Characterization of the Disruptions of Prepulse Inhibition and Habituation of Startle Induced by α-Ethyltryptamine

Martinez, Diana; Geyer, Mark A.

doi:10.1016/s0893-133x(96)00240-0

Cited by 53 publications

(50 citation statements)

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“…The endophenotypes of schizophrenia that have been studied in animals include alterations in sensorimotor gating, latent inhibition, attention, social behavior, and cognition (Baruch et al, 1988;Dulawa et al, 1997;Feldon and Weiner, 1991;Hoffman and Donovan, 1994;Kline et al, 1998;Martinez and Geyer, 1997;Mohn et al, 1999;Solomon et al, 1981;Swerdlow and Geyer, 1998;Weiner et al, 1996). Prepulse inhibition of the startle response is a form of sensorimotor gating that has been studied intensely, because it can easily be measured in both humans and laboratory animals, and because patients with schizophrenia, Huntington's disease, obsessive compulsive disorder, Tourette's syndrome, or attention deficit disorder show reliable deficits in PPI (Geyer and Braff, 1987;Koch, 1999;Swerdlow and Geyer, 1998).…”

Section: Discussionmentioning

confidence: 99%

Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα

Gould

Bizily

Tokarczyk

et al. 2003

Neuropsychopharmacol

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Schizophrenia is a complex disorder characterized by wide-ranging cognitive impairments, including deficits in learning as well as sensory gating. The causes of schizophrenia are unknown, but alterations in intracellular G-protein signaling pathways are among the molecular changes documented in patients with schizophrenia. Using the CaMKIIα promoter to drive expression in neurons within the forebrain, we have developed transgenic mice that express a constitutively active form of G s α (G s α*), the G protein that couples receptors such as the D 1 and D 5 dopamine receptors to adenylyl cyclase. We have also generated mice in which the CaMKIIα promoter drives expression of a dominant-negative form of protein kinase A, R(AB). Here, we examine startle responses and prepulse inhibition of the startle reflex (PPI) in these G s α* and R(AB) transgenic mice. G s α* transgenic mice exhibited selective deficits in PPI, without exhibiting alterations in the startle response, whereas no deficit in startle or PPI was found in the R(AB) transgenic mice. Thus, overstimulation of the cAMP/PKA pathway disrupts PPI, but the cAMP/ PKA pathway may not be essential for sensorimotor gating. G s α* transgenic mice may provide an animal model of certain endophenotypes of schizophrenia, because of the similarities between them and patients with schizophrenia in G-protein function, hippocampus-dependent learning, and sensorimotor gating.

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Section: Discussionmentioning

confidence: 99%

Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα

Gould

Bizily

Tokarczyk

et al. 2003

Neuropsychopharmacol

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: The 5-ht 1a Agonist 8-oh-dpat Has Been Reported To Disrupt Pmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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

Prinssen

Assié

Koek

et al. 2002

Neuropsychopharmacology

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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...

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“…Acute increases in 5-hydroxytryptamine (5HT) levels alone or via serotonergic agonists alter startle activity (Fechter 1974;Geyer et al 1975;Davis 1980;Johansson et al 1995), although serotonergic activity in the brain and the spinal cord may have opposite effects (Davis et al1980;Astrachan and Davis 1981;Davis et al 1986;Commissaris and Davis 1982). PPI is likewise sensitive to serotonergic stimulation (Mansbach et al 1989;Martinez and Geyer 1997;Padich et al 1996;Kehne et al 1996;Vollenweider et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Diminished Acoustic Startle in Chronic Cocaine Users

Efferen

Duncan

Szilágyi

et al. 2000

Neuropsychopharmacology

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Chronic cocaine use has been shown to produce neurochemical alterations which persist after acute withdrawal. This study assessed the effects of cocaine use on the acoustic startle response and sensorimotor gating using prepulse inhibition (PPI) Chronic cocaine use causes physiological and neurochemical alterations which persist well after drug cessation. At the commencement of abstinence, adaptive decreases in dopamine (DA) receptor density (Kleven et al. 1990;Laurier et al. 1994) and DA uptake (Izenwasser and Cox 1990), as well as increases in DA transporter (DAT) mRNA expression (Pilotte et al. 1994;Wamsley and Alburges 1993) and cocaine binding sites (Malison et al. 1998), have been reported. As abstinence continues, there are decreases in basal DA efflux (Parsons et al. 1991;Weiss et al. 1992), DAT mRNA expression (Pilotte et al. 1994), DAT in nucleus accumbens (Wilson et al. 1994), and D 1 receptor density (Kleven et al. 1990), leading to an overall state of decreased dopaminergic neurotransmission (Kuhar and Pilotte 1996).The acoustic startle response under observation in this study is a well characterized response consisting of a reflexive contraction of the skeletal musculature in response to an intense, abrupt stimulus. It is mediated by a simple 3-synapse subcortical circuit Koch et al. 1993). In humans, the response is quantified using electromyographic (EMG) measurements of the obicularis oculi facial muscle (Hoffman and Searle 1968). This response is sensitive to dopaminergic modulation. Direct and indirect DA agonists, such as apomorphine, cocaine and d-amphetamine, increase startle amplitude in animals (Kehne and Sorenson 1978;Davis 1980;Johansson et al. 1995), whereas DA antagonists such as haloperidol and clozapine reduce startle amplitude (Mansbach et al. 1988;Johansson et al. 1995 The acoustic startle response can be attenuated if a weak, non-startling prestimulus (a prepulse) immediately precedes the startle stimulus (Graham 1975;Braff et al. 1992). This phenomenon is known as prepulse inhibition of startle (PPI), the pharmacology of which has been well characterized in animal studies. Dopamine agonists, both direct and indirect, reduce or eliminate PPI; D2 antagonists reverse the effect of agonists such as apomorphine (Mansbach et al. 1988). On the other hand, D1 antagonism fails to reverse the effect (Swerdlow et al. 1991).The aim of the present study was to examine the functional consequences of long-term cocaine use by studying the acoustic startle response and PPI of the acoustic startle response during abstinence following prolonged cocaine use. MATERIALS AND METHODS SubjectsSixty cocaine subjects and 20 normal individuals were screened in consideration for participation. Nine healthy male normal controls and 15 male cocaine users were enrolled in the study after signing a VA/NYU IRB approved consent form.All subjects were screened to rule out presence or history of psychiatric or medical pathology (excluding substance induced disorders for the cocaine users) using the Structured Cli...

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Characterization of the Disruptions of Prepulse Inhibition and Habituation of Startle Induced by α-Ethyltryptamine

Cited by 53 publications

References 30 publications

Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα

Sensorimotor Gating Deficits in Transgenic Mice Expressing a Constitutively Active Form of Gsα

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

Diminished Acoustic Startle in Chronic Cocaine Users

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