Intrahippocampal injections of Tat: effects on prepulse inhibition of the auditory startle response in adult male rats

The presence of human immunodeficiency virus (HIV-1) in the brain mediates the pathogenesis of HIV-associated dementia complex (HAD), partially through the viral toxins gp120 and Tat. This study characterized potential deficits in sensorimotor gating, as measured by prepulse inhibition (PPI), following hippocampal administration of Tat. Adult, male Sprague-Dawley rats were bilaterally injected with 50 microg Tat or saline (1 microl volume), into the hippocampus. Following 7 weeks of recovery, all animals were tested using the auditory startle response (ASR) with habituation, control, and PPI trials. Assessment of ASR habituation [100dB(A) white noise stimulus, 70dB(A) background, 5-min acclimation period, 36 habituation trials with fixed interstimulus interval (ISI) of 10 s] demonstrated a significant approximately 50% reduction in the overall peak ASR amplitude, but no change in peak ASR latency, nor an effect on the rate of habituation. PPI measures demonstrated robust alterations in sensorimotor gating. The PPI test (ISI of 0, 8, 40, 80, 120, or 4000 ms, 6-trial blocks, Latin-square) showed an attenuated response on peak ASR amplitude during the control trials (0 and 4000 ms ISI), but not on the PPI trials (8-120 ms ISI). Most striking was the rightward shift in ISI for maximal inhibition of the response (chi2(1)=4.7, p相似文献   

Schizophrenic-like sensorimotor gating abnormalities in rats following dopamine infusion into the nucleus accumbens

Previous studies have demonstrated that several dopamine agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats. Schizophrenic patients also exhibit deficits in PPI when the prepulse preceeds the startle stimulus by less than 500 ms. In experiment 1, dopamine (0–40 µg) infused directly into the nucleus accumbens in rats caused a dose-dependent decrease in PPI at prepulse intervals shorter than 500 ms. In experiment 2, this effect of accumbens dopamine infusions on sensorimotor gating was found to vary with changes in prepulse intensity. These findings strongly suggest that increased mesolimbic dopamine activity is one substrate of the sensorimotor gating deficits in rats that are caused by treatment with dopamine agonists; similar substrates might mediate deficits in PPI exhibited by schizophrenic patients.     

Amphetamine disruption of prepulse inhibition of acoustic startle is reversed by depletion of mesolimbic dopamine

Previous studies have demonstrated that dopamine (DA) agonists disrupt sensorimotor gating as measured by prepulse inhibition (PPI) of the acoustic startle response (ASR) in rats; other reports suggest that this stimulant-induced disruption of PPI may reflect drug-induced increases in ASR amplitude rather than changes in sensorimotor gating. In the current study, 6-hydroxydopamine lesions that depleted dopamine from the nucleus accumbens, olfactory tubercles and anterior striatum reversed the disruption of PPI caused by amphetamine (AMPH), but did not disrupt AMPH potentiation of ASR baseline. These findings strongly suggest that increased mesolimbic DA activity is one substrate of the AMPH-induced disruption of PPI; in contrast, AMPH potentiation of baseline startle amplitude may be independent of mesolimbic DA activation.     

Effects of pergolide on sensorimotor gating of the startle reflex in rats

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders, including schizophrenia. This study was designed to assess the effects of the D2-family agonist pergolide in rats, in anticipation of human studies of the dopaminergic regulation of PPI. METHODS: The effects of pergolide (0.0001-0.5 mg/kg) on PPI of the acoustic startle reflex were studied in rats using a wide range of prepulse intensities [1-15 dB(A) over background] and prepulse intervals (5-100 ms, onset to onset). Studies also examined the effects of the D2 antagonist haloperidol on pergolide-induced changes in PPI. RESULTS: Pergolide exhibited dose- and stimulus-dependent effects on PPI. Pergolide increased PPI when startle stimuli were preceded by weak prepulses [1-5 dB(A) over background] at the longest prepulse interval (100 ms), or intense prepulses [15 dB(A) over background] at short prepulse intervals (5-20 ms). Pergolide (0.5 mg/kg) also decreased PPI elicited by intense prepulses at long intervals (60-100 ms). Both PPI-enhancing and PPI-disruptive effects of pergolide were reversed by the D2 antagonist haloperidol. CONCLUSIONS: These effects of pergolide suggest that D2 substrates mediate opposing influences on PPI under different stimulus conditions. The dopaminergic regulation of sensorimotor gating appears to interact with stimulus characteristics such as relative intensity and temporal separation, allowing for dynamic shifts in both the quantity and quality of "gated" information.     

