Corticotropin-releasing factor potentiates acoustic startle in rats: Blockade by chlordiazepoxide

A series of experiments was performed to investigate the effects of corticotropin-releasing factor (CRF) on the amplitude of the acoustic startle response (ASR) in rats. Intracerebroventricular (ICV) administration of 1 g rat CRF significantly potentiated acoustic startle amplitude; these effects were reversed in a dose-dependent manner by pretreatment with the benzodiazepine chlordiazepoxide (CDP). Doses of CDP that anatgonized CRF-potentiated ASR did not lower startle baseline or antagonize amphetamine-or strychnine-potentiated ASR. These results suggest that CRF has anxiogenic properties and may serve as a neuroendocrine modulator of stress-enhanced behaviors.     

Traumatic stress in rats induces noradrenergic-dependent long-term behavioral sensitization: role of individual differences and similarities with dependence on drugs of abuse

Rationale

The aim of this paper is to provide evidence for the hypothesis that posttraumatic stress disorder (PTSD) and drug addiction rely on common processes.

Objective

Our objective is to show that a noradrenergic-dependent behavioral sensitization occurs after the development of PTSD, in a way similar to that recently demonstrated after repeated drug injections.

Methods

Rats classified into high and low responders to novelty (HR/LR) were subjected to a single prolonged stress (SPS). Cross-sensitization was evaluated after d-amphetamine injection (1.0 mg/kg) in a locomotor activity test given either 4, 15, or 90 days later. To determine the involvement of the noradrenergic system, rats were injected with the α2-receptor agonist, clonidine (20 μg/kg), during the SPS. Subsequently, their auditory startle response (ASR) and cross-sensitization were assessed.

Results

SPS affected both the hypothalamic–pituitary–adrenal axis and the ASR, replicating some PTSD-like symptoms. Behavioral sensitization was found after 15, 21, and 90 days after the SPS in LR rats, and a behavioral desensitization in HR rats after 15 days. Clonidine delivered during the SPS prevented the behavioral sensitization in LR rats, as well as the effects on ASR in HR and LR rats.

Conclusions

Exposure to SPS is shown to affect behavior and induce a behavioral sensitization to d-amphetamine that is modulated by individual differences. Both of these effects depend on the noradrenergic system. Altogether, the present results (1) replicate findings obtained after repeated drug exposure and (2) strengthen our hypothesis of a common physiological basis between PTSD and drug addiction.     

The effect of nicotine and trauma context on acoustic startle in smokers with and without posttraumatic stress disorder

Rationale  

Exaggerated startle response is a prominent feature of posttraumatic stress disorder (PTSD) although results examining differences in the acoustic startle response (ASR) between those with and without PTSD are mixed. One variable that may affect ASR among persons with PTSD is smoking. Individuals with PTSD are more likely to smoke and have greater difficulty quitting smoking. While smokers with PTSD report that smoking provides significant relief of negative affect and PTSD symptoms, the effects of smoking or nicotine deprivation on startle reactivity among smokers with PTSD are unknown.     

Cannabinoids Prevent the Development of Behavioral and Endocrine Alterations in a Rat Model of Intense Stress

Cannabinoids have recently emerged as a possible treatment of stress- and anxiety-related disorders such as post-traumatic stress disorder (PTSD). Here, we examined whether cannabinoid receptor activation could prevent the effects of traumatic stress on the development of behavioral and neuroendocrine measures in a rat model of PTSD, the single-prolonged stress (SPS) model. Rats were injected with the CB1/CB2 receptor agonist WIN55,212-2 (WIN) systemically or into the basolateral amygdala (BLA) at different time points following SPS exposure and were tested 1 week later for inhibitory avoidance (IA) conditioning and extinction, acoustic startle response (ASR), hypothalamic-pituitary-adrenal (HPA) axis function, and anxiety levels. Exposure to SPS enhanced conditioned avoidance and impaired extinction while enhancing ASR, negative feedback on the HPA axis, and anxiety. WIN (0.5 mg/kg) administered intraperitoneally 2 or 24 h (but not 48 h) after SPS prevented the trauma-induced alterations in IA conditioning and extinction, ASR potentiation, and HPA axis inhibition. WIN microinjected into the BLA (5 μg/side) prevented SPS-induced alterations in IA and ASR. These effects were blocked by intra-BLA co-administration of the CB1 receptor antagonist AM251 (0.3 ng/side), suggesting the involvement of CB1 receptors. These findings suggest that (i) there may be an optimal time window for intervention treatment with cannabinoids after exposure to a highly stressful event, (ii) some of the preventive effects induced by WIN are mediated by an activation of CB1 receptors in the BLA, and (iii) cannabinoids could serve as a pharmacological treatment of stress- and trauma-related disorders.     

