Genetic influences on cardiovascular responses to an acoustic startle stimulus in rats

1. The aim of the present study was to assess the cardiovascular differences among five inbred rat strains (n=16 per strain), including spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) rats, Wistar Furth (WF) rats, Fischer (F344) rats and Lewis (Lew) rats and the usual outbred Wistar (W) rat strain (n=25). 2. These strains were compared under resting conditions for blood pressure (BP) and heart rate (HR) levels and for their baroreceptor-HR reflex sensitivity. In addition, their responses to an acoustic startle stimulus were measured. 3. A consistent rise in BP was observed among the groups as a result of the noise stimulus. This rise in systolic BP (SBP) averaged (+/-SEM) 37 +/- 2 mmHg in the SHR and 34 +/- 4 mmHg in F344 rats, while the response was only 23 +/- 3 mmHg in WKY rats. Pulse pressure (PP) was increased following noise in all groups. The delay for the BP response for all groups combined was 1.6 +/- 0.1 s. 4. Most animals had minimal HR variations, except F344 rats, responding with a 42 +/- 13 b.p.m. decrease 3.0 s after the stimulus (i.e. 1.3 s after the maximal 34 +/- 4 mmHg SBP rise). 5. The highest SBP (160 +/- 3 mmHg) and diastolic BP (104 +/- 3 mmHg) were observed in inbred SHR. Other groups were normotensive. Resting PP was elevated for SHR (56 +/- 2 mmHg) compared with the other groups (40 +/- 2 mmHg). The highest HR was found in F344 and WF rats, with 389 +/- 11 and 372 +/- 7 b.p.m., respectively. The lowest HR was observed in SHR and Lewis rats, with 335 +/- 7 and 323 +/- 7 b.p.m., respectively. The least sensitive baroreflex function was observed in SHR (0.8 +/- 0.1 b.p.m./mmHg) compared with the other strains (1.4 +/- 0.2 b.p.m./mmHg). 6. The present study confirms the importance of genetic factors on the cardiovascular responses of rats to a noise startle stimulus. Two inbred normotensive rat strains, namely F344 and WKY rats, which exhibit a substantial difference in pressor response to noise, may be used to unravel the mechanisms of sympathetic activation.     

Antihypertensive monotherapy and cardiovascular responses to an acoustic startle stimulus

To determine contribution of the autonomic nervous system to cardiovascular reactivity to noise, acoustic startle stimulus (110 dB, 1-20 kHz, 0.150 s) was administered to 35 subjects (19 women, 16 men) with mild essential hypertension. Among these patients, 10 were unmedicated and 25 were receiving long-term monotherapy (10 were taking 100 mg atenolol, 5 were taking 10 mg prazosin, and 10 were taking 50 mg losartan daily). Polygraphic recordings were obtained in supine position. Blood pressure (BP) and heart rate (HR) levels were stable until the noise was administered. In the unmedicated group BP and HR were elevated during the first 10 s. BP returned to resting levels after this period. The calculated hemodynamic indexes showed a biphasic change in total peripheral resistance (TPR), with an overall vasoconstriction associated with the BP rise phase, preceding a delayed vasodilation. The lowest HR changes were observed in the beta-blocker group with increases of 6 beats/min and 3 beats/min after the first and second noise stimulations, compared with 10 beats/min and 5 beats/min in the unmedicated group. Prazosin significantly reduced the BP rises to 7 mm Hg and 6 mm Hg for systolic BP and diastolic BP after the first stimulation compared with 22 mm Hg and 17 mm Hg in the untreated group (p < 0.01). The second stimulation after prazosin determined -5 mm Hg and 1 mm Hg changes for systolic BP and diastolic BP respectively, compared to rises of 13 mmHg for systolic BP and 10 mmHg for diastolic BP in the untreated group (p < 0.01). The hemodynamic percentage changes resulting from the first stimulation indicated prazosin markedly reduced the noise-induced rise in TPR (p < 0.05). No effect of beta-blocker was detectable using percentage changes. The rises in BP were amplified in the losartan-treated subjects compared with the other groups. Because of a low resting TPR in this group, the percentage changes in TPR resulting from noise were amplified in the subjects treated with the AT1 receptor antagonist. In conclusion the acoustic startle stimulus appeared as a simple and reliable procedure for inducing transient increases due to a rise in TPR. Cardiovascular responses differed according to the antihypertensive monotherapy, with a limited effect of noise in the prazosin-treated group.     

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.     

Diethyldithiocarbamate depresses the acoustic startle response in rats

The relationship between norepinephrine (NE) content in cortex and spinal cord and acoustic startle amplitude was investigated in two experiments. Administration of diethyldithiocarbamate (DDC) depressed startle amplitude at the same time and dose that it most severely depleted NE content. These results support the conclusion that NE facilitates the normal elaboration of the acoustic startle reflex and also support evidence that NE activity in the spinal cord may be of particular importance in the maintenance of normal startle amplitude.     

