.1 mg/kg MK-801. Total distance moved following 0.5 and 2.5 mg/kg PCP injection was significantly higher in DHI rats compared to controls (see text for details).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3756227&req=5

Figure 1: Effect of 5,7-DHT-lesions targeting the dorsal or ventral hippocampus on locomotor hyperactivity induced by 0.5 and 2.5 mg/kg PCP and 0.1 mg/kg MK-801. Panels show mean distance moved (cm) in 5 min intervals ± SEM for DHI (n = 16), VHI (n = 8) and sham-operated rats (n = 17) treated with (A) saline (B) 0.5 and (C) 2.5 mg/kg PCP and (D) 0.1 mg/kg MK-801. Total distance moved following 0.5 and 2.5 mg/kg PCP injection was significantly higher in DHI rats compared to controls (see text for details).
Mentions: Analysis of variance of average pre-injection distance moved found no group differences, indicating that 5,7-DHT administration into the dorsal or ventral hippocampus did not affect levels of baseline activity (Figure 1). Locomotor activity diminished over this 30 min pre-injection habituation period similarly in all animals (main effect of time: F5,190 = 163.5, p < 0.001).

Bottom Line: Ventral hippocampus lesions did not alter the hyperlocomotion elicited by either compound.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.

View Article: PubMed Central - PubMed

Affiliation: Behavioural Neuroscience Laboratory, Florey Institute for Neuroscience and Mental Health, University of Melbourne Melbourne, VIC, Australia ; Centre for Neuroscience, University of Melbourne Melbourne, VIC, Australia.

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.

No MeSH data available.


Related in: MedlinePlus