Yohimbine facilitated acoustic startle in combat veterans with post-traumatic stress disorder

Preclinical and clinical studies have suggested that the acoustic startle reflex (ASR) is a useful model to investigate the neurochemical basis of anxiety and fear states. This work has revealed that the anxiogenic alpha-2 receptor antagonist, yohimbine, increases the amplitude of the ASR in laboratory animals and in healthy human controls. Because of the growing body of data that support the hypothesis that severe stress results in substantial alterations in noradrenergic neuronal reactivity, the present investigation evaluated the effects of yohimbine on the ASR of 18 patients with PTSD and 11 healthy combat controls. Subjects received IV yohimbine (0.4 mg/kg) or saline placebo on 2 separate days in a randomized double blind placebo control design. A trial of two tone frequencies with varied intensity (90, 96, 102, 108, 114 dB) white noise and instantaneous rise time, was delivered binaurally through headphones. Tones were delivered every 25–60 s, for a 40-ms duration. Startle testing was performed 80 min post-infusion and lasted 15–20 min. Yohimbine significantly increased the amplitude, magnitude and probability of the ASR in combat veterans with PTSD, but did not do so in combat controls. Overall startle was significantly larger in the PTSD subjects; however, this did not account for the differential effect of yohimbine, since yohimbine had no significant effect in the control group. This study demonstrates an excitatory effect of yohimbine on the amplitude, magnitude and probability of the ASR in PTSD patients that is not seen in combat controls. In the context of the key role of this reflex in the alarm response, this finding adds to the array of documented behavioral, biochemical and cardiovascular effects of yohimbine in humans which support the relationship between increased noradrenergic function and exaggerated startle symptomatology of PTSD.     

Prazosin administered prior to inescapable stressor blocks subsequent exaggeration of acoustic startle response in rats

Exposure to traumatic stress can result in a number of pathophysiological conditions, including post-traumatic stress disorder (PTSD). PTSD is characterized by a number of persistently heightened physiological and behavioral indicators, including increased sensory arousal and increased startle response. Similar effects can be seen in an animal model of PTSD in which stress results from restraint and inescapable tailshocks to rats. The present study used this animal model to investigate the effects of prazosin, an alpha(1) adrenoceptor antagonist, on stress-induced elevation of acoustic startle response (ASR). To investigate this, male Sprague-Dawley rats were injected with 0.5 mg/kg of prazosin 30 min before restraint and inescapable tail shock on three consecutive days. ASR testing was performed 1, 4, 7 and 10 days post-stress and compared to baseline and control values. Results show a significant reduction of ASR hyperarousal in the group treated with prazosin prior to stress compared to vehicle treated stressed animals and controls. Pre-stress treatment with lower levels of prazosin (0.25, 0.1 and 0.05 mg/kg) showed similar results. These findings further implicate an alpha(1) adrenoceptor role in the pathophysiological response to traumatic stress and suggest a potential preventative role for prazosin.     

Prepulse inhibition of the acoustic startle response in cocaine-withdrawn rats.

Prepulse inhibition (PPI) of startle is a sensorimotor gating task in which a low-intensity acoustic stimulus presented prior to a high-intensity, startle-eliciting stimulus can attenuate the acoustic startle response (ASR). Previous studies on startle reactivity in cocaine-withdrawn rats have found minimal changes; the present study extends this work to the gating of ASR. In Experiment 1, rats were injected daily with either saline or cocaine (30 mg/kg i.p.) for 2 weeks. ASR and PPI were measured prior to, and at 3- and 14-day withdrawal from, the chronic treatment. No effect of cocaine treatment was found on either measure. In Experiment 2, treatment was extended to 8 weeks, and an earlier withdrawal time point (1 day) was added. Rats treated with cocaine for 8 weeks exhibited lower startle reactivity during withdrawal compared with saline-treated controls. PPI did not differ between treatment groups. Thus, extended chronic treatment with cocaine rendered significant effects on startle responsivity. Further, this finding mirrors the blunted ASR exhibited in chronic cocaine users [Neuropsychopharmacology 22 (2000) 89.].     

