Effects of strain and serotonergic agents on prepulse inhibition and habituation in mice
Introduction
Sensorimotor gating is a neural mechanism that inhibits extraneous sensory, cognitive, and motor information to permit mental integration and adaptive behavior. Prepulse inhibition (PPI), an operational measure of sensorimotor gating, is the normal reduction in the magnitude of the startle response that occurs when a weak prestimulus or “prepulse” precedes the startling stimulus by 30–500 ms (Graham, 1975). PPI levels indicate the current integrity of sensorimotor gating mechanisms by measuring the extent to which current information processing routines elicited by the prepulse are interrupted by the subsequent startling stimulus. Reduced levels of PPI have been reported in patients with several neuropsychiatric disorders, including schizophrenia (Braff et al., 1978, Braff et al., 1992), obsessive-compulsive disorder (OCD) (Swerdlow et al., 1993), Tourette's syndrome (Castellanos et al., 1996), and Huntington's disease (Swerdlow et al., 1995). Startle habituation is also deficient in schizophrenia patients, and refers to the decrement in responding to repeated presentations of an initially novel and intense stimulus (Braff et al., 1992, Geyer and Braff, 1982). Although the core symptoms of these disorders are diverse, a feature common to all of them is deficient sensorimotor gating, with a gating deficit predominating in the cognitive sphere in some disorders, and in the sensory or motor domains in others.
The serotonergic system modulates both PPI and habituation. Most murine studies that have identified some of the receptors involved have used the 129Sv strain. For example, serotonin1A (5-HT1A) receptor agonists increase PPI in 129Sv mice (Dulawa et al., 1997, Dulawa et al., 2000), although they decrease PPI in rats (Rigdon and Weatherspoon, 1992, Sipes and Geyer, 1995a). 5-HT1B agonists decrease PPI in 129Sv mice (Dulawa et al., 1997, Dulawa et al., 2000), as in rats (Sipes and Geyer, 1994). Serotonin releasing compounds such as (+)3,4-methylenedioxy-N-methylamphetamine (MDMA) decrease PPI and habituation in rats (Kehne et al., 1992, Mansbach et al., 1989, Martinez and Geyer, 1997) and some substrains of 129Sv mice (Dulawa and Geyer, 1996), but not in others (Dulawa et al., 1998). The effects of serotonin2A/2C receptor agonists on PPI and habituation in mice are largely unknown, although in rats they decrease PPI and habituation (Geyer and Tapson, 1988, Sipes and Geyer, 1995b). Characterization of the effects of these compounds in other mouse strains will help to elucidate the genes involved in these drug responses using transgenic or “knockout” technology.
The combination of pharmacological and gene knockout technology has led to novel findings regarding the neural substrates modulating PPI. For instance, the report that the 5-HT1A/1B agonist RU24969 decreases PPI in wild-type, but not 5-HT1B knockout mice showed that the activation of 5-HT1B, and not 5-HT1A receptors decreases PPI before selective 5-HT1B ligands were available (Dulawa et al., 1997). Furthermore, the report that amphetamine disrupts PPI in dopamine4 (D4) and D3, but not D2, knockout mice suggests that D2, but not D3 or D4, receptor activation disrupts PPI (Ralph et al., 1999). Studies using pharmacological and molecular genetic techniques will undoubtedly continue to reveal important insights into the neural substrates of PPI.
Many murine strain differences in the effects of drugs on behavior have been reported, including cocaine-induced stereotypy, (Schlussman et al., 1998) and self-administration (Deroche et al., 1997), imipramine-induced immobility (Vaugeois et al., 1997), nicotine-induced seizures and oral self-selection (Robinson et al., 1996), MK-801-induced “popping” behavior (Deutsch et al., 1997), and alcohol-, cocaine-, amphetamine-, and PCP-induced locomotion (Alexander et al., 1996, Phillips et al., 1995, Schlussman et al., 1998). Although few reports exist regarding murine strain differences in drug effects on PPI or habituation (McCaughran et al., 1997), many differences likely exist. A knowledge of these strain differences will allow the selection of an appropriate background strain for the study of a particular drug effect. Furthermore, few studies have assessed murine strain differences in startle habituation or outbred strains.
We examined the effects of serotonergic drugs on PPI and habituation in the two most commonly used background strains for knockouts, the inbred C57BL/6J and 129Sv strains, and the outbred ICR strain (Dulawa and Geyer, 1998). We assessed the effects of the direct 5-HT1A agonist 8-OH-DPAT, the direct 5-HT1A/1B agonist RU24969, which binds preferentially to 5-HT1B sites (Doods et al., 1985, Sills et al., 1984), the hallucinogenic direct 5-HT2A/2C agonist DOM, and the serotonin releasing agent MDMA.
Section snippets
Animals
Female mice of seven to nine weeks of age and weighing 20–35 g were subjects. 129SvEms-+Ter?/J and C57BL/6J mice were obtained from Jackson Labs (Bar Harbor, Maine), and ICR mice from Harlan Labs (San Diego, CA). Animals were housed in groups of four, with food and water provided ad libitum. Animals were maintained on a reversed 12 L: 12 D schedule and were tested during the dark phase between 08.00 and 18.00 h. Animals were naive to experimentation, except for 129Sv mice treated with RU24969,
Startle magnitude
Startle magnitude was evaluated within each of the 12 experiments. Drug treatment altered block one startle magnitude in three experiments, as summarized in Table 1. First, 129Sv mice treated with 20 mg/kg MDMA exhibited reduced startle magnitude compared to mice treated with vehicle, as indicated by a main effect of drug [F3,27=4.08, P<0.05] and post hoc tests (P<0.05, Dunnett's). Second, a main effect of drug [F3,32=3.78, P<0.05] and post hoc tests indicated that 5 and 10 mg/kg RU24969 (P
Discussion
The present results demonstrate strain differences in baseline PPI and habituation, and in the effects of serotonergic agents on these behaviors. Baseline differences were found in which C57BL/6 mice exhibited reduced PPI compared to 129Sv and ICR mice, and 129Sv mice exhibited reduced habituation compared to C57BL/6 and ICR mice. Strain differences in drug effects were observed in which MDMA decreased PPI in C57BL/6 and ICR, but not 129Sv mice, and RU24969 decreased habituation in C57BL/6 and
Acknowledgements
This work was supported by grants from the National Institute on Drug Abuse (R02 DA02925), the National Alliance for Research on Schizophrenia and Depression (NARSAD), and the Department of Veterans Affairs, VISN 22 Mental Illness, Research, Education, and Clinical Center (MIRECC). S.C. Dulawa was supported by a predoctoral NRSA from the National Institute of Mental Health (F31-MH12249-01). M.A. Geyer holds an equity interest in San Diego Instruments, Inc. The authors gratefully acknowledge the
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