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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

Spatial patterns of locomotor hyperactivity shown by representative, individual sham-operated (top) and DHI (bottom) animals. Plots show activity traces in the 60–90 min time block following treatment with (A) saline (B) 2.5 mg/kg PCP and (C) 0.1 mg MK-801. Enhanced PCP-induced locomotor hyperactivity in DHI rats is clearly depicted by the increased density of tracings in the chamber (panel B, bottom).
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Figure 3: Spatial patterns of locomotor hyperactivity shown by representative, individual sham-operated (top) and DHI (bottom) animals. Plots show activity traces in the 60–90 min time block following treatment with (A) saline (B) 2.5 mg/kg PCP and (C) 0.1 mg MK-801. Enhanced PCP-induced locomotor hyperactivity in DHI rats is clearly depicted by the increased density of tracings in the chamber (panel B, bottom).

Mentions: Analysis of variance of all post-injection distance moved data found that the effects of drug treatment were, again, dependent on lesion group (drug by group interaction: F2,42 = 6.3, p = 0.004; Figure 2A). As expected, total PCP-induced hyperactivity was greater in DHI rats than in sham-operated controls (51 ± 13% increase in total distance moved; main effect of group: F1,21 = 8.5, p = 0.008; drug by group interaction: F1,21 = 11.3, p = 0.003; Figure 2A, middle panel). In addition, MK-801 treatment caused a time-dependent increase in locomotor activity that was unaffected by dorsal hippocampus lesions (main effect of drug: F1,21 = 125.1, p < 0.001; drug by time interaction: F2,42 = 52.1, p < 0.001; Figure 2A, bottom panel). The lack of significant interactions between time and group in analyses of distance moved data for both compounds also corresponded with Experiment 1. Representative plots of post-injection activity are provided in Figure 3, in which enhanced PCP-induced hyperlocomotion in a DHI animal is clearly depicted (Figure 3B, bottom panel).


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)

Spatial patterns of locomotor hyperactivity shown by representative, individual sham-operated (top) and DHI (bottom) animals. Plots show activity traces in the 60–90 min time block following treatment with (A) saline (B) 2.5 mg/kg PCP and (C) 0.1 mg MK-801. Enhanced PCP-induced locomotor hyperactivity in DHI rats is clearly depicted by the increased density of tracings in the chamber (panel B, bottom).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Spatial patterns of locomotor hyperactivity shown by representative, individual sham-operated (top) and DHI (bottom) animals. Plots show activity traces in the 60–90 min time block following treatment with (A) saline (B) 2.5 mg/kg PCP and (C) 0.1 mg MK-801. Enhanced PCP-induced locomotor hyperactivity in DHI rats is clearly depicted by the increased density of tracings in the chamber (panel B, bottom).
Mentions: Analysis of variance of all post-injection distance moved data found that the effects of drug treatment were, again, dependent on lesion group (drug by group interaction: F2,42 = 6.3, p = 0.004; Figure 2A). As expected, total PCP-induced hyperactivity was greater in DHI rats than in sham-operated controls (51 ± 13% increase in total distance moved; main effect of group: F1,21 = 8.5, p = 0.008; drug by group interaction: F1,21 = 11.3, p = 0.003; Figure 2A, middle panel). In addition, MK-801 treatment caused a time-dependent increase in locomotor activity that was unaffected by dorsal hippocampus lesions (main effect of drug: F1,21 = 125.1, p < 0.001; drug by time interaction: F2,42 = 52.1, p < 0.001; Figure 2A, bottom panel). The lack of significant interactions between time and group in analyses of distance moved data for both compounds also corresponded with Experiment 1. Representative plots of post-injection activity are provided in Figure 3, in which enhanced PCP-induced hyperlocomotion in a DHI animal is clearly depicted (Figure 3B, bottom panel).

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