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.     

Diazepam withdrawal: effects of diazepam and gepirone on acoustic startle-induced 22 kHz ultrasonic vocalizations

It has proven difficult to demonstrate and study the anxiogenic quality of drug withdrawal states in animals. Ultrasonic vocalizations (USV) in response to acoustic startle stimuli have shown promise as a measure of affect and may represent distress responses during diazepam withdrawal. Three experiments evaluated the association between USV and distress by comparing the effects of diazepam as a prototypic benzodiazepine agonist and the putative anxiolytic gepirone with affinity for 5-hydroxytryptamine (5-HT_1A) receptors in naive and diazepam-withdrawn subjects. Adult male Long-Evans rats were exposed to acoustic startle sessions consisting of nine 105 dB and nine 115 dB stimuli. USV at 20–30 kHz were readily emitted during startle and often commenced after the third or fourth stimulus presentation. Acutely, intraperitoneal (IP) administration of diazepam (0.1–3 mg/kg) and gepirone (0.1–1 mg/kg) decreased USV dose-dependently without affecting the startle reflex; gepirone also decreased tail flick latency. Startle-induced USV were also sensitive to the anxiogenic effects of withdrawal from diazepam exposure (0, 2.5, 5, 10 mg/kg b.i.d. IP×5 days). Twenty-four hours after the last diazepam injection, rats were hyperreactive to startle stimuli and doubled their rate of USV over vehicle-treated controls. Gepirone (0.1–1 mg/kg IP), but not diazepam (3–20 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 10 mg/kg b.i.d. diazepam. Diazepam (2.5–10 mg/kg IP) antagonized the increased rate of USV in rats withdrawn from 2.5 mg/kg b.i.d. diazepam. USV induced by acoustic startle stimuli are sensitive to the anxiolytic effects of benzodiazepine and 5-HT_1A receptor agonists and permit the assessment of the anxiogenic properties of diazepam withdrawal. The potent effect of gepirone on USV suggests a serotonergic amelioration of the anxiogenic aspects of diazepam withdrawal.     

Calcium channel function and regulation in β<Subscript>1</Subscript>- and β<Subscript>2</Subscript>-adrenoceptor transgenic mice

Cardiac effects of catecholamines on the L-type calcium channel depend on -adrenoceptor subtype (₁- vs. ₂-adrenoceptor). Chronic overexpression of these receptors leads to hypertrophy and early death at moderate (₁) or excessive (₂) levels of overexpression respectively. In order to examine the role of L-type calcium channels in altered cardiomyocyte calcium homeostasis found with ₁-adrenoceptor overexpression, and to understand the quantitative differences between -adrenoceptor subtypes regarding calcium channel regulation, we examined single channels in myocytes obtained from ₁- and ₂-adrenoceptor transgenic mice. The effects of the agonist isoproterenol were investigated and compared with acute receptor stimulation in the respective non-transgenic littermates.Channels from ₁-adrenoceptor transgenic mice have normal baseline activity, and channel number is not reduced. This contrasts to previous findings with ₂-adrenoceptor transgenic mice, where channel activity is depressed. Isoproterenol is unable to stimulate channel activity in both transgenic models.In conclusion, the L-type calcium channel is not likely to be involved in alterations of calcium handling of ₁-adrenoceptor transgenic myocytes. Furthermore, chronic ₁-adrenoceptor overexpression does not depress channel activity, giving another example of the difference between ₁- and ₂-adrenoceptor signal transduction.K.F. and T.K. equally contributed to this work     

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

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

Role of basolateral amygdala dopamine in modulating prepulse inhibition and latent inhibition in the rat

