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Rationale: 22q11 deletion syndrome (22q11DS) is associated with an increased risk for psychotic disorders, suggesting a relationship between genotypes and the pathophysiology of psychotic disorders. Two genes in the deleted region, catechol-O-methyl-transferase (COMT) and proline dehydrogenase (oxidase) 1 (PRODH), contain polymorphisms associated with neuropsychiatric phenotypes., Objectives: Here, we explored the association between polymorphisms and full-scale intelligence (FSIQ), startle reactivity (SR) and prepulse inhibition (PPI) in adults with 22q11DS., Methods: Forty-five adults with 22q11DS were genotyped for PRODH rs450046, rs372055 and COMT Val(158)Met. Plasma proline levels, FSIQ, SR and PPI were measured., Results: Thirty-five percent of the subjects were hyperprolinemic with a median proline value of 456 μmol/L. C allele carriers of PRODH rs450046 had a lower FSIQ compared to T allele carriers, indicating the C allele to be a risk allele (C allele: mean FSIQ 60.2 (sd 8.7); T allele: mean FSIQ 73.7 (sd 11.5); F 1,43 = 7.59; p = 0.009; partial η (2) = 0.15). A significant interaction effect of proline levels and COMT Val(158)Met genotype was found for SR (F 1,16 = 7.9; p = 0.01; partial η (2) = 0.33), but not for PPI and FSIQ. In subjects with hyperprolinemia, the COMT Val(158)Met genotype effect on SR was stronger than in subjects with normal proline levels., Conclusions: Overall, these data provide further evidence for the risk effect of elevated proline levels combined with the COMT Met allele and support the possibilities of using 22q11DS as a model to investigate genotype effects on psychiatric disorders.

Rationale/objectives: The pathogenetic mechanism of emotion-related disorders such as anxiety disorders is considered to be complex with an interaction of genetic, biochemical, and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic system-partly conferred by catechol-O-methyltransferase (COMT) gene variation-and for distorted emotional processing to constitute risk factors for anxiety and anxiety-related disorders., Methods: Applying a multilevel approach, we analyzed the main and interactive effects of the functional COMT val158met polymorphism and L-dopa (single-dose 50 mg levodopa and 12.5 mg carbidopa; double-blind, placebo-controlled design) on the emotion-potentiated (unpleasant, neutral, and pleasant IAPS pictures) startle response as an intermediate phenotype of anxiety in a sample of 100 healthy probands (f = 52, m = 48)., Results: The COMT 158val allele was associated with an increased startle potentiation by unpleasant stimuli as compared with neutral stimuli irrespective of L-dopa or placebo intervention. COMT 158met/met genotype carriers, while displaying no difference in startle magnitude in response to unpleasant or neutral pictures in the placebo condition, showed startle potentiation by unpleasant pictures under L-dopa administration only., Conclusions: The present proof-of-concept study provides preliminary support for a complex, multilevel impact of the dopaminergic system on the emotion-potentiated startle reflex suggesting increased phasic dopamine transmission driven by the more active COMT 158val allele and/or a single dose of L-dopa to predispose to maladaptive emotional processing and thereby potentially also to anxiety-related psychopathological states.

Rationale: Prepulse inhibition (PPI) of the acoustic startle response, a measure of sensorimotor gating, can be enhanced by nicotine. Moreover, the TT genotype of the nicotinic acetylcholine receptor (nAChR) α3-subunit (CHRNA3) rs1051730 polymorphism has previously been associated with diminished PPI and nicotine dependence., Objectives: We tested whether this CHRNA3 polymorphism also modulates the nicotine-induced enhancement of PPI., Methods: We assessed the effect of nicotine on PPI, startle reactivity, and habituation in 52 healthy nonsmoking volunteers genotyped for CHRNA3 rs1051730 in a double-blind, placebo-controlled, counterbalanced, within-subjects design. Additionally, cotinine plasma levels were measured., Results: Nicotine significantly enhanced PPI in TT homozygotes only and tended to worsen PPI in TC and CC carriers. Additionally, nicotine significantly reduced startle habituation., Conclusions: The present findings imply that the effect of nicotine on sensorimotor gating is modulated by nAChR α3-subunits. Thus, genetic variation in nicotinic receptor genes might be an important connecting link between early attentional processes and smoking behavior.

