Biomedical subjects

Mark A Geyer

Publications and source records attributed to Mark A Geyer.

At least 19 recordsLinked to original sources

PubMed2006

The roles of 5-HT1A and 5-HT2 receptors in the effects of 5-MeO-DMT on locomotor activity and prepulse inhibition in rats.

RATIONALE: The hallucinogen 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is structurally similar to other indoleamine hallucinogens such as LSD. The present study examined the effects of 5-MeO-DMT in rats using the Behavioral Pattern Monitor (BPM), which enables analyses of patterns of locomotor activity and exploration, and the prepulse inhibition of startle (PPI) paradigm. OBJECTIVES: A series of interaction studies using the serotonin (5-HT)(1A) antagonist WAY-100635 (1.0 mg/kg), the 5-HT(2A) antagonist M100907 (1.0 mg/kg), and the 5-HT(2C) antagonist SER-082 (0.5 mg/kg) were performed to assess the respective contributions of these receptors to the behavioral effects of 5-MeO-DMT (0.01, 0.1, and 1.0 mg/kg) in the BPM and PPI paradigms. RESULTS: 5-MeO-DMT decreased locomotor activity, investigatory behavior, the time spent in the center of the BPM chamber, and disrupted PPI. All of these effects were antagonized by WAY-100635 pretreatment. M100907 pretreatment failed to attenuate any of these effects, while SER-082 pretreatment only antagonized the PPI disruption produced by 5-MeO-DMT. CONCLUSIONS: While the prevailing view was that the activation of 5-HT(2) receptors is solely responsible for hallucinogenic drug effects, these results support a role for 5-HT(1A) receptors in the effects of the indoleamine hallucinogen 5-MeO-DMT on locomotor activity and PPI in rats.

Animals↗

PubMed2006

The neural correlates of habituation of response to startling tactile stimuli presented in a functional magnetic resonance imaging environment.

Functional magnetic resonance imaging (fMRI) provides a means of identifying neural circuitry associated with startle and its modulation in humans. Twelve subjects who demonstrated eyeblink startle in the laboratory were recruited for an fMRI study in which they were scanned while presented with two identical runs consisting of alternating blocks of no stimuli and startling tactile stimuli. Together, behavioral and imaging data are consistent with a pattern of general cortical and thalamic activation induced by startling stimuli that shows habituation both across and within runs. From Run 1 to Run 2, both the eyeblink amplitude and the fMRI signal decreased. Within Run 1, there was a graded decrease in eyeblink amplitude and whole-brain fMRI signal across blocks of startling stimuli. A similar graded decrease was observed in the thalamus signal, as well. Thus, startling tactile stimuli initially induce widespread cortical and thalamic activity, perhaps mediated by the reticular activating system. The activity then habituates in a graded fashion with repeated presentations of the stimuli.

Adult↗

PubMed2006

A fMRI investigation of startle gating deficits in schizophrenia patients treated with typical or atypical antipsychotics.

A key feature of schizophrenia is the inability to screen out irrelevant sensory input. Prepulse inhibition (PPI) of the startle response, a cross-species measure of sensorimotor gating, provides a valuable opportunity to study this feature. PPI is reliably impaired in schizophrenia. Animal models of disrupted PPI have proved valuable for the evaluation of antipsychotic substances. The cortico-striato-pallido-thalamic circuitry is primarily responsible for modulation of PPI in animals. We examined PPI and its brain correlates, using functional magnetic resonance imaging (fMRI), in men with schizophrenia treated with typical or atypical antipsychotics. Thirty men with schizophrenia on stable doses of typical antipsychotics (n=10), risperidone (n=10) or olanzapine (n=10; 9 with usable fMRI data) and 12 healthy men underwent psychophysiological testing and fMRI during a tactile PPI paradigm. The results showed reduced PPI of the eye-blink startle response in patients compared with healthy controls. Within the patient group, those on typical antipsychotics showed significantly impaired PPI but risperidone- or olanzapine-treated patients showed a milder (non-significant) deficit. Increased activity in the striatum, thalamus, insula, hippocampal, temporal, inferior frontal and inferior parietal regions occurred in association with PPI in controls. Patients treated with risperidone or olanzapine, but not with typical antipsychotics, showed significant activation in PPI-relevant regions. Our findings provide preliminary evidence that atypical antipsychotics positively influence PPI and partially restore associated brain functions in schizophrenia. Imaging data buttress the validity of PPI as a useful animal model of schizophrenia.

Acoustic Stimulation↗

PubMed2006

Prepulse inhibition and P50 suppression: commonalities and dissociations.

