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.     

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.     

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.     

Responding to acoustic startle during chronic ethanol intoxication and withdrawal

Ethanol (EtOH) withdrawal is characterized by a hyperexcitable state that includes anxiety, tremor, muscle rigidity and seizures. The present three experiments examined the effects of EtOH dependence and withdrawal on the acoustic startle response, an easily quantifiable measure of behavioral reactivity to exteroceptive stimuli. Two intensities of startle stimuli, 105 and 120 dB pulses, were presented to rats during chronic EtOH exposure and during EtOH withdrawal. Prepulse inhibition, which is a sensitive measure of sensorimotor gating processes associated with filtering sensory stimulation, was also assessed during chronic EtOH exposure and withdrawal. Prepulse inhibition was induced by the presentation of a weak 80 dB acoustic stimulus 100 ms prior to a 120 dB stimulus pulse. After 14 days of EtOH liquid diet administration the magnitude of responses elicited by 105 and 120 dB startle stimuli was less in ethanol-treated subjects during continued EtOH access than in animals fed a control liquid diet. When EtOH liquid diet treatment was continued for an additional 3-day period and animals were tested 8 h after withdrawal from EtOH, withdrawn animals were more reactive to startle stimuli at both intensities than were animals maintained on the EtOH liquid diet. A time-course experiment with repeated startle testing at 4, 8, and 12 h post-EtOH exposure revealed significant increases in responding to the 105 dB startle intensity at 8 h post-EtOH exposure. The ability of animals to respond to a prepulse stimulus was not affected during chronic EtOH treatment, but was reduced during withdrawal. At 8 h post-EtOH exposure, chronically treated EtOH animals showed less prepulse inhibition that animals maintained on EtOH and control liquid diet. Decreased prepulse inhibition was apparent as early as 4 h post-EtOH exposure. These results suggest that the central nervous system hyperexcitability during EtOH withdrawal may be reflected in an activation of the neural circuitry involved in the acoustic startle response.     

Effects of smoking on acoustic startle and prepulse inhibition in humans

RATIONALE: Prepulse inhibition of the acoustic startle response (PPI) is a paradigm in which a startle response to an auditory stimulus is reduced when that stimulus is preceded by a lower intensity, non-startling stimulus (prepulse). PPI is used as an operational measure of sensorimotor gating in both humans and other mammals. Acute administration of nicotine enhances PPI in rats, an effect that has been recently demonstrated in humans. OBJECTIVES: We compared PPI in 12 male smokers and 14 male non-smokers tested in four repeat startle sessions across 2 test days in order to examine further the effects of smoking and smoking withdrawal on acoustic startle and PPI. METHODS: In a crossover design, the smokers smoked ad lib or abstained from smoking overnight prior to 9 a.m. testing. These 2 test days were in randomized order. On both days, smokers were immediately retested after smoking three cigarettes. Non-smokers were tested twice on each of 2 separate days. RESULTS: Across sessions, the smokers had reduced startle to pulse alone stimuli in the first block of each session when compared to the non-smokers. The non-smokers had no change in gating across their four test sessions. For the smokers, the abstinence condition produced a non-significant reduction in PPI compared to that of the ad lib smoking day. During the smoking abstinence session, smokers had comparable gating to non-smokers. Smoking immediately after washout produced a significant improvement in PPI such that gating in the smokers exceeded that of the non-smokers. CONCLUSION: Smoking after overnight washout from cigarettes enhanced sensorimotor gating compared to pre-smoking values and compared to gating in non-smokers.     

