Heritable differences in the effects of amphetamine but not DOI on startle gating in albino and hooded outbred rat strains

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 reported heritable differences in sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine (APO) in Harlan Sprague-Dawley (SDH) and Long-Evans (LEH) rats, offspring (F1) of an SDHxLEH cross, and subsequent offspring (N2) of an SDHxF1 cross. In this study, we assessed the neurochemical specificity of this heritable phenotype across parental SDH and LEH strains, and their F1 and N2 offspring, based on their sensitivity to the PPI-disruptive effects of the indirect DA agonist D-amphetamine (AMPH) and the 5HT2A agonist DOI. AMPH sensitivity followed a gradient of SDH>N2>F1>LEH, consistent with past findings with APO. DOI sensitivity did not differ across strains or generations. These findings demonstrate that the heritable phenotype in this model is not specific to a particular compound (APO), and reflects physiological differences in the DAergic, but not serotonergic, regulation of PPI.     

Sensitivity to drug effects on prepulse inhibition in inbred and outbred rat strains

Genetic differences in the neurochemical regulation of PPI in rats may help clarify the neural basis of inherited PPI differences in neuropsychiatric disorders. We reported and characterized substantial heritable differences in sensitivity to PPI-disruptive effects of DA agonists in outbred Sprague Dawley (SDH) versus Long-Evans (LEH) rats. Other strains might yield large group separations and facilitate studies of the neural basis for these strain differences; inbred strains might also allow us to map genes associated with differential PPI sensitivity. Sensitivity to the PPI-disruptive effects of the DA agonist apomorphine (APO) and the NMDA antagonist phencyclidine (PCP) were compared across inbred and outbred strains. APO sensitivity was greatest in SDH and buffalo rats, but the effect in buffalo rats was complicated by significant APO-induced startle suppression. PPI APO sensitivity was least in ACI and LEH rats; F344s exhibited intermediate sensitivity and Lewis rats showed a nonlinear dose response (sensitivity at low but not higher doses). PPI APO insensitivity in ACI rats developed over time, with ACI pups exhibiting robust sensitivity. Substantial strain differences were observed in short-interval (10-30 ms) prepulse effects, and APO-induced increases in short-interval PPI occurred in SDH, LEH, and Lewis rats, but not in F344, ACI, or buffalo rats. Sensitivity to PPI-disruptive effects of PCP was generally greater in outbred than inbred rats. These findings identify strains suitable for comparisons of PPI neural circuitry and others for whom such comparisons would be complex and perhaps less informative.     

Heritable differences in the dopaminergic regulation of behavior in rats: relationship to D2-like receptor G-protein function.

We reported heritable differences between Sprague-Dawley (SD) and Long Evans (LE) rats in their sensitivity to the disruption of prepulse inhibition of startle (PPI) by dopamine (DA) agonists, and in their basal levels and turnover of forebrain DA. In an effort to better understand these differences, we assessed strain patterns in the efficacy of D2-like receptor-G-protein coupling using [35S]GTPgammaS binding in brain regions that contribute to the dopaminergic regulation of PPI. Sensitivity to the PPI-disruptive effects of apomorphine (APO) was examined in SD, LE, and F1 (SD x LE) rats. Basal and DA-stimulated [35S]GTPgammaS binding were then assessed in these rats using conditions that preferentially exclude Gs proteins to favor visualization of D2-like receptors. To explore the behavioral specificity of these strain differences, locomotor responses to APO and amphetamine (AMPH) were also assessed in SD, LE, and F1 rats. Strain differences were evident in the PPI-disruptive effects of APO (SD>F1>LE), and in the locomotor responses to AMPH (LE>F1>SD) and APO (SD exhibited motor suppression, LE exhibited motor activation). Compared to SD rats, LE rats exhibited greater DA-stimulated [35S]GTPgammaS binding in nucleus accumbens and caudatoputamen, while F1 progeny had intermediate levels. In conclusion, SD and LE rats exhibit heritable differences in D2-mediated behavioral and biochemical measures. Conceivably, genes that regulate heritable differences in forebrain D2 function may contribute to heritable differences in PPI in patients with specific neuropsychiatric disorders, including schizophrenia and Tourette Syndrome.     