Trimethyltin disrupts acoustic startle responding in adult rats

Trimethyltin (TMT) is a limbic-system toxicant which also produces sensory dysfunction in adult animals. In the present experiment, we examined the effects of TMT on the acoustic startle response. Adult male, Long-Evans rats (N = 12/dose) received a single i.p. injection of either 0, 4.0, 5.0 or 6.0 mg/kg TMT hydroxide as the base. The number of responses, latency and peak amplitude of the startle response to a 13 kHz, 120 dB tone were measured 2 h, 2 weeks, and 4 weeks after dosing. For each test session, 10 stimuli were presented at each of three background noise levels (50, 65 and 80 dB). By 2 h after dosing, the number of responses and response amplitude were decreased following 4.0-6.0 mg/kg TMT; these treatment effects persisted through 4 weeks after dosing. Increases in latency were also seen following all dosages of TMT. These data suggest that TMT produces disruption of function within the acoustic-startle pathway.     

Effects of nicotine on the acoustic startle reflex amplitude in rats

The acoustic startle reflex was used to measure changes in sensorimotor reactivity in response to nicotine administration and cessation. Male rats received saline, 6 mg/kg/day or 12 mg/kg/day nicotine delivered subcutaneously by osmotic minipumps. The pumps delivered their contents during a 10-day period of implantation, after which time they were explanted. Animals were tested for startle reflex amplitudes using two levels of white noise bursts prior to pump implantation, on days 1 and 7 of nicotine or saline administration, and on several days following drug cessation. Nicotine produced a dose-dependent increase in startle amplitude during the period of administration that decreased during cessation. Results are interpreted in terms of nicotine's actions to enhance attentional processes.This research was supported in part by USUHS protocol CO 7223. The views and opinions contained herein are the private ones of the authors and do not represent the opinions of the Uniformed Services University of the Health Sciences, the Department of Defense, or the Armed Forces Radiobiology Research Institute.     

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.].     

Estrogen increases prepulse inhibition of acoustic startle in rats.

Epidemiological studies have shown gender differences in the age of onset and symptoms of schizophrenia. Because sensorimotor gating mechanisms are deficient in schizophrenia, we studied the effect of administration of estrogen on prepulse inhibition of startle in rats, an animal model of sensorimotor gating. Rats were tested in an automated startle apparatus for their responses to random combinations of 115-dB sound pulses and prepulses of various intensity. Startle responses were reduced by increasing intensities of prepulses, indicating prepulse inhibition. Repeated administration of startle pulses caused gradual habituation of startle responses. Ovariectomy did not induce significant changes in either habituation of the startle response or prepulse inhibition of startle. Treatment with 17beta-estradiol caused an increase in percentage prepulse inhibition at all prepulse intensities at 18 h, but only at higher prepulse intensities at 30 min after injection. Habituation of startle responses was not affected. The enhancing effect of estradiol on prepulse inhibition was mimicked by testosterone, but not by dihydrotestosterone. Estradiol treatment increased prepulse inhibition similarly in controls or after disruption of prepulse inhibition induced by treatment with apomorphine or dizocilpine (MK-801). Our results may help to explain gender differences in schizophrenia and some of the beneficial clinical effects of estrogen treatment in this disease.     

Effects of selected anticholinergics on acoustic startle response in rats

The present study compared the effects of the anticholinergics aprophen hydrochloride, atropine sulfate, azaprophen hydrochloride, benactyzine hydrochloride, biperiden hydrochloride, diazepam, procyclidine hydrochloride, scopolamine hydrobromide and trihexyphenidyl hydrochloride on acoustic startle response in rats. Peak startle amplitude, latency to peak startle amplitude and prepulse inhibition following 100- and 120-dB tones were recorded 15 min following drug administration in food-restricted rats. Aprophen, atropine, azaprophen, benactyzine, biperiden and scopolamine significantly increased peak startle amplitude and decreased latency to peak startle amplitude following 100-dB pulses. In contrast, only biperiden increased peak startle amplitude following 120-dB pulses, whereas atropine and trihexyphenidyl decreased latency to peak startle amplitude following 120-dB pulses. Benactyzine decreased prepulse inhibition following both 100- and 120-dB pulses, whereas both biperiden and scopolamine decreased prepulse inhibition following 120-dB pulses. Acoustic startle response measures were effective in differentiating the effects of anticholinergic compounds. The comparison of drug effects on the acoustic startle response may be useful in selecting efficacious anticholinergic drug therapies with a minimal range of side-effects. In addition, these data may be useful in down-selecting the number of anticholinergic drugs that need to be tested in comparison studies involving more complex behavioral tests.     