Relation of sex and estrous phase to deficits in prepulse inhibition of the startle response induced by ecstasy (MDMA)

Sensorimotor gating is the ability of a weak sensory event to inhibit the motor response to an intense stimulus. Drugs that act as serotonin releasers, such as MDMA (3,4-methylenedioxymethamphetamine), impair sensorimotor gating, which is measured as a prepulse inhibition (PPI) of the acoustic startle response. The first objective of the present study was to compare the effect of different doses of MDMA on PPI and the acoustic startle response (ASR) in male and female Wistar rats. The second objective was to examine the effect of MDMA on PPI across the estrous cycle in female rats. MDMA was administered in doses of 2.5, 5 and 10 mg/kg s.c. 15 min before the start of the experiment. The controls received saline in equivalent volumes. MDMA dose-dependently decreased PPI in both the male and female rats and produced higher levels of ASR in the male rats compared to the females. In addition, we found that female rats in the diestrous and metestrous phases are more sensitive to MDMA and showed higher deficits in PPI than female rats in the proestrous and estrous phases. Our result showed that female rats in the proestrous and estrous phases were less sensitive to the disruption of PPI by MDMA.     

Reduced brain serotonin activity disrupts prepulse inhibition of the acoustic startle reflex. Effects of 5,7-dihydroxytryptamine and p-chlorophenylalanine.

These experiments examined the impact of extensive depletions of forebrain 5-hydroxytryptamine (5-HT; serotonin) levels on prepulse inhibition (PPI) of the acoustic startle reflex in rats. In Experiment 1, injection of the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into the dorsal and median raphe nuclei disrupted PPI. This deficit was observed beginning 2 days after lesioning and was still apparent 8 weeks later. Basal startle reactivity was not altered. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.1 mg/kg) and the dopamine receptor agonist apomorphine (1mg/kg) also disrupted PPI; the effect of 8-OH-DPAT, but not apomorphine, was potentiated in 5-HT-depleted rats. Basal startle reactivity was enhanced by 8-OH-DPAT in sham-lesioned rats but not in 5,7-DHT-lesioned rats. In Experiment 2, a second method for depleting 5-HT was used. The tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) also disrupted PPI without altering basal startle reactivity. Again, 8-OH-DPAT disrupted PPI in control animals; this effect was not altered in PCPA-treated rats but the increase in basal startle reactivity induced by 8-OH-DPAT was not observed in PCPA-treated rats. Taken together with the results of previous experiments involving drugs that enhance 5-HT neurotransmission it appears that both increases and decreases in 5-HT activity disrupt PPI.     

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.     

Nicotine increases sensory gating measured as inhibition of the acoustic startle reflex in rats

Chronic nicotine administration has been reported to increase acoustic startle response (ASR) amplitude in rats, which has been offered as evidence that some dosages of nicotine can enhance attention. The present experiments examined effects of acutely administered nicotine on amplitude and pre-pulse inhibition (PPI) of acoustic startle in rats. PPI, the decrease in ASR amplitude by a stimulus preceding the startle-eliciting event, reflects pre-attentive neural processes underlying sensory gating. Nicotine had a biphasic dose effect on startle amplitude, with increases at lower dosages (0.01 mg/kg) and decreases at higher dosages (0.5–5.0 mg/kg SC). Lower dosages of nicotine (0.001–0.01 mg/kg) increased PPI and the increase at 0.001 mg/kg occurred independently of changes in ASR amplitude. These results confirm that increases in PPI are not dependent upon changes in ASR amplitude. Results are consistent with nicotine's enhancements of performance on cognitive tasks in humans and are the first reported use of the PPI paradigm to model such effects. These findings indicate that ASR paradigms are useful to study effects of nicotine.This work was supported by USUHS protocol CO 7223. The views contained herein are the private ones of the authors and do not reflect those of the Uniformed Services University of the Health Sciences, the Department of Defense, or the Food and Drug Administration     

Effects of serotonergic and noradrenergic antidepressants on auditory startle response in patients with major depression

