5-HT modulation of auditory and visual sensorimotor gating: II. Effects of the 5-HT2A antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5-HT agonists in Wistar rats

Abstract

Increasing evidence suggests an important role of 5-HT, and 5-HT2A receptors in particular, in the etiology and treatment of schizophrenia. The prepulse inhibition paradigm is used as a model for sensorimotor gating processes that are disrupted in schizophrenia. The present study used the selective serotonin2A (5-HT2A) antagonist and putative antipsychotic agent MDL 100,907 to evaluate the contribution of 5-HT2A receptors to the disruptions of prepulse inhibition produced by several 5-HT agonists. The D2 antagonist haloperidol was used to evaluate a possible interaction with dopamine neurons. Sound or light prepulses were used to measure the generality of these drug effects on cross-modal prepulse inhibition. In the first study, MDL 100,907 antagonized the disruptions of auditory prepulse inhibition produced by the 5-HT releasing agents fenfluramine and 3,4-methylenedioxymethamphetamine (MDMA). These effects on prepulse inhibition were modality-specific in that MDL 100,907 did not reverse the effects of the 5-HT releasers on visual prepulse inhibition. Haloperidol did not alter the disruptive effects of MDMA or fenfluramine on either auditory or visual prepulse inhibition. In the second study, the direct acting 5-HT2A/2C receptor agonist/hallucinogen (+)1-4-iodo-2,5-dimethoxyphenyl-2-aminopropane (DOI) consistently disrupted auditory prepulse inhibition, and this effect was blocked by MDL 100,907 but not by haloperidol. A dose-response analysis demonstrated that MDL 100,907 potently antagonized DOI disrupted auditory prepulse inhibition, with an ED50 of 0.04 mg/kg, IP. DOI did not consistently disrupt visual prepulse inhibition. In summary, these data indicate that, at least under the conditions of the present studies, the disruptions of auditory prepulse inhibition produced by fenfluramine, MDMA, and DOI result from stimulation of 5-HT2A receptors. Furthermore, these disruptions do not involve direct or indirect stimulation of D2 receptors. The identity of the 5-HT receptor(s) underlying the disruptive effects of fenfluramine or MDMA on visual prepulse inhibition has not yet been identified. MDL 100,907 may be generally useful in CNS disorders in which excessive 5-HT2A receptor tone disrupts sensory gating processes.

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

“…Pharmacologically-induced release of 5-HT disrupts PPI in rats (Padich et al 1996;Martinez and Geyer 1997), but enhances PPI in humans (Vollenweider et al 1999). A recent study by Fletcher et al (2001) suggested that not only 5-HT release, but also 5-HT depletion, can disrupt PPI in rats.…”

“…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).…”

“…Nevertheless, its site of action remains unclear and may involve somatodendritic 5-HT 1A receptors in several brain regions, and, possibly, postsynaptic 5-HT 1A receptors that regulate 5-HT firing via a long-loop feedback mechanism (Bosker et al 1997;Casanovas et al 1999). Pharmacologically-induced release of 5-HT disrupts PPI in rats (Padich et al 1996;Martinez and Geyer 1997), but enhances PPI in humans (Vollenweider et al 1999). A recent study by Fletcher et al (2001) suggested that not only 5-HT release, but also 5-HT depletion, can disrupt PPI in rats.…”

“…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.…”

The Selective Serotonin-2A Receptor Antagonist M100907 Reverses Behavioral Deficits in Dopamine Transporter Knockout Mice

“…The PPI-disruptive effects of both DOI (Padich et al, 1996;Sipes and Geyer, 1997) and dizocilpine are potently reversed by M100907, although its capacity to reverse PPI deficits caused by a pharmacologically induced hyperdopaminergic state, such as through the use of amphetamines, remains unknown. In addition, M100907 exhibits positive responses in a number of alternative preclinical models used for the detection of antipsychotic compounds, including disruption of latent inhibition (Moser et al, 1996) and potentiation of the effects of typical antipsychotics in the conditioned avoidance response task (Wadenberg et al, 1998(Wadenberg et al, , 2001).…”