D1 and D2 dopamine receptor antagonists reverse prepulse inhibition deficits in an animal model of schizophrenia

Hoffman, Diane C.; Donovan, Hilary

doi:10.1007/bf02245567

Cited by 69 publications

(35 citation statements)

References 22 publications

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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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“…These findings were unexpected because there are several lines of evidence indicating that the D2 receptor subtype modulates PPI in both rats and mice. In rats, other D2-family agonists such as bromocriptine and ropinirole also disrupt PPI , while apomorphine-induced reductions in PPI can be reversed using selective D2-family receptor antagonists such as raclopride, spiperone, and eticlopride (Hoffman and Donovan, 1994;Swerdlow et al, 1991). We have previously reported that the indirect DA agonist amphetamine fails to reduce PPI in DA D2 receptor knockout mice, despite being effective in wild-type mice and in both DA D3 and D4 knockout mice (Ralph et al, 1999).…”

Section: D1 Agonists Disrupt Ppi In Mice Rj Ralph-williams Et Almentioning

confidence: 99%

Dopamine D1 Rather than D2 Receptor Agonists Disrupt Prepulse Inhibition of Startle in Mice

Ralph-Williams

Lehmann-Masten

Geyer

2003

Neuropsychopharmacol

102

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Although substantial literature describes the modulation of prepulse inhibition (PPI) by dopamine (DA) in rats, few reports address the effects of dopaminergic manipulations on PPI in mice. We characterized the effects of subtype-specific DA agonists in the PPI paradigm to further delineate the specific influences of each DA receptor subtype on sensorimotor gating in mice. The mixed D1/D2 agonist apomorphine and the preferential D1-family agonists SKF82958 and dihydrexidine significantly disrupted PPI, with differing or no effects on startle. In contrast to findings in rats, the D2/D3 agonist quinpirole reduced startle but had no effect on PPI. Pergolide, which has affinity for D2/D3 and D1-like receptors, reduced both startle and PPI, but only at the higher, nonspecific doses. In addition, the D1-family receptor antagonist SCH23390 blocked the PPI-disruptive effects of apomorphine on PPI, but the D2-family receptor antagonist raclopride failed to alter the disruptive effect of apomorphine. These studies reveal potential species differences in the DA receptor modulation of PPI between rats and mice, where D1-family receptors may play a more prominent and independent role in the modulation of PPI in mice than in rats. Nevertheless, due to the limited selectivity of DA receptor agonists, further studies using specific receptor knockout mice are warranted to clarify the respective roles of specific DA receptor subtypes in modulating PPI in mice.

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“…Direct pharmacological injections and lesion studies indicate that structures contributing to prepulse inhibition include the nucleus accumbens (Wan and Swerdlow 1993;Wan et al 1994), hippocampus (Caine et al 1992;Koch 1996), amygdala (Decker et al 1995), medial prefrontal cortex Koch and Bubser 1994), pedunculopontine tegmental nucleus (Koch et al 1993;Swerdlow and Geyer 1993), ventral and caudodorsal striatum Swerdlow 1994, 1995a), median and dorsal raphe nucleus (Sipes and Geyer 1995b), and the superior colliculus (Fendt et al 1994). Neurotransmitters affecting prepulse inhibition include dopamine (Mansbach et al 1988;Hoffman and Donovan 1994;Caine et al 1995), acetylcholine (Koch et al 1993;Stevens et al 1993b;Wu et al 1993;Curzon et al 1994), serotonin Geyer 1994, 1995a, b;Varty and Higgins 1995), glutamate (Hoffman et al 1993;Reijmers et al 1995), GABA (Kodsi and Swerdlow 1995b) and norepinephrine (Stevens et al 1993a).…”

Section: Introductionmentioning

confidence: 99%

Inbred strain differences in prepulse inhibition of the mouse startle response

Paylor¹,

Crawley²

1997

Psychopharmacology

358

250

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Prepulse inhibition is the phenomenon in which a weak prepulse stimulus suppresses the response to a startling stimulus. Patients with schizophrenia have impaired prepulse inhibition which is thought to reflect dysfunctional sensorimotor gating mechanisms. To investigate the potential genetic basis for differences in sensorimotor gating, the responses of 13 inbred strains of mice were evaluated using the prepulse inhibition paradigm. Ten male mice from A/J, AKR/J, BALB/cByJ, BUB/BnJ, C3H/HeJ, C57BL/6J, C57BL/10J, DBA/2J, FVB/NJ, ST/bJ, 129/J, 129/SvJ, 129/SvEvTac inbred strains were tested for acoustic prepulse inhibition of acoustic and tactile startle responses. There was a wide range of responses among the inbred strains of mice. Exact strain distributions were determined for each combination of prepulse sound level and startle stimulus. In general, mice from the 129/SvEvTac, AKR/J, 129/J, and 129/SvJ strains displayed high levels of prepulse inhibition of both the acoustic and tactile startle responses. C57BL/6J, C57BL/10J and BUB/BnJ mice showed low levels of prepulse inhibition. There was also a wide range in the amplitude of the acoustic and tactile startle responses. C57BL/10J and FVB/NJ mice displayed the greatest startle responses and DBA/2J, 129/J and 129/SvJ had the poorest startle responses. There was no correlation between the level of prepulse inhibition and the amplitude of the startle response. These findings indicate that inbred strains of mice may be a useful tool to study the genetic basis of sensorimotor gating.

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D1 and D2 dopamine receptor antagonists reverse prepulse inhibition deficits in an animal model of schizophrenia

Cited by 69 publications

References 22 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

Dopamine D1 Rather than D2 Receptor Agonists Disrupt Prepulse Inhibition of Startle in Mice

Inbred strain differences in prepulse inhibition of the mouse startle response

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