Rationale Amplitude, habituation and prepulse inhibition (PPI) of the acoustic startle response (ASR) in rodents and humans are sensitive to psychotropic drugs. Studies with rodents suggest that an increase or decrease in serotonin level in the brain alters several modalities of the ASR. So far, little is known about serotonergic and noradrenergic startle modulation in humans.Objective This study was designed to investigate the effects of the selective serotonin uptake inhibitor sertraline versus the selective noradrenalin uptake inhibitor reboxetine on magnitude, habituation and PPI of ASR in patients with major depression.Methods We studied ASR in 23 patients with the diagnosis of major depression according to DSM-IV who were randomly treated either with sertraline or with reboxetine. Initially, ASR assessment was carried out when patients were drug-free for at least 2 weeks and again after 14 days of treatment.Results The habituation of ASR was strongly attenuated by sertraline and not significantly altered by reboxetine. None of the substances altered the startle reactivity. In addition, PPI was not altered by sertraline, but reboxetine tended to decrease PPI. The startle reactivity at baseline was correlated with improvement of depressive symptoms at the end of the study.Conclusion These results provide the first evidence for different effects of noradrenergic and serotonergic antidepressants on the startle response in depressed 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 acute ethanol or amphetamine administration on the acoustic startle response and prepulse inhibition in adolescent and adult rats

Rationale Adolescents differ from adults in their sensitivity to a variety of psychoactive drugs. For example, adolescent rats are less sensitive to locomotor stimulant and stereotypic effects of amphetamine as well as to motor-impairing and hypnotic effects of ethanol while more sensitive to ethanol-induced disruption of brain plasticity.Objective The current study further explored age differences in psychopharmacological sensitivity by examining the effects of d-amphetamine (1.0 and 4.0 mg/kg) or ethanol (0.5, 1.0 and 1.5 g/kg) given interperitoneally on the acoustic startle response (ASR) and prepulse inhibition (PPI) in male adolescent and adult Sprague–Dawley rats.Materials and methods The animals were given five startle trials (120 dB for 40 ms) before semi-randomized presentation of 12 startle trials interspersed with ten trials at each prepulse intensity (40 ms pulse of 5, 10, or 20 dB above background; 100 ms before the startle stimulus).Results Adolescent controls showed significantly less PPI than adults, replicating previous ontogenetic findings. The higher dose of amphetamine disrupted PPI in adult but not in adolescent animals, extending previous reports of an adolescent insensitivity to amphetamine to include this measure of sensorimotor gating. Ethanol exposure failed to alter PPI at either age, although both the 1.0 and 1.5 g/kg doses of ethanol significantly suppressed the magnitude of the ASR at both ages, potentially reflecting sedative or anxiolytic effects.Conclusion These data provide further evidence of the relative insensitivity of adolescent animals to amphetamine, although no age effects were found in terms of ethanol sensitivity using these measures of startle and sensorimotor gating.     

Anxiogenic-like effects of opiate withdrawal seen in the fear-potentiated startle test, an interdisciplinary probe for drug-related motivational states

RATIONALE: Anxiety-like effects may be universal to withdrawal from drugs of abuse. The study of withdrawal would benefit from the acoustic startle response (ASR), a discrete, cross-species reflex which is increased by fear-related states. However, existing reports of opiate-related effects on baseline ASR have not validated ASR as a measure of drug-related motivation. OBJECTIVE: The effects of opiate treatment and withdrawal were examined using fear-potentiated startle, a startle test more sensitive to fear than baseline changes. METHODS: Fear-conditioned rats were treated with Alzet osmotic pumps delivering 0.25 mg/kg per day fentanyl or placebo pumps. Experiment I examined changes before and during opiate treatment on locomotor activity and baseline, prepulse inhibition, and fear-potentiated startle. Experiment 2 examined the same responses during withdrawal precipitated after 4-7 days of treatment using IV naloxone. RESULTS: Experiment 1 revealed an attenuated fear-potentiated startle on the first test after the start of fentanyl treatment (4 h); this was not seen on subsequent tests and suggested tolerance to this acute effect. Experiment 2 found an enhancement of fear-potentiated startle precipitated in fentanyl-treated rats after injection of 0.025 and 0.16 mg/kg naloxone; this was not seen at 1 mg/kg naloxone, even though more physical withdrawal signs were most prevalent at this dose. In neither experiment did locomotor activity, baseline ASR, or prepulse inhibition of the ASR show any treatment effect. CONCLUSIONS: Fear-potentiated startle may provide a specific and valid measure of anxiety-like effects of drug withdrawal. Discussed were conditions needed to see this effect and the relevance of the findings for different mechanisms of withdrawal discomfort.     