Rationale The dopamine (DA) projection to the basolateral amygdala (BLA) modulates nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) DA transmission. Given the involvement of the BLA, and of NAc and mPFC DA, in select forms of information processing, we sought to determine the role of BLA DA in modulating prepulse inhibition (PPI) and latent inhibition (LI).Objective The effects of BLA D₁ (SCH 23390) and D₂/D₃ (raclopride) receptor blockade on PPI and LI were examined.Methods Separate groups of male Long–Evans rats received bilateral intra-BLA infusions of SCH 23390 (3.2 or 6.4 g/0.5 l per side), raclopride (2.5 or 5.0 g/0.5 l per side) or saline prior to testing. In two experiments, the effects of BLA DA receptor antagonism on PPI of the acoustic startle response (ASR) and LI of conditioned taste aversion were determined. A control group received bilateral intra-striatal infusions of SCH 23390 or raclopride prior to PPI testing.Results Intra-BLA SCH 23390 or raclopride had no effect on the ASR. Intra-BLA SCH 23390 enhanced and raclopride disrupted PPI, both in a dose-related manner. Intra-striatal SCH 23390 or raclopride had no effect on PPI or ASR magnitude. Finally, BLA DA receptor blockade had no effect on LI.Conclusions These results indicate that PPI is modulated by BLA DA and suggest that this modulation occurs independently of changes in NAc and/or mPFC DA transmission. They also suggest that BLA DA is not involved in modulating LI and add to evidence indicating that PPI and LI are mediated by different neural substrates.     

Oxytocin Reduces Background Anxiety in a Fear-Potentiated Startle Paradigm

Oxytocin reportedly decreases anxious feelings in humans and may therefore have therapeutic value for anxiety disorders, such as post-traumatic stress disorder (PTSD). As PTSD patients have exaggerated startle responses, a fear-potentiated startle paradigm in rats may have face validity as an animal model to examine the efficacy of oxytocin in treating these symptoms. Oxytocin (0, 0.01, 0.1, or 1.0 μg, subcutaneously) was given either 30 min before fear conditioning, immediately after fear conditioning, or 30 min before fear-potentiated startle testing to assess its effects on acquisition, consolidation, and expression of conditioned fear, respectively. Startle both in the presence and absence of the fear-conditioned light was significantly diminished by oxytocin when administered at acquisition, consolidation, or expression. There was no specific effect of oxytocin on light fear-potentiated startle. In an additional experiment, oxytocin had no effects on acoustic startle without previous fear conditioning. Further, in a context-conditioned test, previous light-shock fear conditioning did not increase acoustic startle during testing when the fear-conditioned light was not presented. The data suggest that oxytocin did not diminish cue-specific conditioned nor contextually conditioned fear, but reduced background anxiety. This suggests that oxytocin has unique effects of decreasing background anxiety without affecting learning and memory of a specific traumatic event. Oxytocin may have antianxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in PTSD patients.     

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.     

Brief post-stressor treatment with pregabalin in an animal model for PTSD: Short-term anxiolytic effects without long-term anxiogenic effect.

BACKGROUND:: The short- and long-term behavioral effects of a brief course of pregabalin, an antiepileptic structural analogue of alpha-aminobyturic acid with analgesic and anxiolytic effects, were assessed in an animal model of post-traumatic stress disorder (PTSD). METHOD:: Two-hundred thirty-three adult male Sprague-Dawley rats were employed. Behavioral responses to traumatic stress exposure (predator urine scent) were assessed immediately after (1 h) and 30 days after treatment with saline or pregabalin (at doses of 30, 100 and 300 mg/kg) in terms of behavior in the elevated plus maze (EPM) and the acoustic startle response (ASR) paradigms. At day 31 the freezing response to a trauma cue (clean cat litter) was assessed. The same treatment regimen initiated at day 7 was assessed at day 30 and in response to the trauma cue on day 31 in a separate experiment. RESULTS:: In the short term, doses of 100 mg/kg and 300 mg/kg of pregabalin effectively attenuated anxiety-like behaviors. In the longer-term, pregabalin did not attenuate the onset of PTSD-like behaviors or the prevalence rates of severe cue-responses, for either the immediate or the delayed treatment regimens. CONCLUSION:: Pregabalin may present an alternative compound for acute anxiolytic treatment after exposure to trauma, but has no long-term protective/preventive effects.     