Effects of ethanol on startle responding in alcohol-preferring and -non-preferring rats

The objectives of the present study were to determine (a) if differences exist between the selectively bred alcohol-preferring (P) and -non-preferring (NP) lines of rats in the acoustic startle response (ASR) and prepulse inhibition (PPI), and (b) the effects of ethanol on these measures. Alcohol-na?ve adult female P and NP rats received a single i.p. injection of saline or ethanol (0.25, 0.5, 1. 0, or 1.5 g/kg) and were placed in the startle apparatus 10 min later. After a 5-min acclimation period, rats received five alternating trials of a startle stimulus alone (SSA) (115-dB white noise) or a PPI trial (90-dB white noise preceding a 115-dB white noise). Analysis of the ASR revealed that P rats exhibited higher startle amplitudes than did NP rats with saline injections. The 0. 5-g/kg ethanol dose reduced the startle amplitude in P, but not NP, rats. The 1.0- and 1.5-g/kg ethanol doses nearly abolished the ASR in the NP line, whereas only the highest ethanol dose had this effect in the P line. Vehicle-treated P and NP rats exhibited comparable PPI levels, but only P rats showed a significant disruption (30%) at the 0.50-g/kg ethanol dose. Neither P nor NP rats were affected by ethanol treatment at the 0.25-g/kg dose. Overall, the results suggest that: (a) the difference in baseline ASR may indicate line differences in the neurocircuitry mediating this response, possibly reflecting higher innate levels of emotional reactivity in the P line; (b) the P line may be more sensitive than the NP line to the effects of ethanol in reducing emotional reactivity; and (c) low-dose ethanol may have a greater disruptive effect on sensorimotor gating mechanisms in the P than NP rat.     

Effects of typical and atypical antipsychotics on the prepulse inhibition of the startle reflex in patients with schizophrenia

Patients with schizophrenia show a loss of sensory (motor) gating, which is reflected in a reduced prepulse inhibition (PPI) of the startle reflex. Furthermore, patients with schizophrenia habituate less than healthy subjects. From previous studies, it is clear that typical antipsychotics have little or no effect on either sensorimotor gating or habituation, while only limited data is available on the effects of atypical antipsychotics on these processes.Forty-four schizophrenic patients (27 stable on typical and 17 stable on atypical antipsychotics) and 35 healthy control subjects were tested in a PPI paradigm. The prepulse and startle stimuli were pure tones of 1500 Hz (duration 40 ms, intensity 80 dB and 110 dB respectively), with a fixed interstimulus interval of 120 milliseconds. Block effects in PPI and startle amplitude to the pulse alone trials (habituation) were analyzed over the three groups, using comedication (i.e., benzodiazepines) as a covariate.Main effect for block was found for startle amplitude (habituation), while main effects for group and block were found for percentage PPI. Further analysis displayed significant differences in PPI between the patients treated with typical antipsychotics and the healthy control group, while patients treated with atypical antipsychotics did not differ from either the healthy control group, or the patients treated with typical antipsychotics. Furthermore, post-hoc division of the patients treated with atypical antipsychotics in patients treated with clozapine and risperidone revealed that this superiority from atypical antipsychotics over typical antipsychotics appeared to be mainly based on the effects of clozapine.Patients with schizophrenia who are treated with atypical antipsychotics appear to have levels of sensorimotor gating that are more consistent with healthy controls than patients who are treated with typical antipsychotics. Furthermore, within the class of atypical antipsychotics, clozapine appears most potent in restoring this process.     