Rationale: A number of studies have associated reduced Akt1 expression with vulnerability for schizophrenia. Although mice with deletion of a single copy of the Akt1 gene (Akt1(+/-)) show reduced Akt1 expression relative to wild-type (WT) animals, the extent to which these mice show schizophrenia-like phenotypic changes and/or increased susceptibility to epigenetic or non-genetic factors related to schizophrenia is unknown., Objectives: Mutant mice were assessed on electroencephalographic/event-related potential (EEG/ERP) and behavioral (acoustic startle and pre-pulse inhibition) measures relevant to schizophrenia. Mice were also assessed following exposure to the NMDA receptor antagonist ketamine, a potent psychotomimetic drug, in order to assess the role of reduced Akt1 expression as a vulnerability factor for schizophrenia. Methods Akt1(+/-), Akt1(-/-), and WT mice received a series of paired-click, white noise stimuli, following ketamine (50 mg/kg) and saline injections. EEG was analyzed for ERPs and event-related power. Akt1(+/-) and WT mice were also assessed on PPI following ketamine (50 mg/kg) or saline injection., Results: Akt1(+/-) and Akt1(-/-) mice displayed reduced amplitude of the P20 component of the ERP to the first click of a paired-click stimulus, as well as reduced S1-S2 difference for P20 and N40 components, following ketamine. Mutant mice also showed increased reduction in gamma synchrony and theta suppression following ketamine. Akt1(+/-) mice displayed reduced pre-pulse inhibition., Conclusions: Reduced genetic expression of Akt1 facilitated ketamine-induced changes of EEG and behavior in mice, suggesting that reduced Akt1 expression can serve as a vulnerability factor for schizophrenia.

Rationale: Differences in sensitivity to the prepulse inhibition (PPI)-disruptive effects of D2-family agonists in Sprague-Dawley (SD) vs. Long Evans (LE) rats are heritable, reflect differential activation of DA signaling in the nucleus accumbens (NAC), and are associated with differences in expression of specific NAC genes. These differences may inform us about the biology of PPI deficits in disorders such as schizophrenia., Objectives: After confirming these strain-based PPI differences, we measured expression of four genes in NAC and other regions that regulate PPI: medial prefrontal cortex and ventral hippocampus (VH)., Methods: Startle and PPI were assessed in SD and LE rats administered D-amphetamine (0 vs. 4.5 mg/kg, sc). Two weeks later, brain tissue was processed for comt, nrg1, grid2, and csnk1e expression; blood comt expression was also tested., Results: Data confirmed expected PPI phenotypes. Gene expression levels differed across strains, sexes, and brain regions, with LE > SD expression in most genes and regions, and female > male expression for all NAC genes. Within any brain region, expression of the four genes was highly inter-correlated; across regions, correlations were less robust, reflecting distinct strain- or sex-based subgroups. PPI amphetamine sensitivity at 120 ms correlated significantly with NAC nrg1 expression, while amphetamine sensitivity for 30 ms PPI and startle magnitude correlated significantly with VH nrg1 and blood comt expression., Conclusions: Rat strains differing in a schizophrenia-linked phenotype also differ in expression levels of genes associated both with that phenotype, and with schizophrenia, within brain regions associated with that phenotype and schizophrenia.

Rationale: Heavy cannabis use is linked with an increased risk for schizophrenia. We showed previously that male heterozygous neuregulin 1 transmembrane domain (Nrg1 HET) mice are more sensitive to some effects of the psychotropic cannabis constituent Delta(9)-tetrahydrocannabinol (THC). We report data from a follow-up study in female Nrg1 HET mice, investigating THC effects on behaviours with some relevance to schizophrenia., Methods: Mice were injected with THC (0, 5 or 10 mg/kg i.p.) 30 min before a test battery: open field, elevated plus maze, novel object recognition (set 1) or light-dark, social interaction (SI) and prepulse inhibition (PPI 1: variable interstimulus interval (ISI); set 2). Another set (set 3) was injected with the same doses of THC before a fixed interstimulus interval PPI test (PPI 2)., Results: Female Nrg1 HETs displayed the hallmark increased locomotor activity at 5 months and anxiolytic-like behaviour in the open field at 3 and 5 months. THC decreased locomotor activity in both genotypes. THC selectively reduced some SI behaviours in WT mice. Baseline PPI was enhanced in mutants under a variable ISI, while THC had no effect on PPI using either protocol., Conclusions: This study reports novel findings on the baseline PPI profile and resistance to THC-induced social withdrawal in female Nrg1 HET mice. This is the first description of THC effects in females of this mouse model and suggests that the transmembrane domain Nrg1 mutation does not appear to have a severe impact on the behavioural sensitivity to THC in female mice.