Noradrenergic agonists and antagonists: Effects on conditioned fear as measured by the potentiated startle paradigm

Clonidine (10–40 g/kg) produced a dosedependent reduction of fear as measured by the potentiated startle effect (increased acoustic startle in the presence of a cue which had been previously paired with shock). The reduction of potentiated startle could not be accounted for entirely by a general depressant effect of clonidine on startle nor by an acceleration of extinction. Piperoxane and yohimbine, which are associated with anxiety in humans, increased potentiated startle, whereas propranolol and WB-4101 did not. These results provide further evidence that the potentiated startle paradigm in the rat is sensitive to drugs that alter anxiety in humans. Moreover, they support the hypothesis that norepinephrine transmission is important for the expression of fear or anxiety.     

Apomorphine,d-amphetamine,strychnine and yohimbine do not alter prepulse inhibition of the acoustic startle reflex

Rats were presented with noise bursts alone or noise bursts 60 ms after presentation of either a 60 dB or an 80 dB prepulse after injection of the dopamine agonists apomorphine (3 mg/kg) or d-amphetamine (4 mg/kg), the glycine antagonist strychnine (1.5 mg/kg) or the ₂ antagonist yohimbine (5 mg/kg). Presentation of prepulses inhibited startle, with greater inhibition following an 80 dB versus 60 dB prepulse. Apomorphine, d-amphetamine and strychnine increased overall startle levels but did not attenuate prepulse inhibition, since the absolute change in startle following prepulse presentation was significantly greater after administration of these drugs. A lower dose of apomorphine also increased startle but had no effect on prepulse inhibition using test intervals of 10, 60, 100, 200 or 1000 ms. While these drugs did decrease per cent prepulse inhibition, this seemed wholly attributable to their increasing overall startle levels, rather than a real attenuation of prepulse inhibition. Yohimbine did not alter either startle baseline or prepulse inhibition. The results do not support the conclusion that overactivity of dopamine systems attenuates prepulse inhibition and, in addition, suggest that prepulse inhibition does not result from activation of either glycine or norepinephrine projecting to ₂ adrenergic receptors.     

Elevated startle during withdrawal from acute morphine: a model of opiate withdrawal and anxiety

Rationale An elevated startle response has been observed in humans and animals during withdrawal from multiple substances of abuse, a phenomenon thought to reflect the anxiogenic effects of withdrawal. Although anxiety is a common symptom of opiate withdrawal, few studies have examined the effects of morphine withdrawal on acoustic startle.Objective To develop a procedure for assessing opiate dependence through measurement of the startle reflex in rats.Methods The effects of opiate withdrawal on startle were evaluated using both spontaneous and naloxone-precipitated withdrawal from an acute dose of morphine. The ability of the treatment drugs clonidine and chlordiazepoxide to block withdrawal-induced increases in startle was also tested.Results Spontaneous withdrawal from an injection of morphine sulfate produced a significant increase in acoustic startle 2 h (3.2 mg/kg) or 4 h (10 mg/kg) after drug administration. Morphine withdrawal (10 mg/kg morphine sulfate) precipitated by the opiate antagonist naloxone (2.5 mg/kg) also produced a significant increase in startle magnitude. This elevation of startle was blocked by both clonidine (35 g/kg) and chlordiazepoxide (10 mg/kg).Conclusions These data demonstrate that both spontaneous and precipitated withdrawal from an acutely administered opiate produce anxiety-like effects on acoustic startle. This paradigm may be useful in the study of anxiety and the early mechanisms of drug dependence.     

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.     

5-Methoxy-N,N-dimethyltryptamine: Spinal cord and brainstem mediation of excitatory effects on acoustic startle

The effects of different doses (0.03, 0.06, 0.12, 0.25, 1.0, 2.0, 4.0, and 8.0 mg/kg body weight) of 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) were tested on the acoustic startle reflex in rats. Beginning at 0.12 mg/kg, 5-MeODMT increased startle monotonically up to the highest dose used. 5-MeODMT still increased startle in acutely decerebrate rats or when infused directly onto the spinal cord. The excitatory effects of a high systemic dose of 5-MeODMT were completely blocked by cinanserin, cyproheptadine, and propranolol, but not by parachlorophenylalanine, -methyl-p-tyrosine, haloperidol, sotalol, or phenoxybenzamine. The results were discussed in terms of a new theory, which suggests that stimulation of serotonin receptors in the spinal cord enhance startle whereas serotonin receptors in the forebrain inhibit startle.