Heritable differences in the dopaminergic regulation of sensorimotor gating

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.     

Sensitivity to the dopaminergic regulation of prepulse inhibition in rats: evidence for genetic, but not environmental determinants.

Prepulse inhibition (PPI), a measure of sensorimotor gating, is reduced in schizophrenia patients and in rats treated with dopamine (DA) agonists. Reported strain and supplier-based differences in sensitivity to PPI-disruptive effects of DA agonists presumably reflect the differential impact of genetics and/or environment on DAergic substrates regulating PPI. In 2000, Harlan Laboratories established a Texas Sprague-Dawley line (SDHt; facility 211) using breeders from Indianapolis (SDHi; facility 202A). SDHi rats had been used, approximately 11 years earlier, to establish a colony in San Diego (SDHsd; facility 235). SDHt and SDHi rats are thus genetically similar, but raised in distinct environments; approximately 11 years of genetic "drift" separates SDHsd rats from both SDHi and SDHt rats. Harlan Long-Evans hooded rats (LEH; Madison, WI; facility 207) are genetically distinct from albino SDH. All except SDHsd rats were shipped to our facility by air freight. We used SDHt, SDHi, SDHsd, and LEH rats to assess genetic and environmental contributions to the DAergic regulation of PPI. Acoustic startle/PPI were assessed in rats treated with the D1/D2 agonist apomorphine (APO), the D2 agonist quinpirole, or the D1 agonist SKF 82958. The relative sensitivities to the PPI-disruptive effects were: APO: SDHt=SDHsd=SDHi>LEH; SKF 82958: SDHt=SDHsd=SDHi (LEH not sensitive); quinpirole: SDHt=SDHsd=SDHi; SDHi>LEH. Strain/supplier differences in sensitivity to drug effects on startle magnitude did not correspond to patterns of PPI sensitivity. In these rats, strain differences in the DAergic regulation of PPI are most easily explained by genetic, rather than environmental influences that differentially impact both D1 and D2 substrates. This finding is consistent with published reports in other strains. Pharmacogenetic studies of PPI in rats may identify a genetic basis for a model of deficient sensorimotor gating in schizophrenia.     

Rat strain differences in startle gating-disruptive effects of apomorphine occur with both acoustic and visual prepulses

Prepulse inhibition of startle (PPI) is an operational measure of sensorimotor gating that is impaired in schizophrenia and is disrupted in rats by dopamine (DA) agonists like apomorphine (APO). Using acoustic prepulses and acoustic startle pulses, previous studies have demonstrated heritable strain differences between Sprague Dawley (SD) and Long Evans (LE) rats in the sensitivity to the PPI-disruptive effects of APO. As PPI deficits in schizophrenia are evident with both uni- and cross-modal stimuli, we tested whether strain differences in the gating-disruptive effects of APO occur with a cross-modal visual and acoustic stimulus combination. APO caused a dose-dependent disruption of both acoustic and visual PPI in SD rats. Compared to LE rats, SD rats were more sensitive to the PPI-disruptive effects of APO with both acoustic and visual PPI. These findings suggest that SD vs. LE strain differences in PPI APO sensitivity are mediated outside of the auditory system, within higher circuitry that regulates or processes multi-modal information. The present findings provide further validation for this heritable model of impaired sensorimotor gating in schizophrenia, which can be detected across multiple sensory modalities.     

Heritable differences in the dopaminergic regulation of sensorimotor gating

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 D₁/D₂ 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 SDH×LEH cross, and subsequent offspring (N2) of an SDH×F1 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.     

Sensitivity to sensorimotor gating-disruptive effects of apomorphine in two outbred parental rat strains and their F1 and N2 progeny.

Sensorimotor gating, measured by prepulse inhibition (PPI) of the startle reflex, is reduced in schizophrenia patients and in rats treated with dopamine agonists. Strain and substrain differences in the sensitivity to the PPI-disruptive effects of dopamine agonists may provide insight into the genetic basis for human population differences in sensorimotor gating. We have reported greater sensitivity to the PPI-disruptive effects of the D1/D2 agonist apomorphine in Harlan Sprague-Dawley (SDH) vs Wistar (WH) rats. In the present study, we assessed the inheritance pattern of this phenotypic difference. Sensitivity to the PPI-disruptive effects of apomorphine was compared across parental SDH and WH strains, offspring (F1) of an SDH x WH cross, and subsequent offspring (N2) of an SDH x F1 cross. Apomorphine sensitivity followed a gradient of SDH>N2>F1>WH. Parental SDH and WH strains exhibited comparable sensitivity to the PPI-disruptive effects of phencyclidine. The nature of this gradient of APO sensitivity suggests relatively simple additive effects of multiple genes on the phenotype of PPI sensitivity.     

