Serotonergic lesions of the dorsal hippocampus differentially modulate locomotor hyperactivity induced by drugs of abuse in rats: implications for schizophrenia

Abstract

These findings further implicate a role for serotonin in the dorsal hippocampus in modulating the behavioral effects of dissociative anesthetics, such as ketamine, with more subtle effects on psychostimulant drugs of abuse. The dorsal hippocampus may be a site of serotonergic dysfunction in aspects of schizophrenia.

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

“…In addition, dorsal hippocampus serotonin depletion appears robust in potentiating PCP responses regardless of the additional depletion observed in the ventral domain. In our early study, DHI rats showed no secondary lesion effects in the ventral hippocampus (Kusljic and van den Buuse, 2004); the asymmetric pattern of serotonin depletion observed in our DHI and VHI rats more recently has been discussed in detail elsewhere (Adams et al, 2009). However, with reduced serotonin levels in the whole hippocampus, we cannot definitively conclude that the behavioral changes are due to 5,7-DHT effects in the dorsal hippocampus only.…”

“…Thus, like lesions of serotonergic cell bodies in the MnR (Kusljic et al, 2005), 5,7-DHT-lesions targeting the dorsal hippocampus are sufficient to unmask functional differences between PCP and the more selective NMDA receptor antagonist, MK-801. Together with data from numerous locomotor activity experiments in 5,7-DHT-lesioned rats (see Adams et al, 2008 for review; Adams et al, 2009), these results indicate that serotonin projections from the MnR to the dorsal hippocampus are involved in the hyperlocomotor mechanism of action of the dissociative anesthetics, PCP and ketamine, as opposed to that of psychostimulants, like amphetamine, and in a manner seemingly independent of their ability to block NMDA receptors, or modulate spatial patterns of behavior. Like other reports (Snell et al, 1988; Hiramatsu et al, 1989; Rothman, 1994; Kapur and Seeman, 2002; Seeman et al, 2005; Seeman and Lasaga, 2005), our findings lend strength to the notion that the schizophrenomimetic effects of PCP and ketamine may not be due to NMDA receptor antagonism alone.…”

“…Surgery was conducted when animals were 7–8 weeks old as described previously (Kusljic and van den Buuse, 2004; Adams et al, 2008, 2009; Adams and van den Buuse, 2011). In brief, rats were randomly allocated to one of four groups: dorsal hippocampus-injected (DHI), ventral hippocampus-injected (VHI) or their equivalent sham-operated controls.…”

“…Lesions were confirmed by measuring serotonin levels in the dorsal and ventral hippocampus using Serotonin ELISA kits (Labor Diagnostika Nord GmbH & Co. KG, Nordhorn, Germany), with minor adjustments as described before (Adams et al, 2009; Adams and van den Buuse, 2011). Rats were decapitated at least three days after the end of locomotor testing, and the dorsal and ventral hippocampi dissected out, weighed, and stored at -80°C until ELISA.…”

“…Injection of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the median, but not the dorsal, raphe nucleus (MnR, DR) was found to potentiate PCP-induced locomotor behaviors (Kusljic et al, 2003, 2005), but not the effect of MK-801 (Kusljic et al, 2005), providing evidence of a pharmacological distinction between these drugs at the level of serotonergic projections originating in the MnR. Local 5,7-DHT administration into MnR projection regions revealed that lesions of the dorsal, but not ventral, hippocampus enhanced both PCP- and ketamine-induced hyperlocomotion (Kusljic and van den Buuse, 2004; Adams et al, 2009). Taken together, these findings raised questions about both the selectivity and sensitivity of lesion effects.…”