Altered prepulse inhibition in rats treated prenatally with the antimitotic Ara-C: an animal model for sensorimotor gating deficits in schizophrenia

Rationale Sensorimotor gating disruption is one of many neurocognitive deficits seen in schizophrenia. Disorganized thought is one of the cardinal symptoms associated with sensorimotor gating. In an attempt to model sensorimotor gating deficits in rats relevant to the neurodevelopmental hypothesis for schizophrenia, we have used prenatal injections of the antimitotic drug, cytosine arabinoside (Ara-C) to subtly perturb the development of the rat CNS and disrupt sensorimotor gating.Objective To produce rats with either basal sensorimotor gating deficits or increased vulnerability to the disruption of sensorimotor function by apomorphine or phencyclidine (PCP). Prepulse inhibition (PPI) of the acoustic startle response was used to assess sensorimotor gating.Methods Three different cohorts of pregnant Sprague Dawley female rats were injected with Ara-C (30 mg/kg in saline) or saline at embryonic days 19.5 and 20.5. The Ara-C and control rats were tested for acoustic startle response and PPI at preadolescent and post-adolescent ages; postnatal day (Pnd) 35 and 56, respectively. Apomorphine (2.0 mg/kg) or phencyclidine (3.0 mg/kg), was given prior to PPI sessions in order to disrupt PPI.Results At Pnd 35, Ara-C treatment did not significantly affect acoustic startle amplitudes or PPI. However, at PND 56, Ara-C treated rats had significantly lower acoustic startle amplitudes and significantly diminished sensorimotor gating. Pharmacological challenge with the dopamine agonist apomorphine and the glutamate antagonist PCP significantly disrupted sensorimotor gating in the control subjects. Apomorphine did not further disrupt the existing deficit in the Ara-C treated rats. Ara-C treatment did not cause gross loss of neuronal tissue, although there was a subtle and variable disorganization of the pyramidal cell layer in the hippocampal CA_2/3 region.Conclusion The results provide evidence to suggest that late embryonic exposure to Ara-C disrupts the circuitry involved in mediating PPI. While the dopamine agonist apomorphine caused a significant disruption in the control rats it did not further disrupt the existing deficit in the Ara-C treated rats. These data provide evidence to support the contention that modest neurodevelopmental insults can significantly affect sensorimotor gating processes in an adult onset dependent manner.     

Effects of caffeine on sensorimotor gating of the startle reflex in normal control subjects: impact of caffeine intake and withdrawal

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders. This study was designed to assess caffeine effects on PPI in normal humans, as part of an effort to understand cross-species differences and similarities in the neurochemical regulation of PPI. METHODS: Startle was measured during a screening session; 7 days later, subjects were retested after placebo or caffeine (200 mg; double-blind design). Subjects were characterized as low versus high caffeine drinkers based on established scales (range 11-628 mg/day), and either maintained ad libitum caffeine intake (Ad lib study; n=18) or refrained from caffeine consumption for > or =15 h prior to testing (Withdrawal study; n=12). Autonomic and self-rating measures, acoustic and tactile startle, and unimodal and cross-modal PPI, were measured in divided sessions for 3 h post-treatment. RESULTS: There were significant effects of caffeine and/or caffeine withdrawal on several self-rating and autonomic measures, and on startle reflex habituation, but not on acoustic or tactile startle magnitude or PPI. Difference scores of startle data from screening versus test days revealed no group effects on startle magnitude, but PPI difference scores revealed that caffeine had opposite effects on low versus high caffeine drinkers (means=57 versus 258 mg/day) in the two withdrawal states. In the absence of withdrawal, caffeine reduced PPI in heavy caffeine drinkers; during withdrawal, caffeine increased PPI in heavy caffeine drinkers. The opposite pattern was evident in low caffeine drinkers. CONCLUSIONS: While a physiologically active dose of caffeine has no simple effects on PPI in normal humans, both withdrawal states and normal levels of caffeine consumption may be important factors in understanding this drug's effects on sensorimotor gating.     