Neural basis for a heritable phenotype: differences in the effects of apomorphine on startle gating and ventral pallidal GABA efflux in male Sprague–Dawley and Long–Evans rats

Rationale

Prepulse inhibition (PPI) of startle is a measure of sensorimotor gating that is heritable and deficient in certain psychiatric disorders, including schizophrenia. Sprague–Dawley (SD) rats are more sensitive to PPI disruptive effects of dopamine (DA) agonists at long interstimulus intervals (60–120 ms) and less sensitive to their PPI-enhancing effects at short (10–30 ms), compared with Long–Evans (LE) rats. These heritable strain differences in sensitivity to the PPI disruptive effects of DA agonists must ultimately reflect neural changes "downstream" from forebrain DA receptors.

Objective

The current study evaluated the effects of the DA agonist, apomorphine (APO), on ventral pallidal (VP) gamma-aminobutyric acid (GABA) and glutamate efflux and PPI in SD and LE rats.

Methods

PPI was tested in SD and LE rats after vehicle or APO (0.5 mg/kg, subcutaneously (s.c.)) in a within-subject design. In different SD and LE rats, VP dialysate was collected every 10 min for 120 min after vehicle or APO (0.5 mg/kg, s.c.) and analyzed for GABA and glutamate content by capillary electrophoresis (CE) coupled with laser-induced fluorescence (LIF).

Results

As predicted, SD rats exhibited greater APO-induced PPI deficits at long intervals and less APO-induced PPI enhancement at short intervals compared to LE rats. APO significantly reduced VP GABA efflux in SD but not in LE rats; glutamate efflux was unaffected in both strains.

Conclusion

Heritable strain differences in PPI APO sensitivity in SD vs LE rats parallel, and may be mediated by, strain differences in the VP GABA efflux.     

Methamphetamine facilitates ethanol-induced depressions in cerebellar purkinje neurons of prazocin- or DSP4-treated rats

Prepulse inhibition (PPI) is the normal reduction in startle reflex that occurs when a startling stimulus is preceded by a weak prepulse. PPI is reduced in patients with schizophrenia and in rats after central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus model some features of impaired sensorimotor gating in schizophrenia. Ascending DAergic and descending glutamatergic fibers converge within the nucleus accumbens (NAC), and interactions at this DA-glutamate interface have been implicated in the pathophysiology of schizophrenia. In this study, we examined the role of NAC DA-glutamate interactions in the regulation of PPI in rats. Intra-NAC infusion of the non-NMDA antagonist, CNQX, attenuated the PPI-disruptive effects ofd-amphetamine (AMPH), but CNQX did not affect PPI when injected alone, nor did it reverse the PPI-disruptive effects of the direct D₂/D₃ agonist quinpirole. Intra-NAC infusion of the non-NMDA agonist AMPA significantly reduced PPI. The PPI-disruptive effects of AMPA were blocked by haloperidol and by 6-hydroxydopamine (6OHDA) lesions of the NAC. These data suggest that the PPI-disruptive effects of AMPH are dependent on tonic non-NMDA receptor activation in the NAC, and that non-NMDA receptor activation in the NAC results in a DA-dependent reduction in PPI. The parsimonious interpretation of these data is that non-NMDA glutamate receptors in the NAC facilitate presynaptic DA function, and that this DA-glutamate interaction is a critical regulatory substrate of sensorimotor gating.     

Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice.

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.     