Patients with schizophrenia exhibit reduced levels of both prepulse inhibition of the startle reflex (PPI) and condition-test suppression of the P50 event-related potential. This study investigated the extent to which PPI and P50 suppression, which exhibit similar parametric sensitivities, are intrinsically auditory phenomena or can be induced cross-modally, and reflect common or distinct neural mechanisms of inhibition. PPI, N100, and P50 were assessed in 20 healthy male volunteers, using auditory test probes and both visual and auditory lead stimuli, separated by 100- or 500-ms interstimulus intervals (ISIs). PPI was found in the auditory-lead condition across the complete group, and with visual-lead stimuli in approximately half of the subjects. Intra-modal auditory PPI was significantly higher with the 100-ms ISI than with the 500-ms ISI. P50 suppression was found only with the 500-ms ISI, with no difference between the auditory and visual conditions. Source analyses revealed that suppression was associated with frontal cortical activity. N100 suppression was found only in the auditory condition, with no difference between 100- and 500-ms ISIs. Although both phenomena are considered to provide operational measures of gating, PPI and P50 suppression are differentially sensitive to ISI and therefore reflect partly different neural mechanisms. They are not intrinsically auditory phenomena, and both appear to involve frontal cortical activity. In contrast, N100 suppression is most likely based on refractory mechanisms intrinsic to the auditory system.

Acoustic Stimulation↗

PubMed2006

Differential contributions of dopamine D1, D2, and D3 receptors to MDMA-induced effects on locomotor behavior patterns in mice.

MDMA or 'ecstasy' (3,4-methylenedioxymethamphetamine) is a commonly used psychoactive drug that has unusual and distinctive behavioral effects in both humans and animals. In rodents, MDMA administration produces a unique locomotor activity pattern, with high activity characterized by smooth locomotor paths and perseverative thigmotaxis. Although considerable evidence supports a major role for serotonin release in MDMA-induced locomotor activity, dopamine (DA) receptor antagonists have recently been shown to attenuate these effects. Here, we tested the hypothesis that DA D1, D2, and D3 receptors contribute to MDMA-induced alterations in locomotor activity and motor patterns. DA D1, D2, or D3 receptor knockout (KO) and wild-type (WT) mice received vehicle or (+/-)-MDMA and were tested for 60 min in the behavioral pattern monitor (BPM). D1 KO mice exhibited significant increases in MDMA-induced hyperactivity in the late testing phase as well as an overall increase in straight path movements. In contrast, D2 KO mice exhibited reductions in MDMA-induced hyperactivity in the late testing phase, and exhibited significantly less sensitivity to MDMA-induced perseverative thigmotaxis. At baseline, D2 KO mice also exhibited reduced activity and more circumscribed movements compared to WT mice. Female D3 KO mice showed a slight reduction in MDMA-induced hyperactivity. These results confirm differential modulatory roles for D1 and D2 and perhaps D3 receptors in MDMA-induced hyperactivity. More specifically, D1 receptor activation appears to modify the type of activity (linear vs circumscribed), whereas D2 receptor activation appears to contribute to the repetitive circling behavior produced by MDMA.

Analysis of Variance↗

PubMed2006

Iloperidone reduces sensorimotor gating deficits in pharmacological models, but not a developmental model, of disrupted prepulse inhibition in rats.

Iloperidone is a novel atypical antipsychotic which acts as a broad spectrum dopamine/serotonin/norepinephrine receptor antagonist. To compare iloperidone behaviorally to other known antipsychotics, we evaluated the drug in three pharmacological models and one developmental model of disrupted prepulse inhibition (PPI) in rats. Firstly, 0.5 mg/kg apomorphine induced PPI deficits that were prevented by pretreatment with iloperidone (1 and 3 mg/kg). Secondly, treatment with the N-methyl-D-aspartate (NMDA)-receptor antagonist phencyclidine (PCP) produced robust deficits in PPI. Both doses of iloperidone (1 and 3 mg/kg) prevented the PPI-disruptive effects of treatment with 1 mg/kg PCP. Thirdly, treatment with the alpha1-adrenoceptor agonist cirazoline (0.6 mg/kg) disrupted PPI, and produced a concurrent large increase in startle magnitude. A relatively low dose of iloperidone (0.3 mg/kg) prevented cirazoline-induced PPI deficits, independent of its effects on startle magnitude. Finally, iloperidone (1 mg/kg) did not reverse PPI deficits in the isolation-rearing model of schizophrenia. These results indicate that iloperidone exerts behavioral effects in pharmacological models of disrupted sensorimotor gating consistent with "atypical" antipsychotics, mediated by antagonism of dopaminergic and noradrenergic receptors. The absence of effect in isolation-reared rats may be due to the relatively small effect size of isolation rearing on PPI or dose of iloperidone.

Acoustic Stimulation↗

PubMed2006

A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia.