(+/-) Ketamine-induced prepulse inhibition deficits of an acoustic startle response in rats are not reversed by antipsychotics

Prepulse inhibition (PPI) is the reduction in the startle response caused by a low intensity non-startling stimulus (the prepulse) which is presented shortly before the startle stimulus and is an operational measure of sensorimotor gating. PPI is impaired in psychiatric disorders such as schizophrenia. Ketamine, a non-competitive N-methyl-D-aspartate antagonist has been shown to induce schizophrenia-like behavioural changes in humans and PPI deficits in rats, which can be reversed by antipsychotics. Thus, ketamine-induced PPI deficits in rats may provide a translational model of schizophrenia. The aim of this study was to investigate the effects of antipsychotic drugs and drugs known to alter the glutamate system upon ketamine-induced PPI deficits in rats. Rats were habituated to the PPI procedure [randomized trials of either pulse alone (110 dB/50 ms) or prepulse + pulse (80 dB/10 ms)]. Animals were assigned to pre-treatments based on the level of PPI on the last habituation test and balanced across startle chambers. Ketamine (1-10 mg/kg s.c; 15 min ptt) increased startle amplitude and induced PPI deficits at 6 and 10 mg/kg. PPI deficits induced by ketamine at 6 mg/kg were not attenuated by clozapine (2.5-10 mg/kg s.c.; 60 min ptt), risperidone (0.1-1 mg/kg i.p.; 60 min ptt), haloperidol (0.1-1 mg/kg i.p.; 60 min ptt), lamotrigine (3-30 mg/kg p.o.; 60 min ptt), or SB-271046-A (5-20 mg/kg p.o.; 2 hour ptt) nor potentiated by 2-methyl-6-(phenylethynyl)-pyridine (3-10 mg/kg i.p.; 30 min ptt). These results suggest that under these test conditions ketamine-induced PPI deficits in rats is relatively insensitive and does not represent a translational model for drug discovery in schizophrenia.     

Provisional mapping of quantitative trait loci modulating the acoustic startle response and prepulse inhibition of acoustic startle.

Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating, defined as an inhibition of the startle response when a low intensity stimulus, the prepulse, precedes the startling stimulus. Deficits in PPI have been reported in schizophrenia and other psychiatric/neurological disorders, and correlate with symptom severity in schizophrenia, suggesting that deficient PPI per se or abnormalities in neural circuits regulating PPI may cause some symptoms of schizophrenia. If so, then genes conferring reduced PPI may contribute toward genetic vulnerability to schizophrenia. Studies with selectively bred rodent strains indicate that PPI is under genetic control; however, the identity of the relevant genes is unknown. The current study used recombinant congenic mouse strains derived from C57BL/6J and A/J parents to assess genetic variability in PPI and in ASR and to identify provisional quantitative trait loci (QTLs) modulating these phenotypes. Significant between-strain differences in ASR and in PPI at each of several prepulse intensities (75, 80, 85, 90, 95 dB) were found. Correlations between PPI at the various prepulse intensities were highly significant, suggesting appreciable overlap in genetic regulation of PPI across prepulse intensities. Five QTLs (chromosomes 3, 5, 7, 16) associated with PPI across all prepulse intensities, but not with ASR, were identified. Two additional QTLs (chromosomes 2, 11) associated with both PPI and ASR were found. Fifteen QTLs were associated with ASR alone. Data on genotypes of informative congenic strains were used to support probable involvement of loci modulating PPI and to narrow the probable chromosomal location of QTLs. If confirmed, these QTLs may suggest candidate genes directing novel mechanisms for regulation of PPI     