Strain differences in the disruption of prepulse inhibition of startle after systemic and intra-accumbens amphetamine administration

BACKGROUND: Sprague Dawley (SD) rats are significantly more sensitive than Long Evans (LE) rats to the disruption of prepulse inhibition (PPI) by systemically-administered dopamine (DA) agonists. This strain difference is heritable and insensitive to cross-fostering. Inherited differences in the ability of elevated DA activity to disrupt PPI may be useful for understanding the neural basis for PPI deficits in schizophrenia and other neuropsychiatric disorders. METHODS: PPI was tested in male SD and LE rats after amphetamine (AMPH) was administered: 1) subcutaneously (sc), or intra-cerebrally (ic) into 2) the nucleus accumbens core (NACc; medial or lateral subregions) or the NAC shell; 3) the anteromedial striatum (AMS) or 4) the posterior striatum (PS). RESULTS: SD and LE rats had comparable PPI levels after sc vehicle injection. PPI was disrupted in SD but not LE rats after sc AMPH injection. LE insensitivity to AMPH was confirmed after sc injection into non-pigmented dermis, demonstrating that it did not reflect melanocyte sequestration of AMPH. PPI was also disrupted in SD rats after ic infusion into the NACc (medial core: p<0.005; lateral core: p<0.001); in LE rats, these effects only approached threshold levels (medial core: p<0.06; lateral core: p<0.051). In SD rats, the highest dose of AMPH (40 microg) tended to reduce PPI after infusion into the AMS or PS, while in LE rats, this dose potentiated PPI after PS infusion. Comparisons of PPI in SD vs. LE rats revealed significant main effects of strain (SD>LE) after vehicle infusions into the NACc subregions and the PS. Comparisons of pre-infusion "matching" data, data from the first infusion day, and data from separate rats in a "mock-infusion" paradigm is consistent with the possibility that SD>LE PPI after ic vehicle infusion reflects the impact of restraint stress on PPI in LE rats. CONCLUSIONS: PPI is disrupted by AMPH administered sc or into the NACc in SD but not LE rats. Reduced PPI after ic vehicle infusion in LE vs. SD rats may reflect greater PPI-reducing effects of restraint stress in LE rats. The differential impact of restraint on PPI in SD vs. LE rats complicates the interpretation of strain differences in the effects of ic manipulations, but may provide an avenue for investigating the basis for differences in vulnerability to the gating-disruptive effects of stress.     

Effects of ovariectomy and estradiol on acoustic startle responses in rats

Long-term (3 months) ovariectomized (OVX) rats were used to model hormone withdrawal as occurring in menopause. We previously reported alterations in brain dopamine (DA), GABA and serotonin receptors following ovariectomy in this model. To assess the functional effect of these biochemical changes, we compared rats that were intact, OVX and OVX-treated with 17beta-estradiol (E(2); OVX+E(2)) for 2 weeks on measures of their acoustic startle responses (ASR) and prepulse inhibition (PPI) of acoustic startle. The effects of a mixed D(1)/D(2) dopaminergic agonist, apomorphine (APO; 0.25, 0.5 and 0.75 mg/kg sc) were tested on ASR and PPI of acoustic startle. Without APO, all groups of rats showed no difference in baseline ASR or PPI of acoustic startle. Following administration of APO (0.25, 0.5 and 0.75 mg/kg), ASR was significantly increased in OVX rats compared to intact rats and this was corrected with E(2) treatment. In all groups of animals, APO decreased PPI of acoustic startle. APO disrupted PPI to a lesser extent in OVX animals with or without E(2) treatment compared to intact rats. However, when group differences in APO-induced ASR were statistically controlled for, there were no longer any differences in APO disruption of PPI among the three treatment groups. These results indicate that long-term ovariectomy has persistent effects on the modulation of ASR, and these effects can be at least partly corrected with E(2) replacement therapy.     

Amphetamine effects on prepulse inhibition across-species: replication and parametric extension.