BACKGROUND: As a test of plausibility for the hypothesis that schizophrenia can result from abnormal brain, especially cerebral cortical, development, these studies examined whether, in the rat, disruption of brain development initiated on embryonic day (E) 17, using the methylating agent methylazoxymethanol acetate (MAM), leads to a schizophrenia-relevant pattern of neural and behavioral pathology. Specifically, we tested whether this manipulation leads to disruptions of frontal and limbic corticostriatal circuit function, while producing schizophrenia-like, region-dependent reductions in gray matter in cortex and thalamus. METHODS: In offspring of rats administered MAM (22 mg/kg) on E17 or earlier (E15), regional size, neuron number and neuron density were determined in multiple brain regions. Spontaneous synaptic activity at prefrontal cortical (PFC) and ventral striatal (vSTR) neurons was recorded in vivio. Finally, cognitive and sensorimotor processes mediated by frontal and limbic corticostriatal circuits were assessed. RESULTS: Adult MAM-E17-exposed offspring showed selective histopathology: size reductions in mediodorsal thalamus, hippocampus, and parahippocampal, prefrontal, and occipital cortices, but not in sensory midbrain, cerebellum, or sensorimotor cortex. The prefrontal, perirhinal, and occipital cortices showed increased neuron density with no neuron loss. The histopathology was accompanied by a disruption of synaptically-driven "bistable membrane states" in PFC and vSTR neurons, and, at the behavioral level, cognitive inflexibility, orofacial dyskinesias, sensorimotor gating deficits and a post-pubertal-emerging hyper-responsiveness to amphetamine. Earlier embryonic MAM exposure led to microcephaly and a motor phenotype. CONCLUSIONS: The "MAM-E17" rodent models key aspects of neuropathology in circuits that are highly relevant to schizophrenia.

Amphetamine↗

PubMed2006

Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist.

The in vitro and in vivo pharmacological properties of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonist ACP-103 competitively antagonized the binding of [(3)H]ketanserin to heterologously expressed human 5-HT(2A) receptors with a mean pK(i) of 9.3 in membranes and 9.70 in whole cells. ACP-103 displayed potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a mean pIC(50) of 8.7. ACP-103 demonstrated lesser affinity (mean pK(i) of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC(50) 7.1 in R-SAT) at human 5-HT(2C) receptors, and lacked affinity and functional activity at 5-HT(2B) receptors, dopamine D(2) receptors, and other human monoaminergic receptors. Behaviorally, ACP-103 attenuated head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT(2A) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduced the hyperactivity induced in mice by the N-methyl-d-aspartate receptor noncompetitive antagonist 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.), consistent with a 5-HT(2A) receptor mechanism of action in vivo and antipsychotic-like efficacy. ACP-103 demonstrated >42.6% oral bioavailability in rats. Thus, ACP-103 is a potent, efficacious, orally active 5-HT(2A) receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent.

Animals↗

PubMed2006

Isolation rearing of mice induces deficits in prepulse inhibition of the startle response.

Male 129T2 and C57BL/6J mice were housed either in groups of three (socials) or singly (isolates) at weaning. Six and seven weeks later, prepulse inhibition (PPI), startle reactivity, and locomotor activity (LMA) were measured. Isolation-reared mice of both strains exhibited PPI deficits compared to socially reared controls in at least one of the two PPI test sessions. Isolation rearing had no effect on startle reactivity or habituation and only 129T2 isolates exhibited increased LMA. Isolation rearing induced locomotor hyperactivity and PPI deficits in mice and may be an effective developmental manipulation to use in combination with studies of genetically altered mice.

Acoustic Stimulation↗

PubMed2006

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.

Acoustic Stimulation↗

PubMed2006

Are cross-species measures of sensorimotor gating useful for the discovery of procognitive cotreatments for schizophrenia?

Prepulse inhibition of startle (PPI), a measure of sensorimotor gating used to identify antipsychotics, is reduced in schizophrenia patients and in rodents treated with dopamine agonists or glutamate antagonists. The National Institute of Mental Health (NIMH)-funded Measurement And Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program has initiated a new era in the development of procognitive cotreatments in schizophrenia, independently of treating positive symptoms. Although PPI is not a cognitive process per se, such abnormalities in attention may be predictive of or lead to cognitive deficits. Since first-generation antipsychotics block PPI deficits induced by dopamine agonists, this model cannot identify cognitive enhancers for use as cotreatments with antipsychotics. PPI deficits caused by glutamate antagonists, like the exacerbation of symptoms they produce in patients, are insensitive to dopamine antagonists, but reduced by clozapine. Similarly, both PPI and cognitive deficits in schizophrenia patients are insensitive to first-generation antipsychotics, but attenuated by clozapine. Hence, treatment-induced reversals of glutamate antagonist effects on PPI may provide animal and human models to identify treatments of cognitive deficits in patients already treated with existing antipsychotics.