Dopaminergic stimulation disrupts sensorimotor gating in the rat

Prepulse inhibition is a cross-species phenomenon in which reflex responses to discrete sensory events are modified by weak prestimulation. In experiments designed to investigate the neuropharmacological mechanism of this form of information processing, and its relevance to schizophrenic psychopathology, apomorphine (0.125–4.0 mg/kg) and d-amphetamine (0.5–4.0 mg/kg) were administered to rats in an attempt to modify prepulse inhibition of the acoustic startle response. Rats were presented with 40 ms, 118 dB[A] acoustic pulses which were intermittently preceded by a weak 80 dB[A] acoustic prepulse. Both apomorphine and d-amphetamine induced a significant loss of prepulse inhibition, as reflected by increased pulse-preceded-by-prepulse versus pulse-alone startle magnitudes. Haloperidol (0.1 mg/kg), a specific D2 dopamine receptor antagonist, prevented the effects of 2.0 mg/kg apomorphine on prepulse inhibition, while having little effect by itself. An additional study investigated the effects of chronic intermittent administration of 2.5 mg/kg d-amphetamine. Rats given amphetamine for 8 consecutive days also displayed a loss of prepulse inhibition, with no evidence of tolerance. Finally, prepulse inhibition was examined under high- and low-intensity startle stimulus conditions; apomorphine (1.0 mg/kg) induced a loss of prepulse inhibition under both intensity conditions in approximately equal proportion. The results of these studies suggest a connection between sensorimotor gating, as measured by prepulse inhibition, and dopaminergic overactivity, supporting suggestions that information processing deficits in schizophrenia may be responsible for some psychotic symptoms and their effective treatment by antipsychotic D2 dopamine antagonists.     

Differential effects of apomorphine on prepulse inhibition of acoustic startle reflex in two rat strains

Apomorphine disruption of prepulse inhibition (PPI) has been proposed as an animal model of sensorimotor gating deficits exhibited by schizophrenics. The effects of apomorphine on PPI of the acoustic startle reflex in male rats of Wistar and CD (Sprague-Dawley derived) strains were compared under identical test conditions. In Wistar rats, subcutaneous administration of 0.25–1.0 mg/kg apomorphine blocked PPI without affecting startle amplitude. In CD rats, apomorphine (0.3–3.0 mg/kg, SC) had no effect on PPI, but increased startle amplitude. Therefore, choice of rat strain is an important factor in the design of experiments studying apomorphine effects on PPI.     

Effects of haloperidol and SCH 23390 on acoustic startle in animals depleted of dopamine as neonates: implications for neuropsychiatric syndromes

Animals depleted of dopamine (DA) in the neonatal period and tested in adulthood exhibit some similarities to patients with schizophrenia, including increased sensitivity to DA agonists, altered sensitivity to DA receptor antagonists, and abnormalities of the acoustic startle response (ASR). In this study, we examined the contributions of D₁-like and D₂-like DA receptors to ASR measures in animals depleted of DA as neonates. Male rat pups received intracerebroventricular injections of 6-hydroxydopamine (DA depleted) or its vehicle (controls) at 3 days of age. Animals underwent startle testing ad adults (60–75 days of age) after administration of DA antagonists (haloperidol: 0.1 or 0.3 mg/kg, SCH 23390: 0.01 or 0.05 mg/kg) with and without DA agonist administration (apomorphine 0.5 mg/kg). ASR amplitude and prepulse inhibition (PPI: percentage decrease in startle amplitude due to a low intensity prepulse) were measured. DA depleted animals showed increased ASR amplitude and reduced PPI compared to controls. Administration of D₁-like or D₂-like DA antagonists significantly reduced overall ASR and increased PPI in both control and DA depleted animals, with DA depleted animals showing a relatively greater sensitivity to the D₁-like antagonist SCH 23390. Findings are discussed in terms of the role of residual DA in mediating ASR phenomena in depleted animals, differences between D₁/D₂ DA receptor mediation of ASR compared to other behaviors in DA depleted animals, and potential implications for neuropsychiatric syndromes such as schizophrenia.     