Despite the similarities of prepulse inhibition (PPI) of the startle reflex and its apparent neural regulation in rodents and humans, it has been difficult to demonstrate cross-species homology in the sensitivity of PPI to pharmacologic challenges. PPI is disrupted in rats by the indirect dopamine (DA) agonist amphetamine, and while studies in humans have suggested similar effects of amphetamine, these effects have been limited to populations characterized by smoking status and specific personality features. In the context of a study assessing the time course of several DA agonist effects on physiological variables, we failed to detect PPI-disruptive effects of amphetamine in a small group of normal males. The present study was designed to reexamine this issue, using a larger sample and a paradigm that should be more sensitive for detecting drug effects. PPI in rats was shown to be disrupted by the highest dose of amphetamine (3.0 mg/kg) at relatively longer prepulse intervals (>30 ms). In humans, between-subject comparisons of placebo (n=15) vs 20 mg amphetamine (n=15) failed to detect significant PPI-disruptive effects of amphetamine, but significant PPI-disruptive effects at short (10-20 ms) prepulse intervals were detected using within-subject analyses of postdrug PPI levels relative to each subject's baseline PPI. Post hoc comparisons failed to detect greater sensitivity to amphetamine among subjects characterized by different personality and physiological traits. Bioactivity of amphetamine was verified by autonomic and subjective changes. These results provide modest support for cross-species homology in the PPI-disruptive effects of amphetamine, but suggest that these effects in humans at the present dose are subtle and may be best detected using within-subject designs and specific stimulus characteristics.     

A novel rat strain with enhanced sensitivity to the effects of dopamine agonists on startle gating

BACKGROUND: Compared to outbred Sprague Dawley (SD) rats, inbred Brown Norway (BN) rats exhibit less prepulse inhibition of startle (PPI) at long prepulse intervals, and more PPI at short intervals. Sensitivity to dopaminergic drug effects on PPI differs substantially across strains, and is heritable within SD and other outbred strains. To further understand the heritability of PPI and its sensitivity to dopamine agonists, we assessed PPI and apomorphine sensitivity in SD, BN and F1 (SD x BN) rats. METHODS: PPI was measured in BN, SD and F1 rats under a variety of stimulus conditions, and after treatment with apomorphine. RESULTS: Findings confirmed significantly more PPI in BN compared to SD rats at short prepulse intervals, and significantly more PPI in SD compared to BN rats at long intervals. F1s were "supersensitive" to both the PPI-disruptive effects of apomorphine at longer intervals, and the PPI-enhancing effects of apomorphine at shorter intervals, compared to either parental strain. CONCLUSION: Differences in sensorimotor gating between SD and BN rats are robust, time-locked and consistent across studies. Unlike patterns in other strains, heritability of PPI apomorphine sensitivity phenotypes in SD x BN F1s cannot be easily explained by simple additive effects.     

Probing the molecular basis for an inherited sensitivity to the startle-gating disruptive effects of apomorphine in rats

Background  

Prepulse inhibition of acoustic startle (PPI) is deficient in several heritable brain disorders. In rats, the dopamine agonist, apomorphine (APO), reduces PPI and expression of the early gene, c-fos, within the nucleus accumbens (NAC) core. Both of these effects are greater in Sprague–Dawley (SD) vs. Long Evans (LE) rats, and this PPI strain pattern is inherited. Here, we examined phosphorylation of cyclic-AMP response element-binding protein (CREB), a putative intermediary step between dopamine receptor stimulation and Fos expression, in SD and LE rats.     

Typical but not "atypical" antipsychotic effects on startle gating deficits in prepubertal rats

RATIONALE: Dopamine (DA) agonists and NMDA antagonists disrupt sensorimotor gating in rats, as measured by a loss of prepulse inhibition of the startle reflex. These effects are used in predictive models for antipsychotic efficacy: clinically "typical" and "atypical" antipsychotics restore PPI in adult rats treated with DA agonists such as apomorphine (APO), while clinically "atypical" antipsychotics restore PPI in rats treated with NMDA antagonists such as phencyclidine (PCP). We previously reported that the PPI disruptive effects of both APO and PCP are evident in 16- to 18-day-old rat pups, suggesting that the brain substrates for these effects are functional very early in development. OBJECTIVE: In the present study we assessed the developmental patterns of antipsychotic effects in these measures. METHODS: The PPI-disruptive effects of APO and PCP, and their antagonism by the typical antipsychotic haloperidol, and the atypical antipsychotic quetiapine, were assessed across development in Sprague-Dawley rats. RESULTS: Similar to the pattern seen in adults, both haloperidol and quetiapine opposed APO-induced PPI deficits in 16- to 19-day-old rat pups. However, the "atypical" antipsychotic quetiapine did not oppose PCP-induced PPI deficits in pups or prepubertal (45 day) adolescents, but did oppose these PCP effects in postpubertal rats. CONCLUSIONS: While brain substrates mediating the PPI-disruptive effects of DA agonists and NMDA antagonists are functional early in development, some physiological event associated with puberty is a necessary condition for the "atypical antipsychotic profile" in this predictive model.     