The CB receptor agonist WIN 55,212-2 fails to elicit disruption of prepulse inhibition of the startle in Sprague-Dawley rats

Rationale A growing evidentiary body indicates cannabinoid exposure is conducive to cognitive impairment and psychotic phenomena in vulnerable individuals. In this respect, recent studies have displayed controversial results on the ability of cannabinoids to elicit sensorimotor gating alterations and attentional filtering, whose disruption is a distinctive feature of psychosis.Objectives The goal of this study was to investigate the effects of acute, subchronic, and chronic treatment with the synthetic CB receptor agonist WIN 55,212-2 (WIN) on prepulse inhibition (PPI) of the acoustic startle reflex (ASR), a powerful paradigm for evaluation of sensorimotor gating.Methods Different groups of adult Sprague-Dawley rats were treated with 0.5, 1, and 2 mg/kg WIN (i.p.) acutely, as well as for 7 days and 21 days. All animals underwent testing 40 min after the last treatment and their evaluation was compared with that of animals treated with vehicle. In a separate group, the effects of WIN withdrawal were also analyzed, 24 h after discontinuation of a 21-day treatment.Results No variation in PPI was detected in any of the test groups when compared with controls, whatever the dosage and the treatment.Conclusions These findings suggest WIN does not impair sensorimotor gating in Sprague-Dawley rats and confirm clinical evidence according to which cannabis is an unlikely causative of psychosis among non-vulnerable individuals. Nonetheless, since in other studies the same compound was shown to induce PPI alterations in Wistar rats, our results are also suggestive that genetic differences might be critical for the development of cannabis-induced cognitive disorders.     

The effects of oxytocin and its analog, carbetocin, on genetic deficits in sensorimotor gating

Converging evidence from preclinical and clinical studies suggest that oxytocin has therapeutic potential for schizophrenia and other neuropsychiatric disorders. Prepulse inhibition of the startle reflex (PPI) is a measure of sensorimotor gating, an important brain function involved in filtering environmental information. We previously demonstrated that systemically administered oxytocin reversed psychostimulant-induced PPI deficits in rats suggesting that oxytocin can produce antipsychotic-like central effects. That finding was supported by a recent trial in humans, which found that intranasal oxytocin reduced symptoms of schizophrenia. The goal of this study was to extend this line of investigation by testing the effects of oxytocin, and a structural analog of oxytocin, carbetocin, on non-pharmacological deficits in PPI. In experiment 1, Brown Norway (BN) rats, a rat strain that has naturally low PPI, were given either saline or one of three doses of oxytocin (0.04-1.0 mg/kg, sc). In experiment 2, BN rats were given either saline, one of three doses of carbetocin (0.04-1.0 mg/kg) or oxytocin (1 mg/kg). PPI and acoustic startle response (ASR) of rats were tested. Oxytocin significantly increased PPI (P<0.01) and decreased ASR levels (P<0.01) in BN rats in a dose-dependent fashion. In contrast, carbetocin had no effect on PPI levels or ASR. The facilitation of BN PPI by oxytocin is similar to what we have previously observed with clozapine and thus further supports oxytocin having antipsychotic properties. In contrast to oxytocin, our data do not support the use of carbetocin as an antipsychotic drug.     