Tryptophan-free diet: Effects on the acoustic startle reflex in rats

In Experiment 1, body weights of rats fed a powdered tryptophan-free (TF) diet decreased monotonically during a 13-day period. Control animals fed the same diet supplemented with 0.5% l-tryptophan gained weight. The groups did not differ significantly in acoustic startle amplitude measured at 2, 4, 6, 7, 9, 11, and 13 days despite a 28% decrease in whole-brain serotonin in the TF rats. In Experiment 2, daily intubation of rats with a syrup form of each diet maintained the two groups' body weights at comparable levels. TF diet intubation decreased whole-brain serotonin by 64% and produced significantly elevated startle amplitudes, which returned to control levels when 0.5% l-tryptophan was added to the diet. Changes in whole-brain serotonin level preceded changes in startle amplitude by several days. In Experiment 3, acute injections of 125 mg/kg l-tryptophan significantly reduced the startle amplitude of TF diet intubated rats and significantly raised their brain serotonin levels. The results show that acoustic startle reflex is increased by a TF diet, provided the animals receive adequate nourishment, and suggest that this facilitation may result from depletion of brain serotonin.     

Effects of apomorphine and haloperidol on the acoustic startle response in rats

A series of 3 experiments tested the effects of 0.01, 0.04, 0.19, 0.75, 3.00, and 6.00 mg/kg apomorphine and 0.13, 0.25, and 0.50 haloperidol on the acoustic startle response in rats. Apomorphine markedly facilitated startle amplitude for about 40 min after injection and then depressed startle over the next 40 min. Both the early facilitory and later inhibitory effects were directly related to the dose. Haloperidol (0.5 mg/kg — given 30 min before) completely blocked both the early facilitory and the later depressant effect of apomorphine (3 mg/kg). Haloperidol alone had only a slight depressant effect on startle. The data support the conclusion that DA receptor stimulation enhances acoustic startle amplitude and indicate that a previous report failed to find an effect of apomorphine on startle because startle was only measured 40 min after injection.     

Serotonergic modulation of the acoustic startle response in rats during preweaning development

The involvement of serotonin (5-HT) in modulating the acoustic startle response (ASR) is well established in adult rats, but 5-HT involvement during the preweaning period, when 5-HT neurons undergo extensive development, has not previously been described. Three 5-HT receptor subtypes are reported to modulate the ASR in adult rats: 5-HT1A and 5-HT2 receptor agonists facilitate the ASR, whereas 5-HT1B agonists decrease the response. In the present study, the effects of 5-HT agonists and generalized 5-HT depletion on the ASR were studied in preweanling animals, using independent groups of Long-Evans rats tested on postnatal day (PND) 13, 17 and 21. 8-Hydroxy-2-(di-n-propylamino) tetralin (8OHDPAT, 62-1000 micrograms/kg), a 5-HT1A receptor agonist, and 5-methoxy-N,N-dimethyl tryptamine (MeODMT, 2-4 mg/kg), a nonselective 5-HT agonist, had no effect on PND 13 and then increased the ASR on PND 17 and 21. The 5-HT2 receptor antagonists cyproheptadine (5 mg/kg) and ketanserin (5 mg/kg) blocked the effect of MeODMT at both ages, providing some evidence that MeODMT increased the ASR through 5-HT2 receptors. 1-(m-Chlorophenyl) piperazine (mCPP, 1-5 mg/kg), a 5-HT1B agonist, had no effect on ASR amplitude on PND 13 or 17 and then produced a dose-related decrease in the response on PND 21. Generalized depletion of 5-HT by 80-90% in whole-brain and spinal cord, using p-chlorophenylalanine (PCPA, 300 mg/kg 24 hr prior to testing), did not alter ASR amplitude at any age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Deficient prepulse inhibition of acoustic startle in Hooded-Wistar rats compared with Sprague-Dawley rats

1. Prepulse inhibition of acoustic startle has been suggested as a model of sensorimotor gating and central sensory information processing. Prepulse inhibition is impaired in patients with schizophrenia and responses can be restored by antipsychotic drug treatment. In the present study, startle and prepulse inhibition of startle were compared in different rat strains. 2. Sprague-Dawley rats showed robust inhibition of startle responses by increasing intensities of prepulse delivered just before the startle stimulus. In contrast, at both 4 and 10 weeks of age, rats of the Hooded-Wistar line had markedly reduced prepulse inhibition, although startle responses were not different. 3. Treatment with the dopamine receptor agonist apomorphine (0.1 mg/kg) or the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 (0.1 mg/kg) caused disruption of prepulse inhibition in Sprague-Dawley rats. In Hooded-Wistar rats, apomorphine further reduced the already low level of prepulse inhibition, but MK-801 treatment had no significant effect. This suggests that the impaired prepulse inhibition in Hooded-Wistar rats could be caused by changes in glutamatergic activity and/or NMDA receptors in these rats. 4. In photocell cages, spontaneous exploratory activity and inner zone activity were significantly lower in Hooded-Wistar rats than in Sprague-Dawley rats. Similarly, on the elevated plus-maze, Hooded-Wistar rats showed a lower propensity to visit the open arms. In contrast, amphetamine (0.5 mg/kg)-induced locomotor hyperactivity, an animal model of psychosis, was enhanced in Hooded-Wistar rats. 5. These data suggest that the Hooded-Wistar line could be a useful genetic animal model to study the interaction of glutamatergic and dopaminergic mechanisms in anxiety and schizophrenia.     