Introduction: Under specific conditions, a weak lead stimulus, or "prepulse", can inhibit the startling effects of a subsequent intense abrupt stimulus. This startle-inhibiting effect of the prepulse, termed "prepulse inhibition" (PPI), is widely used in translational models to understand the biology of brainbased inhibitory mechanisms and their deficiency in neuropsychiatric disorders. In 1981, four published reports with "prepulse inhibition" as an index term were listed on Medline; over the past 5 years, new published Medline reports with "prepulse inhibition" as an index term have appeared at a rate exceeding once every 2.7 days (n=678). Most of these reports focus on the use of PPI in translational models of impaired sensorimotor gating in schizophrenia. This rapid expansion and broad application of PPI as a tool for understanding schizophrenia has, at times, outpaced critical thinking and falsifiable hypotheses about the relative strengths vs. limitations of this measure., Objectives: This review enumerates the realistic expectations for PPI in translational models for schizophrenia research, and provides cautionary notes for the future applications of this important research tool., Conclusion: In humans, PPI is not "diagnostic"; levels of PPI do not predict clinical course, specific symptoms, or individual medication responses. In preclinical studies, PPI is valuable for evaluating models or model organisms relevant to schizophrenia, "mapping" neural substrates of deficient PPI in schizophrenia, and advancing the discovery and development of novel therapeutics. Across species, PPI is a reliable, robust quantitative phenotype that is useful for probing the neurobiology and genetics of gating deficits in schizophrenia.

Rationale: G(z), a member of the G(i) G protein family, is involved in the coupling of dopaminergic and serotonergic receptors. In the present study, we investigated behaviour of mice deficient in the alpha subunit of G(z) and focused on pre-pulse inhibition (PPI) and anxiety-like responses and the role of serotonin-1A (5-HT(1A)) receptors., Materials and Methods: We compared male and female wild-type and knock-out mice on either a C57Bl/6 or Balb/c background. We used automated startle boxes to assess startle and PPI and elevated plus maze to assess anxiety-like behaviours., Results: Balb/c mice showed higher baseline PPI than C57Bl/6 mice, and there was no difference between the genotypes. The 5-HT(1A) receptor agonist, 8-hydroxy-di-propylaminotetralin (8-OH-DPAT), had no effect on PPI in C57Bl/6 mice but markedly increased PPI in Balb/c mice, with the effect being attenuated in Galpha(z) knock-outs. On the elevated plus maze, there was little effect of the knock-out or 8-OH-DPAT in C57Bl/6 mice, whereas in Balb/c mice, Galpha(z) knock-outs showed a phenotype of high levels of anxiety-like behaviour. 8-OH-DPAT was anxiogenic in Balb/c mice, but this effect was attenuated in Galpha(z) knock-outs., Conclusions: 5-HT(1A) receptors couple to G(z). In a strictly background strain-dependent manner, Galpha(z) knock-out mice display high levels of anxiety-like behaviour and are less sensitive to the action of 8-OH-DPAT. Balb/c mice show much more clear effects of the Galpha(z) knock-out than C57Bl/6 mice, which are often considered the standard background strain for genetic modifications. Therefore, our results suggest caution when studying the behavioural effects of genetic modifications only in C57Bl/6 mice.