Amphetamine-modified acoustic startle responding and prepulse inhibition in adult and adolescent alcohol-preferring and -nonpreferring rats

Selective breeding has been used to develop the alcohol-preferring (P) and -nonpreferring (NP) rats, with the P rat having lower CNS levels of dopamine (DA) and reduced DA innervation in the nucleus accumbens compared with the NP rat. The acoustic startle response (ASR) and prepulse inhibition (PPI) of the ASR are experimental behaviors altered by DA agonists. We examined whether functional differences in amphetamine (AMPH)-modified ASR and PPI exist between P and NP rats. AMPH [0.0 (saline), 1.0, 2.0, or 4.0 mg/kg] was injected 15 min prior to placement into a startle apparatus. After a 5-min habituation period, rats were given approximately twelve 95-, 105-, or 115-dB white-noise burst (ASR) and PPI trials. As adults, P rats were sensitive to AMPH potentiation of the ASR to a greater extent than NP rats. During adolescence, P and NP rats had similar levels of AMPH-potentiated ASR. As adults, NP rats displayed potentiated, rather than disrupted, PPI at the 1.0-mg/kg dose, whereas P rats displayed the expected disrupted PPI at the 4.0-mg/kg dose. As adolescents, NP rats did not display significant differences in PPI after AMPH, whereas P rats displayed dose-dependent disruption of PPI, which was significant at the 4.0-mg/kg dose. The limited effect of AMPH on increasing the ASR and the presence of AMPH-potentiated PPI at the lowest dose in the adult NP rat suggests reduced functioning of the interactions between DA circuits and the neurocircuitry mediating the ASR and PPI, compared with P rats. However, the neurocircuitry mediating PPI does not appear to be fully developed in the adolescent NP rat. The present findings also indicate that lower levels of DA content and immunoreactive fibers in the P rat may not reflect reduced DA neuronal activity, because the P rat displayed AMPH-potentiated ASR, and, at the highest dose, AMPH disruption of PPI during both adulthood and adolescence.     

Time and Time Again: Temporal Processing Demands Implicate Perceptual and Gating Deficits in the HIV-1 Transgenic Rat

HIV-1-associated neurocognitive disorders (HAND) afflict up to 50 % of HIV-1+ individuals, despite the effectiveness of combination antiretroviral therapy (CART) in reducing the prevalence of more severe neurocognitive impairment. Alterations in brainstem auditory evoked potentials (BAEP), a measure of temporal processing, are one of the earliest neurological abnormalities of HIV-1-positive individuals. Prepulse inhibition (PPI) of the auditory startle response (ASR), a measure of sensorimotor gating, was studied in HIV-1 transgenic (Tg) rats, which express 7 of the 9 HIV-1 genes. Ovariectomized female Fischer HIV-1 Tg and control rats (ns?=?41–42) were tested for PPI at three test periods, with at least 2 months separating each test period, using auditory and visual prepulses, an auditory startle stimulus, and interstimulus intervals (ISI) ranging from 0 to 4000 msec. Auditory and visual prepulse trial blocks were presented in counterbalanced order. For both auditory and visual prepulses, HIV-1 Tg animals exhibited a flatter ISI function, which did not sharpen with age, as it did in controls. Over time, auditory prepulses precipitated a temporal shift in peak inhibition in HIV-1 Tg animals relative to controls, whereas with visual prepulses, both groups displayed peak inhibition at the 40 msec ISI. A lack of perceptual sharpening with age and a relative insensitivity to the temporal dimension of sensorimotor gating are evident in the HIV-1 Tg rat prior to clinical signs of wasting. Deficits in sensorimotor gating may not only provide an early subtle diagnostic marker of HAND, but may also afford a key target for development of potential therapeutics.     

Convergence and divergence in the neurochemical regulation of prepulse inhibition of startle and N40 suppression in rats.

