Brain stem circuits mediating prepulse inhibition of the startle reflex

Fendt, Markus; Li, Liang; Yeomans, John S.

doi:10.1007/s002130100794

Cited by 354 publications

(325 citation statements)

References 106 publications

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“…One candidate is the pedunculopontine nucleus (PPTg), which mediates PPI by a direct inhibitory projection to the primary startle circuit (Fendt et al, 2001;Swerdlow et al, 2001;Swerdlow et al, 2008). The LC projects to the PPTg and under conditions of high NE release such as what might occur with pharmacological stimulation of LC, can inhibit the PPTg (Nakano, 2000).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Alsene

Bakshi

2011

Neuropsychopharmacol

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Surprisingly little is known about the modulation of core endophenotypes of psychiatric disease by discrete noradrenergic (NE) circuits. Prepulse inhibition (PPI), the diminution of startle responses when weak prestimuli precede the startling event, is a widely validated translational paradigm for information-processing deficits observed in several mental disorders including schizophrenia, Tourette's syndrome, and post-traumatic stress disorder (PTSD). Despite putative NE disturbances in these illnesses, NE regulation of PPI remains poorly understood. In these studies, regulation of PPI by the locus coeruleus (LC), the primary source of NE to forebrain, was evaluated in rats using well-established protocols to pharmacologically activate/inactivate this nucleus. The ability of drugs that treat deficient PPI in these illnesses to reverse LC-mediated PPI deficits was also tested. Stimulation of LC receptors produced an anatomically and behaviorally specific deficit in PPI that was blocked by clonidine (Cataprese, an a2 receptor agonist that reduces LC neuronal firing after peri-LC delivery), a postsynaptic a1 NE receptor antagonist (prazosin), and second-generation antipsychotics (olanzapine, seroquel), but not by drugs that antagonized dopamine-1 (SCH23390), dopamine-2 (the first-generation antipsychotic Haloperidol), or serotonin-2 receptors (ritanserin). These results indicate a novel substrate in the regulation of PPI and reveal a novel functional role for the LC. Hence, a hyperactive LC-NE system might underlie a deficient sensorimotor gating endophenotype in a subset of patients suffering from psychiatric illnesses including schizophrenia, Tourette's syndrome, and PTSD, and the ability to normalize LC-NE transmission could contribute to the clinical efficacy of certain drugs (Cataprese, prazosin, and second-generation antipsychotics) in these conditions.

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Section: Discussionmentioning

confidence: 99%

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Alsene

Bakshi

2011

Neuropsychopharmacol

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“…This phenomenon occurs consistently across species and can be assessed in laboratory mice and rats using similar stimuli (tone presentations) and measuring the startle by placing the animal over a platform that detects its movement. 45,50 This test has been receiving wider attention due to its face validity. Nonetheless, it requires a more expensive apparatus (the startle box) and one must control for drug effects on the startle response itself.…”

Section: Disruption Of the Prepulse Inhibition Of The Startle Responsementioning

confidence: 99%

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Gobira

Röpke

Aguiar

et al. 2013

Rev. Bras. Psiquiatr.

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The use of antipsychotic drugs represents an important approach for the treatment of schizophrenia. However, their efficacy is limited to certain symptoms of this disorder, and they induce serious side effects. As a result, there is a strong demand for the development of new drugs, which depends on reliable animal models for pharmacological characterization. The present review discusses the face, construct, and predictive validity of classical animal models for studying the efficacy and side effects of compounds for the treatment of schizophrenia. These models are based on the properties of antipsychotics to impair the conditioned avoidance response and reverse certain behavioral changes induced by psychotomimetic drugs, such as stereotypies, hyperlocomotion, and deficit in prepulse inhibition of the startle response. Other tests, which are not specific to schizophrenia, may predict drug effects on negative and cognitive symptoms, such as deficits in social interaction and memory impairment. Regarding motor side effects, the catalepsy test predicts the liability of a drug to induce Parkinson-like syndrome, whereas vacuous chewing movements predict the liability to induce dyskinesia after chronic treatment. Despite certain limitations, these models may contribute to the development of more safe and efficacious antipsychotic drugs.

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“…PPI is the reduction of the startle response, which occurs when a weak sensory stimulus (prepulse) is presented several hundred milliseconds before a sudden intense stimulus (pulse) (Ison and Hammond, 1971;Swerdlow et al, 2001;Fendt et al, 2001;Yeomans et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABAB Receptor Agonist Baclofen

Arai

Takuma

Mizoguchi

et al. 2008

Neuropsychopharmacol

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We have previously demonstrated that pallidotegmental GABAergic neurons play a crucial role in prepulse inhibition (PPI) of the startle reflex in mice through the activation of GABA B receptors in pedunculopontine tegmental neurons. In this study, we investigated whether PPI disruption induced by methamphetamine (METH) or MK-801 is associated with the dysfunction of pallidotegmental neurons. Furthermore, we examined the effects of baclofen, a GABA B receptor agonist, on METH-and MK-801-induced PPI impairment. Acute treatment with METH (3 mg/kg, subcutaneouly (s.c.)) and MK-801 (40.3 mg/kg, s.c.) significantly disrupted PPI, accompanied by the suppression of c-Fos expression in lateral globus pallidus induced by PPI. Furthermore, acute treatment with METH and MK-801 stimulated c-Fos expression in the caudal pontine reticular nucleus (PnC) in mice subjected to the PPT test, although PPI alone had no effect on c-Fos expression. Repeated treatment with 1 mg/kg METH for 7 days, which did not affect PPI acutely, showed similar effects on PPI and c-Fos expression to acute treatment with METH (3 mg/kg). Baclofen dose-dependently ameliorated PPI impairment induced by acute treatment with METH (3 mg/kg) and MK-801 (1 mg/kg), and decreased METH-and MK-801-stimulated c-Fos expression in PnC to the basal level. These results suggest that dysfunction of pallidotegmental neurons is involved in PPI disruption caused by METH and MK-801 in mice. GABA B receptor may constitute a putative target in treating neuropsychiatric disorders with sensorimotor gating deficits, such as schizophrenia and METH psychosis.

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Brain stem circuits mediating prepulse inhibition of the startle reflex

Abstract: PPI is mediated by a circuit involving the IC, SC, PPTg, LDTg, SNR and PnC. By reducing startle, PPI allows the execution of approach responses and perceptual processing following salient stimuli.

Cited by 354 publications

References 106 publications

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

Animal models for predicting the efficacy and side effects of antipsychotic drugs

Involvement of Pallidotegmental Neurons in Methamphetamine- and MK-801-Induced Impairment of Prepulse Inhibition of the Acoustic Startle Reflex in Mice: Reversal by GABAB Receptor Agonist Baclofen

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