Rationale: Emerging evidence from agonist-antagonist studies suggests a role for the dopamine D(3) receptor subtype in the regulation of PPI in animals, but such evidence is lacking for human subjects., Objectives: This study examines the effect of the preferential D(3) agonist ropinirole on PPI in humans., Methods: PPI was tested in 12 healthy men in three sessions associated with ropinirole 0.25 mg, ropinirole 0.5 mg, or placebo according to a balanced, crossover, double-blind design. Two prepulses (75- and 85-dB white noise bursts) and two lead intervals (50 and 80 ms) were employed., Results: Ropinirole 0.5 mg significantly reduced prepulse inhibition (PPI) with both prepulses at the 80-ms lead intervals. There was no effect of treatment on startle amplitude and habituation., Conclusions: These results suggest a role for the dopamine D(3) receptor in the mediation of human PPI, although a contribution from ropinirole's agonistic activity at the D(2) receptor cannot be entirely excluded. Firm conclusions on the role of the D(3) receptor in the modulation of human PPI can only be drawn with the use of genetic approaches or more selective ligands for this receptor.

Rationale: Reduced N-methyl D-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle., Objectives: The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1-/-) mice would be affected by antipsychotic drug treatment., Methods: Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli., Results: Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1-/- mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1-/- or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice., Conclusions: The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.

Rationale: The phenotype of genetically modified animals is thought to result from an interaction of gene manipulation with the genetic background and environmental factors., Objectives: To test the behavioral and drug responses of Penk1(-/-) mice on different genetic backgrounds., Methods: Congenic C57BL/6J and DBA/2J mouse strains with a targeted deletion of the Penk1 gene were generated. Behavior and drug effects were tested in models of pain and anxiety., Results: Penk1(-/-) mice showed exaggerated responses to painful or threatening environmental stimuli, but the expressivity of the mutant phenotype was strongly dependent on the behavioral paradigm and on the genetic background. For example, elevated levels of anxiety were readily detectable in C57BL/6J-Penk1(-/-) mice in the light-dark and startle response tests, but not in the social interaction test. In contrast, we found elevated levels of anxiety in DBA/2J-Penk1(-/-) mice only in the zero-maze and social interaction tests. In some cases, the idiosyncratic behavior masked the appearance of the knockout gene effect. The activity of the anxiogenic drug, m-chlorophenylpiperazine, but not the anxiolytic drug diazepam, was strain and genotype dependent. Mice with the Penk1 mutation on the DBA/2J, but not on other genetic backgrounds, showed an increased opioid-dependent stress-induced analgesia., Conclusions: (1) The behavioral effects of the Penk1 gene deletion persists on different genetic backgrounds, but its detection sometimes requires the use of different behavioral paradigms. (2) The behavior of the background strain should be considered in the analysis of knockout mice to avoid floor and ceiling effects, which may mask the phenotype.

Rationale and Objectives: The disruption of prepulse inhibition (PPI) of startle in rats by dopamine agonists has been used in a predictive model for antipsychotics, and more recently, to study the neural basis of strain differences in dopaminergic function. We have previously reported that Sprague-Dawley (SDH) and Long Evans (LEH) rats differed in their sensitivity to the PPI-disruptive effects of the D(1)/D(2) agonist apomorphine (APO) in two distinct ways: 1) compared to LEH rats, SDH rats were more sensitive to the ability of APO to disrupt PPI with relatively long prepulse intervals (60-120 ms), and 2) APO enhanced PPI in LEH rats with 10-30 ms prepulse intervals, but this effect was limited to 10 ms prepulse intervals in SDH rats., Methods: In the present study, we replicated this temporal profile in SDH versus LEH rats, assessed the role of D(1) versus D(2) substrates in the two components of this strain difference, and assessed the heritability of these temporally distinct processes., Results: Pharmacologic studies revealed that: 1) D(2) blockade prevented the long interval PPI-disruptive effects of APO in both strains, and extended the temporal range of the PPI-enhancing effects of APO from 10 to 30 ms in SDH rats, and 2) D(1) blockade increased PPI and blocked the PPI-enhancing effects of APO at short intervals in both strains. Generational studies in adult F0 (SDH and LEH), F1 (SDHxLEH) and N2 (SDHxF1) rats demonstrated that sensitivity to APO of both short and long interval PPI were inherited in a manner suggestive of relatively simple additive effects of multiple genes., Conclusions: The present findings demonstrate that inherited differences in the dopaminergic regulation of sensorimotor gating are manifested not only in quantitative shifts (more versus less), but also in qualitative shifts in the temporal properties of sensorimotor gating that appear to be under separate control of D(1) and D(2) substrates.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of DA agonists may provide insight into the basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI disruptive effects of the D(1)/D(2) agonist apomorphine in Harlan Sprague-Dawley (SDH) versus Long Evans (LEH) rats. In the present study, we assessed the generational pattern of this phenotypic difference across parental SDH and LEH strains under in- and cross-fostering conditions, offspring (F1) of an SDHxLEH cross, and subsequent offspring (N2) of an SDHxF1 cross. Apomorphine sensitivity followed a gradient across generations that suggested relatively simple additive effects of multiple genes. Cross fostering studies confirmed that SDH>LEH apomorphine sensitivity did not reflect post-natal maternal influences. Generational patterns of PPI apomorphine sensitivity were not associated with albino versus hooded phenotypes per se, but apomorphine sensitivity in hooded N2 rats was strongly related to body surface area of fur pigmentation. The association between pigmentation and PPI apomorphine sensitivity may provide an important clue to specific biochemical and genetic substrates responsible for population differences in the regulation of sensorimotor gating.