Reduced startle gating after D1 blockade: effects of concurrent D2 blockade

BACKGROUND: Prefrontal D1 systems have been implicated in the regulation of working memory and in the pathophysiology of schizophrenia. D1 hypofunction might contribute to reduced sensorimotor gating in schizophrenia patients since D1 activity in the medial prefrontal cortex (MPFC) regulates prepulse inhibition of startle (PPI) in animal models. We studied the neurochemical basis for the D1 regulation of PPI in rats. METHODS: PPI to weak (1-5 dB over background) prepulses was measured after systemic or intra-MPFC administration of the D1 antagonist, SCH 23390, in rats pretreated systemically with the D2 antagonist, haloperidol (vehicle or 0.1 mg/kg). RESULTS: After vehicle pretreatment, systemic and intra-MPFC SCH 23390 disrupted PPI produced by weak prepulses. This effect was not significantly opposed by pretreatment with haloperidol (0.1 mg/kg). In contrast, the PPI-disruptive effects of the DA agonist amphetamine were significantly opposed by this dose of haloperidol. CONCLUSIONS: D1 blockade reduces PPI, but this effect does not appear to be mediated entirely via increased dopamine transmission at D2 receptors.     

Amphetamine-induced enhancement of neostriatal in vivo microdialysate dopamine content in rats, quinpirole-primed as neonates

Amphetamine (AMPH)-induced sensitization of central dopamine (DA) receptors, produced by repeated AMPH treatments, is associated with increased AMPH-induced DA release in the rat forebrain. However, for DA receptor sensitization produced by repeated DA receptor agonist treatments, the effects on forebrain DA release are not known. The objective of our study was to determine this. DA receptor sensitization was produced by administering the DA D2 agonist quinpirole (50 microg/kg/day) to rats, from the 1st to 11th days after birth - a process known as 'priming'. When these rats were tested at 3 months, DA receptor sensitization was manifested as increased quinpirole-induced yawning. We also found that AMPH (1.0 mg/kg, ip) acutely induced a 5-fold greater increase in DA content in the neostriatal in vivo microdialysate of these quinpirole-primed rats (vs. controls), accompanied by a reduction in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in the microdialysate. Conversely, an acute injection of quinpirole x HCl (100 microg/kg, ip) reduced the microdialysate contents of DA, DOPAC and HVA to comparable levels in quinpirole-primed and control rats. Therefore, we can conclude that long-lived DA receptor sensitization, produced by repeated DA D2 agonist treatments in ontogeny, is associated with enhanced AMPH-induced DA release in the neostriatum in adulthood, but is not accompanied by evident alteration in quinpirole-induced DA release.     

"Early" and "late" effects of sustained haloperidol on apomorphine- and phencyclidine-induced sensorimotor gating deficits.

Both dopamine (DA) agonists and NMDA antagonists produce prepulse inhibition (PPI) deficits in rats that model PPI deficits in schizophrenia patients. While DA agonist effects on PPI are reversed by acute treatment with either "typical" high-potency D2 DA antagonists or "atypical" antipsychotics, PPI deficits produced by phencyclidine (PCP) are preferentially reversed by acute treatment with "atypical" antipsychotics. Acute effects of antipsychotics may not accurately model the more clinically relevant effects of these drugs that emerge after several weeks of continuous treatment. In the present study, sustained treatment with haloperidol via subcutaneous minipumps blocked the PPI-disruptive effects of apomorphine and attenuated the PCP-induced disruption of PPI. Restoration of PPI in apomorphine-treated rats was evident within the first week of sustained haloperidol administration. A partial reversal of PCP effects on PPI did not develop until the second week of sustained haloperidol treatment, followed a fluctuating course, but remained significant into the seventh week of sustained haloperidol administration. The delayed emergence of anti-PCP effects of haloperidol suggests that the brain substrates responsible for the DAergic and NMDA regulation of PPI are differentially sensitive to acute and chronic effects of antipsychotics.