Depletion of 5-HT Disrupts Prepulse Inhibition in Rats Dependence on the Magnitude of Depletion, and Reversal by a 5-HT Precursor

Abstract

The 5-HT 1A agonist 8-OH-DPAT has been reported to disrupt prepulse inhibition (PPI) of the acoustic startle reflex after local administration into the raphe nuclei. Because it is likely that 8-OH-DPAT disrupted PPI by activation of somatodendritic inhibitory receptors, and thereby, via a decrease in 5-HT neurotransmission, we tested whether chronic, drug-induced, depletions of 5-HT have similar effects. Rats were drug-treated for three consecutive days and tested in a short PPI paradigm on day 4, and retested 2 h later, after acute saline or drug administration. Repeated treatment with the 5-HT synthesis inhibitor p -chlorophenylalanine methyl ester (PCPA; 160 mg/kg) produced a small, but significant, attenuation of PPI, and a large decrease in extracellular 5-HT levels in the hippocampus, as measured in independent microdialysis experiments. An even larger depletion of 5-HT was obtained by substituting the 3 rd PCPA administration with the 5-HT releaser d-fenfluramine (10 mg/kg); this combined treatment nearly abolished PPI in the majority of animals. The involvement of 5-HT in the latter effects was confirmed by the finding that low doses of the 5-HT precursor 5-hydroxy- Microdialysis; Serotonin; Prepulse inhibition (PPI) of the startle response refers to the phenomenon that a startle response to a strong stimulus is reduced when this stimulus is preceded by a small prestimulus within a short time period (Graham 1975). The paradigm has gained interest both clinically and preclinically as it was observed that certain patient populations such as schizophrenics, and animals treated with psychotogenics, show attenuated PPI (Swerdlow et al. 1986;Geyer and Braff 1987). Early preclinical pharmacological studies of the mechanisms underlying PPI focused mainly on dopamine, but also on 5-HT, which appears to play an important role. For example, pharmacologically-induced release of 5-HT disrupts PPI in the rat (Padich et al. 1996;Martinez and Geyer 1997). More than one subtype of 5-HT receptor may be involved in these effects as selective stimulation of 5-HT 2A (Sipes and Geyer 1995;Padich et al. 1996), 5-HT 1B Geyer 1994, 1996), and 5-HT 1A receptors (Rigdon and Weatherspoon 1992;Sipes and Geyer 1995) disrupts PPI in the rat. In contrast to the extensive examination of increased function, the effects of de- (Sharp and Hjorth 1990;Blier et al. 1998). The finding that the 5-HT 1A agonist 8-OH-DPAT disrupts PPI after local administration in the raphe nuclei (Sipes and Geyer 1995), the main 5-HT neuron-containing nuclei, suggests that it acts on 5-HT 1A somatodendritic receptors, i.e., via a decrease in 5-HT neurotransmission. Here, we further studied whether decreases in 5-HT levels are indeed able to alter PPI, by examining the effects of chronic, drug-induced, 5-HT depletions. We first examined the effects of repeated administration of the 5-HT synthesis inhibitor p -chlorophenylalanine (PCPA), because this reportedly leads to a large and selective depletion of 5-HT (cf., Koe and Weissman 1966;Sarnek and Baran 1975;Ba...

The effect of corticotropin-releasing factor on prepulse inhibition is independent of serotonin in Brown Norway and Wistar-Kyoto rats

“…PCPA decreases PPI in male Sprague-Dawley rats (Fletcher et al, 2001;Prinssen et al, 2002), similar to our findings in BN rats. We did observe that PCPA treatment decreased NE levels in the hippocampus of WKY rats only and this may help explain the differential effect of PCPA on PPI in the two rat strains.…”

Prepulse Inhibition and Habituation of Acoustic Startle Response in Male MDMA (‘Ecstasy’) Users, Cannabis Users, and Healthy Controls

“…Acute administration of the 5-HT-depleting agent p-chlorophenylalanine (PCPA) disrupted PPI in rodents (Fletcher et al, 2001;Prinssen et al, 2002). This finding is consistent with results of a previous study, which reported decreased PPI after dietary tryptophan depletion in humans (Phillips et al, 2000).…”

“…Acute 5-HT depletion decreased PPI in animals and humans consistently (Phillips et al, 2000; Fletcher et al, Figure 2 Habituation curve diagrammed as mean amplitude of 116-dBpulse-alone trials in six blocks and a single initial 116-dB-pulse-alone trial (means7SEM). 2001; Prinssen et al, 2002), but surprisingly, we found increased PPI for chronic users of MDMA, indicating alterations of neurotransmission other than just lowered 5-HT. One possible explanation is specific alterations at the receptor level that occur due to chronic MDMA exposure.…”

Differential Effects of Acute Serotonin and Dopamine Depletion on Prepulse Inhibition and P50 Suppression Measures of Sensorimotor and Sensory Gating in Humans

“…It is more likely that effects are related to the potency of serotonergic modulation. Indeed animal studies have shown evidence for dose-dependant effects of serotonin depletion (Prinssen et al, 2002) and serotonin agonists Vollenweider et al, 2007) on PPI. Secondly, it is possible that differences between studies may be related to the stimulus characteristics of the PPI paradigm (eg the interval between prepulse and pulse) and their subsequent sensitivity to serotonergic manipulation.…”