Rationale: Glutamate signalling through the N-methyl-D-aspartate (NMDA) receptor is of critical importance for normal central nervous system (CNS) function, as indicated by the marked behavioural disturbances produced by non-subtype selective NMDA antagonists such as dizocilpine (MK-801)., Objective: The present studies were designed to investigate the involvement of the two major NMDA receptor subunits in the central nervous system, i.e. NR2A and NR2B, on sensorimotor gating in mice., Methods: These experiments utilised the non-subtype-selective NMDA antagonist dizocilpine, a line of NR2A-KO mice and the selective NR2B antagonist Ro 63-1908, in the study of pre-pulse inhibition of the startle response (PPI)., Results: The non-selective NMDA receptor antagonist dizocilpine (0.1-1 mg/kg, IP) robustly disrupted PPI in wild-type mice. Conversely, selective genetic or pharmacological inhibition of either the NMDA NR2A or NR2B receptor subunit containing receptors, respectively, had no effect on PPI. Thus, NR2A KO mice showed normal PPI compared with wild-type littermate controls, and administration of Ro 63-1908 (1-10 mg/kg IP) to wild-type mice did not affect PPI. However, selective inhibition of NR2A and NR2B by administration of Ro 63-1908 to NR2A KO mice significantly disrupted PPI., Conclusions: These data imply that concomitant inhibition of both NR2A and NR2B subunit-containing NMDA receptors is necessary to disrupt PPI, suggesting that inhibition of NR2A and NR2B-containing NMDA receptors is required to elicit behaviours suggestive of psychomimetic effects in man.

Rationale: Schizophrenia is a heterogeneous syndrome both at the etiological and clinical levels. In particular, patients with schizophrenia exhibit important variability in their therapeutic and metabolic responses to clozapine, an antipsychotic medication., Objective: Here, we determine whether two mouse strains show differing clozapine responses with respect to weight gain, enhancement of prepulse inhibition of acoustic startle, and reversal of amphetamine-induced locomotion. Observed between-strain differences may be partly due to genetic factors that can be subsequently mapped using quantitative genetic approaches., Methods: We treated the A/J and C57BL/6J inbred mouse strains with clozapine for 22 days. Prepulse inhibition and amphetamine-induced locomotion were measured after 3-4 days of clozapine treatment and again after 21-22 days of treatment. Weight gain was also monitored during treatment. RESULTS. Three-day treatment with clozapine increased prepulse inhibition in both strains. Four-day clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain. Long-term (21-22 days) clozapine treatment did not affect these behaviors in either strain. After an initial weight loss during the first 5 days, clozapine (4 mg/kg) induced a significant weight gain in both strains., Conclusions: The reversal of schizophrenia-related behaviors after short-term, but not long-term, clozapine treatment is consistent with other rodent studies. Although short-term clozapine treatment reduced amphetamine-induced locomotion only in the C57BL/6J strain, strain differences in amphetamine responses confound the interpretation of these results; therefore, quantitative genetic approaches may be difficult to carry out with this trait. In contrast, enhancement of prepulse inhibition after three days of clozapine treatment and weight gain induced by clozapine are relatively straightforward to quantify, making these trait more amenable to quantitative genetic approaches.