Prepulse inhibition of startle ('PPI'), a cross-species measure of sensorimotor gating, is impaired in schizophrenia patients. Suppression of P50 event-related potentials (ERPs) in response to the second of two clicks ('P50 gating') is also impaired in schizophrenia. Suppression of N40 ERPs to the second of two clicks ('N40 gating') is thought by some to be a rat homolog of human P50 gating. Emerging evidence suggests differences in the neurobiology of deficits detected by PPI vs P50 (or N40) gating. We recorded PPI and N40 gating contemporaneously in rats, to assess convergence and divergence in the neurochemical regulation of these measures. Dose-response studies examined the effects of apomorphine (APO), phencyclidine (PCP) or the 5HT2A agonist DOI on PPI, and on motor responses to stimuli (S1 and S2) that elicit N40 gating. Effects of optimal drug doses on PPI and N40 gating were then assessed in other rats with implanted cortical surface electrodes. APO, PCP and DOI caused dose-dependent disruptions of both PPI and gating of motor responses to N40 stimuli. Reduced PPI reflected diminished prepulse effectiveness, demonstrated by increased startle levels on prepulse+pulse trials. In contrast, reduced gating of motor responses to N40 stimuli reflected a reduced motor response to S1. In separate rats, robust PPI, N40 potentials and N40 gating could be detected within one test. PPI and N40 gating were disrupted by APO, PCP, and DOI. Again, drug effects on PPI reflected increased startle on prepulse+pulse trials, while those on N40 gating reflected reduced ERP responses to S1. In conclusion, when PPI and N40 gating were studied concurrently in rats, drug effects on PPI reflected reduced inhibition of startle by the prepulse, while diminished N40 gating reflected S1 response suppression. Despite similarities in drug sensitivity, these results suggest that distinct neurobiological mechanisms underlie drug-induced deficits in PPI and N40 gating.     

Role of the pedunculopontine tegmental nucleus in sensorimotor gating and reward-related behavior in rats

Rationale The pedunculopontine tegmental nucleus (PPTg) is involved in the execution and regulation of a variety of behaviors. Most investigations used brain lesions that have certain disadvantages, such as functional compensation over time.Objectives In the present study, we investigated by temporary, reversible inhibition of neurons the role of the PPTg in sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR) using variable interstimulus intervals (ISI). In a second set of experiments we examined by the same technique the role of the PPTg in a progressive-ratio instrumental response task.Methods Local infusions of the GABA_A-receptor agonist muscimol (0.05 g and 0.5 g/0.3 l, or vehicle) were applied through indwelling microinfusion cannulae into the PPTg of freely moving rats. ASR and PPI were measured using acoustic stimuli of 100 dB (pulse) and 80 dB (prepulse) using ISIs of 25, 120, 520 and 1,020 ms. Instrumental behavior (lever pressing for casein pellets) was assessed in a Skinner box. Motor activity was measured in an open field.Results Intra-PPTg infusions of muscimol dose-dependently attenuated PPI at ISIs of 120 ms and 520 ms, but not at longer or shorter ISIs. ASR magnitude in pulse-alone trials was not significantly affected. Intra-PPTg infusion of 0.5 g muscimol reduced the break point of instrumental responding (testing sequence where the rats fail to respond according to an increased ratio of reinforcement). No effects on food-preference and open-field activity were found.Conclusions These findings suggest that GABAergic neurotransmission in the PPTg plays an important role for sensorimotor gating at intermediate ISIs and for response selection under demanding schedules of reinforcement.     

Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats

RATIONALE: Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders. However, recent studies have questioned the robustness of this paradigm. OBJECTIVE: The existence of a substantial dataset generated over 4 years in our laboratory has allowed the investigation of the robustness and reliability of the procedure under a variety of environmental conditions. The effects of atypical antipsychotics (clozapine, olanzapine and risperidone) under different experimental conditions are also reported. METHOD: At weaning, Hooded Lister pups were singly (isolates) or group (n=5) housed (grouped). Eight weeks later, the startle and PPI response of isolates and grouped rats was investigated using conditions of fixed inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse=80 dB/30 ms; ISI=100 ms) or variable     

Changes in the acoustic startle response and prepulse inhibition of acoustic startle in rats after local injection of pertussis toxin into the ventral tegmental area

The effect of local injection of pertussis toxin (PTX) into the ventral tegmental area (VTA) on acoustic startle in rats was investigated. The PTX treatment caused only minor effects of its own on the acoustic startle response (ASR) or prepulse inhibition (PPI) of acoustic startle. However, systemic treatment with the indirect DA receptor agonist, amphetamine (2 mg/kg, SC) caused a significant increase in ASR magnitude and a significant disruption of PPI in PTX-treated rats while no such effects were observed in sham-treated rats. Treatment with the direct DA receptor agonist, apomorphine (2 mg/kg, SC), caused a significant disruption of PPI, an effect that was observed in both PTX-and sham-treated rats. Treatment with the 5-HT_1A receptor agonist, 8-OH-DPAT (0.5 mg/kg, SC), did not affect PPI in either group but caused a marked increase in ASR magnitude in sham-treated rats. Interestingly, this effect was blocked in PTX-treated rats. The present results suggest that local injection of PTX into the VTA causes an increased sensitivity to the behavioural effects of psychostimulants on acoustic startle and may also suggest that intact midbrain 5-HT_1A receptors are essential for the effect of 5-HT_1A agonists on acoustic startle.     