Effects of the phosphodiesterase inhibitor rolipram on the acoustic startle response in rats

Systemic administration of the phosphodiesterase inhibitor rolipram (0.05–10.0 mg/kg, IP) produced a rapid and dose-related increase in the amplitude of the acoustic startle response in rats. The (−) isomer was more potent than the (+) isomer in enhancing startle amplitude. Rolipram increased startle responses that were elicited by brief electrical stimulation of the ventral cochlear nucleus or nucleus reticularis pontis caudalis, two brainstem relay nuclei of the startle neural circuit. A low (5 μg) dose of rolipram produced an excitatory effect on startle following spinal (lumbar intrathecal) infusion but not following supraspinal (lateral ventricle) infusion. Rolipram (0.5 mg/kg, IP) excitation of startle was not blocked by drugs which differentially disrupt the release of monoamines (DSP4, reserpine + alpha-methylpara-tyrosine, reserpine + para-chloro-phenylalanine) or by drugs which differentially block monoamine receptors (haloperidol, prazosin, idazoxan, cinanserin, or cyproheptadine). The marked increase in startle seen following systemic rolipram injection is attributable, at least in part, on an action in the lumbar spinal cord that directly or indirectly facilitates neural transmission along the reticulospinal component of the startle reflex neural pathway. The startle reflex should be a useful behavioral test system for studying the mechanism of action of rolipram and related compounds purported to selectively inhibit calmodulin-independent forms of phosphodiesterase.     

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.     

Effects of tryptophan deficiency on prepulse inhibition of the acoustic startle in rats

Rationale Serotonin (5-HT) plays a key role in the pathophysiology of psychotic disorders, presumably through a modulation of dopamine (DA) transmission. Reduction of 5-HT signaling has been suggested to enhance dopaminergic responses in animal models of psychosis. An intriguing naturalistic strategy to reduce 5-HT brain content is afforded by the dietary restriction to its precursor, l-tryptophan (TRP). Objective We investigated the impact of a TRP-deficient diet in rats on the prepulse inhibition of the startle (PPI), a measure of sensorimotor gating which is typically impaired by psychotomimetic substances. Materials and methods After either short-term (6 h) or long-term (14 days) TRP deprivation, rats were tested for startle reflex and PPI. Moreover, we assessed the impact of both TRP deprivation regimens on PPI reduction induced by the psychotomimetic substance d-amphetamine (AMPH). Results Both TRP-deficient regimens failed to significantly affect PPI responses. However, chronic, but not short-term, TRP-deficient diet induced a significant sensitization to the effects of AMPH (1.25–2.5 mg/kg, subcutaneous). The enhanced predisposition to PPI disruption elicited by prolonged TRP deprivation was completely reversed 24 h after reinstatement of TRP in the diet, as well as pretreatment with antipsychotic drugs haloperidol (0.1 mg/kg, intraperitoneal) and clozapine (5 mg/kg, intraperitoneal), which exert their therapeutic action mostly through blockade of DA D₂ receptors. Conclusions The present results confirm and extend previous findings on the impact of serotonergic signaling in the modulation of DA transmission in schizophrenia and point to chronic TRP deprivation as a potential model of environmental manipulation that may produce a sensitization to psychotic-like symptoms induced by dopaminergic activation. Fabio Fadda and Roberto Stancampiano contributed equally to the study.     

Apomorphine disrupts the inhibition of acoustic startle induced by weak prepulses in rats

Separate experiments conducted in two different laboratories assessed the importance of the prepulse intensity in the ability of apomorphine to reduce prepulse inhibition of acoustic startle responses. Rats were presented with noise bursts alone or noise bursts 100 ms after presentation of prepulse stimuli ranging from 70 to 85 or 90 dB. Throughout testing, the background noise was maintained at 65 dB. In both laboratories, apomorphine markedly decreased the absolute magnitude of prepulse inhibition when the prepulse stimuli were no more than 10 dB above the background. With more intense prepulse stimuli, apomorphine had no significant effect on prepulse inhibition. Hence, apomorphine does not interfere with the inhibitory process which actually mediates prepulse inhibition, but appears to affect the detectability of the prepulse.     

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.     

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.     

Effects of topiramate on the prepulse inhibition of the acoustic startle in rats.

The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.