Introduction: Schizophrenia is a common and debilitating psychiatric disorder that is partially under genetic control. Because of difficulties in mapping the genes that influence susceptibility to schizophrenia in humans, there has been substantial interest in mapping genes that control endophenotypes for schizophrenia in both human and rodent populations. Deficient prepulse inhibition (PPI) of the startle response has shown promise as an endophenotype for schizophrenia, as well as several other psychiatric disorders., Methods: Brown Norway (BN/SsNHsd) and Wistar Kyoto (WKY/lj-cr) rats were used because they show a large, unconfounded difference in PPI. We used interval mapping methods to identify quantitative trait loci (QTL) for PPI in a backcross population., Results: We identified a QTL on chromosome 2 with a LOD score of 3.63 and a suggestive QTL on chromosome 18 with a LOD score of 2.71., Conclusions: Both of the identified regions contain several candidate genes. Furthermore, the implicated rat chromosomes are syntenic with human chromosomal regions that have been reported to contain QTL for schizophrenia, bipolar disorder, and Tourette's syndrome. These results identify the chromosomal location of gene(s) that modulate an endophenotype for schizophrenia, and other psychiatric disorders, and may provide a shortcut to identifying specific genes and/or biochemical pathways involved in human psychiatric diseases.

Rationale: A number of previous studies have reported that the Maudsley reactive (MR/Har) and non-reactive (MNRA/Har) strains of rats show behavioural and physiological differences consistent with the hypothesis that these strains differ in emotionality and could therefore be considered a model of trait anxiety in humans., Objectives: We sought to confirm this observation by determining their behaviour in various animal models of conditioned and unconditioned fear., Methods: Both strains were evaluated in the open field (OF), conditioned avoidance (CA), elevated plus maze (EPM) and fear-potentiated startle (FPS) tests. In the OF the behaviour of both strains was consistent with previous results showing that reactive rats had significantly higher levels of defecation and lower levels of activity than the non-reactive rats. However, there were no significant strain differences in CA responses or in the time spent on the open arms of the EPM. In addition, the full benzodiazepine receptor agonist, chlordiazepoxide, induced quantitatively similar effects in both strains of rats. In the FPS test, MNRA/Hars had a higher baseline level of startle and fear potentiation than the MR/Har rats., Conclusions: These data show that the behaviour of MR/Har and MNRA/Har rats in some models of conditioned and unconditioned fear is inconsistent with that predicted by their behaviour in the OF test, suggesting that they are not a model of trait fear.

The acoustic startle response (ASR), prepulse inhibition (PPI) of the ASR and the effects of haloperidol on the ASR and PPI were examined in C57BL/6J (B6) and DBA/2 (D2) inbred mouse strains and their F1 and F2 progeny. The startle stimulus was a 60-ms, 110-dB, 10-kHz tone; the prepulse stimuli were 20-ms, white noise bursts at 56, 68 and 80 dB against a 50-dB background presented 100-ms before the startle pulse. The B6 strain showed modest PPI (25-40%); in contrast, the D2 strain showed on average no PPI and numerous individuals showed prepulse augmentation (PPA). The F2 progeny showed an intermediate PPI; however, the extreme values ranged from 200% PPA to essentially 100% PPI. Haloperidol in dose-dependent fashion, increased PPI in both the B6 and D2 strains; the threshold dose was in the range of 0.1-0.2 mg/kg. Raclopride (0.3 mg/kg), clozapine (2 mg/kg) and risperidone (0.4 mg/kg) also increased PPI in both strains. The effects of haloperidol (0.4 mg/kg) on PPI in 140 F2 progeny were examined. For all prepulse intensities, there were highly significant (r > 0.80) and negative correlations between baseline PPI and the haloperidol-induced change in PPI. Thus, those animals that showed the greatest PPA showed the greatest haloperidol-induced increase in PPI. There was, however, significant variance in the haloperidol response; plots of the regression residuals showed the most and least responsive animals differed by almost 100% in effect on PPI. The F2 progeny were subsequently phenotyped for haloperidol-induced catalepsy. There was no association between the variation in effects on catalepsy and PPI. However, it was observed that those individuals with the poorest baseline PPI were catalepsy non-responsive.

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.