Sprague Dawley rats from different vendors vary in the modulation of prepulse inhibition of startle (PPI) by dopamine, acetylcholine, and glutamate drugs.

RATIONALE: Rodent vendors are often utilized interchangeably, assuming that the phenotype of a given strain remains standardized between colonies. Several studies, however, have found significant behavioral and physiological differences between Sprague Dawley (SD) rats from separate vendors. Prepulse inhibition of startle (PPI), a form of sensorimotor gating in which a low-intensity leading stimulus reduces the startle response to a subsequent stimulus, may also vary by vendor. Differences in PPI between rat strains are well known, but divergence between colonies within the SD strain lacks thorough examination. OBJECTIVES: We explored intrastrain variation in PPI by testing SD rats from two vendors: Envigo and Charles River (CR). METHODS: We selected drugs acting on four major neurotransmitter systems that have been repeatedly shown to modulate PPI: dopamine (apomorphine; 0.5, 1.5, 3.0 mg/kg), acetylcholine (scopolamine; 0.1, 0.5, 1.0 mg/kg), glutamate (dizocilpine; 0.5, 1.5, 2.5 mg/kg), and serotonin (2,5-Dimethoxy-4-iodoamphetamine, DOI; 0.25, 0.5, 1.0 mg/kg). We determined PPI and startle amplitude for each drug in male and female Envigo and CR SD rats. RESULTS: SD rats from Envigo showed dose-dependent decreases in PPI after apomorphine, scopolamine, or dizocilpine administration, without significant effects on startle amplitude. SD rats from CR were less sensitive to modulation of PPI and/or more sensitive to modulation of startle amplitude, across the three drugs. CONCLUSIONS: SD rats showed vendor differences in sensitivity to pharmacological modulation of PPI and startle. We encourage researchers to sample rats from separate vendors before experimentation to identify the most suited source of subjects for their specific endpoints.

Effects of D3/D2 dopamine receptor agonists and antagonists on prepulse inhibition of acoustic startle in the rat.

Prepulse inhibition (PPI) is the normal reduction in a startle response that occurs when a weak stimulus ("prepulse") precedes the startling stimulus by 30 to 500 msec. Schizophrenic patients are deficient in this operational measure of sensorimotor gating; therefore, animal models of deficient PPI may provide information useful in the understanding and treatment of schizophrenia. Prepulse inhibition is disrupted in rats by systemic administration of direct dopamine agonists having affinity for the D2 subtype family (D2, D3, and D4) of dopamine receptors. This study tested the hypothesis that dopamine agonists and antagonists with different affinities for D3 and D2 receptors differ in their relative potencies to modulate PPI. The dopamine agonists quinpirole, 7-hydroxy-N,-N-di-n-propyl-2-aminotetralin (7-OH-DPAT) and apomorphine were approximately equipotent in decreasing PPI. Pretreatment with haloperidol (13 to 130 nmol/kg sc), but not equimolar doses of UH 232, prevented the disruption of PPI produced by the highest dose (0.6 mumol/kg sc) of each agonist. Given the 100-fold higher affinity of haloperidol relative to UH 232 for D2 receptors, and equal relative affinities of these antagonists for D3 receptors, these data are consistent with previous studies suggesting that dopamine agonists may modulate PPI in the rat through the D2 subtype of dopamine receptors.

Regionally selective effects of intracerebral dopamine infusion on sensorimotor gating of the startle reflex in rats.

Systemic administration of dopamine (DA) agonists markedly disrupts sensorimotor gating in rats as measured by prepulse inhibition (PPI) of the acoustic startle response. A qualitatively similar, but quantitatively weaker disruption of PPI follows DA infusion into the nucleus accumbens (NAC). The present study was designed to determine whether forebrain DA terminal fields other than the NAC contribute to the DAergic modulation of PPI. PPI was impaired significantly after infusion of DA (0-40 micrograms) into the NAC or anteromedial striatum, but not after DA infusion into the orbital cortex or posterolateral striatum. DA infusion into the amygdala also disrupted PPI, but this disruption was accompanied by a dose-dependent decrease in startle amplitude. These results suggest that DA overactivity in the both NAC and anteromedial striatum contribute to the gating-disruptive effects of systemically administered DA agonists, and that DA overactivity in mesocortical, mesoamygdaloid and "non-limbic" mesostriatal DA systems are not major substrates for a DAergic modulation of PPI.

Carbachol infusion into the dentate gyrus disrupts sensorimotor gating of startle in the rat.

Prepulse inhibition (PPI) is the decrease in a startle response that occurs when the startling stimulus is preceded by a weaker stimulus or "prepulse". Schizophrenic patients exhibit abnormally low levels of PPI when the prepulse precedes the startle stimulus by less than 500 ms. A similar deficit in sensorimotor gating can be demonstrated in rats after stimulation of D2 dopamine (DA) receptors by systemic administration of DA agonists or by infusion of DA directly into the nucleus accumbens. We now demonstrate that carbachol infusion into the dentate gyrus of the hippocampal formation disrupts PPI in the rat. This disruption of sensorimotor gating occurs when the startling stimulus is either acoustic or tactile. Carbachol infusion into the neocortex has no effect on PPI. While pretreatment with the D2 DA receptor antagonist spiperone reverses the disruption of PPI caused by systemic administration of apomorphine, this pretreatment fails to reverse the disruption of PPI induced by carbachol infusion into the hippocampus. These results demonstrate that pharmacologic stimulation of the hippocampus disrupts sensorimotor gating in the rat by a mechanism distinct from that of DA agonists. Prepulse inhibition of the startle reflex is an animal model in which pharmacologic stimulation of the hippocampus mimics the deficits in sensorimotor gating observed in schizophrenic patients.