Startle and sensorimotor gating in rats lacking CCK-A receptors.

Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the non-competitive NMDA antagonist, dizocilpine (0.1 mg/kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 mg/kg) produced a comparable facilitation of PPI in both groups. In a separate study, OLETF rats were found to be less sensitive to the locomotor stimulating effects of amphetamine. These results suggest that CCK-A receptors play a significant role in the behavioral effects of amphetamine and dizocilpine. The PPI response of OLETF rats to amphetamine and dizocilpine is similar to normal rats pretreated with atypical antipsychotics, suggesting that CCK-A receptors may play an important role in the restoration of drug-disrupted PPI by antipsychotics.     

Sensorimotor gating in mice is disrupted after AM404, an anandamide reuptake and degradation inhibitor

Rationale Prepulse inhibition (PPI) represents a normal sensorimotor gating response that is typically impaired in schizophrenic patients. It is known that cannabinoid CB1 agonists reduce sensorimotor gating in rats, suggesting that the CB1 receptor and the cannabinoid system are involved in sensorimotor gating.Objective The objective was to study the effects of AM404, an anandamide reuptake and degradation inhibitor, on PPI and startle response in Swiss mice.Methods AM404 was injected either acutely (0, 2.5 and 5 mg/kg i.p.) or chronically (5 mg/kg daily, 7 days). The PPI protocol was based on standard methodologies using acoustic stimuli (pulse 120 dB; prepulses 70 dB and 80 dB). SR141716A, a CB1 antagonist, was employed for further confirmation of the involvement of CB1 receptors.Results Acute AM404 (5 mg/kg) disrupted PPI (70-dB prepulse, P<0.05) and enhanced the startle response after the 2.5-mg/kg dose (P<0.01). Chronic AM404 disrupted PPI after both 70-dB (P<0.01) and 80-dB prepulses (P<0.05). These effects were blocked after SR141716A cotreatment.Conclusions The data indicate that AM404 (5 mg/kg) acts as a psychodysleptic, altering PPI through stimulation of cannabinoid CB1 receptors, pointing to a possible psychosis-like state after enhancement of anandamide bioavailability. The startle response was enhanced only following a lower AM404 dose (2.5 mg/kg), indicating that AM404 induced hyperreactivity at a dose that did not affect PPI, further reinforcing a selective disruption of PPI.     

Effects of phencyclidine and phencyclidine biologs on sensorimotor gating in the rat

Prepulse inhibition of the startle response occurs when a weak prestimulus precedes a startling stimulus and decreases the resulting reflex response. Prepulse inhibition provides a measure of sensorimotor gating that is readily assessed in humans and animals. As in event-related-potential models of sensory gating, prepulse inhibition is decreased in schizophrenic patients. In the present study, prepulse inhibition was measured in rats following injections of the N-methyl-D-aspartate (NMDA) antagonists phencyclidine, ketamine, and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclohepten-5,10-imine (MK-801). Startle was elicited by two different noise intensities or by air-puffs (tactile) and was inhibited by weak acoustic prepulse stimuli presented 100 msec before the startle stimuli. The different eliciting stimuli produced different levels of startle in both control and drug-treated animals, startle being increased by phencyclidine and MK-801. Both phencyclidine (3.0 to 10.0 mg/kg) and MK-801 (0.3 to 1.0 mg/kg) significantly reduced the amount of acoustic prepulse inhibition whereas ketamine did not. These results demonstrate that putative noncompetitive NMDA antagonists disrupt sensorimotor gating in rats and suggest that their effects may provide a model of the deficits in sensory gating exhibited by schizophrenic patients.