Interactions between corticotropin-releasing factor and the serotonin 1A receptor system on acoustic startle amplitude and prepulse inhibition of the startle response in two rat strains

Both the neuropeptide, corticotropin-releasing factor (CRF) and the serotonin 1A (5-HT(1A)) receptor systems have been implicated in anxiety disorders and there is evidence that the two systems interact with each other to affect behavior. Both systems have individually been shown to affect prepulse inhibition (PPI) of the acoustic startle response. PPI is a form of sensorimotor gating that is reduced in patients with anxiety disorders including post-traumatic stress and panic disorder. Here, we examined whether the two systems interact or counteract each other to affect acoustic startle amplitude, PPI and habituation of the startle response. In experiment 1, Brown Norway (BN) and Wistar-Kyoto (WKY) rats were administered ether an intraperitoneal (IP) injection of saline or the 5-HT(1A) receptor agonist, 8-OH-DPAT 10 min prior to receiving an intracerebroventricular (ICV) infusion of either saline or CRF (0.3 μg). In a second experiment, rats were administered either an IP injection of saline or the 5-HT(1A) receptor antagonist, WAY 100,635 10 min prior to receiving an ICV infusion of saline or CRF. Thirty min after the ICV infusion, the startle response and PPI were assessed. As we have previously shown, the dose of CRF used in these experiments reduced PPI in BN rats and had no effect on PPI in WKY rats. Administration of 8-OH-DPAT alone had no effect on PPI in either rat strain when the data from the two strains were examined separately. Administration of 8-OH-DPAT added to the effect of CRF in BN rats, and the combination of 8-OH-DPAT and CRF significantly reduced PPI in WKY rats. CRF alone had no effect on baseline startle amplitude in either rat strain, but CRF enhanced the 8-OH-DPAT-induced increase in startle in both strains. Administration of WAY 100,635 did not affect the CRF-induced change in PPI and there were no interactions between CRF and WAY 100,635 on baseline startle. The results suggest that activation of the 5-HT(1A) receptor can potentiate the effect of CRF on endophenotypes of anxiety disorders in animal models. This article is part of a Special Issue entitled 'Anxiety and Depression'.     

A comparison of the effects of amphetamine, strychnine and caffeine on prepulse inhibition and latent inhibition

Sensorimotor gating deficits characterize several neuropsychiatric disorders, including schizophrenia. Prepulse inhibition (PPI) and latent inhibition (LI) are measures that are used to assess sensorimotor gating and have been found to be reduced in schizophrenia patients. In PPI, a weak stimulus presented immediately prior to a startling stimulus attenuates the startle response. In LI, pre-exposure to a stimulus retards the subsequent association of that stimulus with a consequence (e.g. footshock). In rats, indirect dopamine (DA) agonists such as amphetamine disrupt both PPI and LI. Amphetamine has also been reported to increase exploratory locomotion at doses that decrease PPI and LI. Such behavioral activation might complicate the interpretation of amphetamine-induced changes in measures of sensorimotor gating. The present study was conducted in order to compare the effects of three behaviorally activating drugs on PPI, LI and locomotor activity. Separate groups of rats were treated with either vehicle, the DA releaser amphetamine (1.5mg/kg), the glycine antagonist strychnine (0.75mg/kg), or the adenosine receptor antagonist caffeine (10mg/kg) and then tested in either startle chambers (for PPI) or an active avoidance chamber (for LI). Locomotion was measured by inter-trial crossing in the avoidance chamber. Amphetamine stimulated locomotion and disrupted both PPI and LI, but did not elevate startle amplitude. In contrast, caffeine increased locomotion, but had no effect on PPI or LI. Strychnine did not increase locomotion significantly, but did increase startle amplitude and disrupt PPI and LI. Hence, neither increased startle amplitude nor locomotor activation are necessary or sufficient conditions for disruption of sensorimotor gating as measured by PPI and LI.     

Acoustic startle reduction in cocaine dependence persists for 1 year of abstinence

Rationale  

Chronic cocaine use results in long-lasting neurochemical changes that persist beyond the acute withdrawal period. Previous work from our group reported a profound reduction in the acoustic startle response (ASR) in chronic cocaine-dependent subjects in early abstinence compared to healthy controls that may be related to long-lasting neuroadaptations following withdrawal from chronic cocaine use.