Acoustic Stimulation↗

PubMed2005

New approaches to measurement and treatment research to improve cognition in schizophrenia.

An overview is provided of the set of articles included in this special issue of Schizophrenia Bulletin that were derived from the final meeting of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) program. These essays summarize the presentations and discussions of the MATRICS New Approaches Conference that examined the future needs of the field for a coordinated research effort to improve the preclinical and clinical science required to optimize new cotreatments for the cognitive deficits in patients with schizophrenia. Specific priorities for a research agenda involving collaborations among academic, industrial, and governmental participants are addressed.

Cognition Disorders↗

PubMed2005

An investigation of the efficacy of mood stabilizers in rodent models of prepulse inhibition.

Acutely manic bipolar patients, like patients with schizophrenia, Tourette's syndrome, panic disorder, and obsessive compulsive disorder, exhibit deficits in sensorimotor gating, as measured by prepulse inhibition (PPI) of the startle response. Here, we assessed the ability of four drugs used in the treatment of bipolar mania-phenytoin, carbamazepine, valproate, and lithium-to reduce the PPI-disruptive effects of ketamine or amphetamine in the 129SvPasIco inbred strain of mice. For comparison, we also assessed the interaction of lithium and amphetamine in C57BL/6J mice. This set of studies yielded four major results. 1) Lithium chloride (85 mg/kg) prevented amphetamine-induced but not ketamine-induced disruption of PPI in both strains of mice. 2) Carbamazepine (50 mg/kg) prevented ketamine-induced but not amphetamine-induced disruption of PPI. 3) Sodium valproate (100 mg/kg) did not prevent amphetamine- or ketamine-induced disruption of PPI. 4) Phenytoin (30 mg/kg) did not prevent amphetamine- or ketamine-induced disruption of PPI but increased PPI on its own. These studies did not reveal a consistent relationship between the ability of a drug to protect PPI from disruption by ketamine or amphetamine and efficacy in the treatment of bipolar mania. Instead, the diverse effect profiles of these four treatments in reversing the PPI deficits produced by amphetamine or ketamine in mice presumably reflect the differences in their respective pharmacological mechanisms. Hence, further studies using these dopaminergic and glutamatergic models of deficient PPI may provide valuable insights into the mechanisms underlying the differential therapeutic effects of antimanic and mood-stabilizing treatments.

Amphetamine↗

PubMed2005

Developing predictive animal models and establishing a preclinical trials network for assessing treatment effects on cognition in schizophrenia.

Animal models are an essential initial phase in the discovery of novel drugs to treat psychiatric disorders. At the sixth Measurement and Treatment Research to Improve Cognition in Schizophrenia conference, "New Approaches to Assessing and Improving Cognition in Schizophrenia," a discussion group was formed to address issues related to the development of predictive animal models of cognition that may be used as preclinical assays for putative cognitive enhancers. We identified 2 complementary approaches used to model cognitive impairments in animals. First, basic lesion/pharmacological models provide information about the particular neural substrates that may underlie different types of cognitive deficits found in schizophrenia. Findings from these studies can be mapped onto the second, more elaborate and etiologically relevant neurodevelopmental models of the disorder to ascertain which cognitive systems may be altered by early developmental insults. Particular attention must be given to the types of animal tasks used, in order to relate directly to the cognitive domains that are affected in schizophrenia patients. Importantly, the validation and standardization of the methodologies used in these preclinical assays would require the establishment of a preclinical trials network, serving as a counterpart to the recently established Treatment Units for Research on Neurocognition and Schizophrenia. The need to validate specific approaches to assess cognitive functions relevant to schizophrenia could be satisfied by a concerted effort enabled by a new funding directive from the National Institute of Mental Health with the explicit purpose of facilitating research on these models and assessing novel drug therapies that may be used to ameliorate the cognitive deficits in schizophrenia.

Animals↗

PubMed2005

The effects of sex and neonatal maternal separation on fear-potentiated and light-enhanced startle.

This study was based on the higher prevalence of anxiety disorders in women than in men, and on the finding that early adverse experiences are a major risk factor for the development of anxiety disorders later in life. The object of this study was to investigate in rats, the sensitivities of the light-enhanced startle (LES) and fear-potentiated startle (FPS) paradigms to sex differences and to determine the effects of maternal separation (MS) on the baseline startle magnitude and potentiated startle response in these paradigms. Pups in the MS group were separated daily from their mother for 180 min/day from postnatal day 2 (PND2) to PND14. Control litters remained undisturbed. The adult male and female progeny were tested in the FPS and LES. As predicted, females showed a significantly greater potentiation of startle than males in the FPS, and a strong trend towards greater startle potentiation in the LES. Contrary to predictions, MS had no effect on startle potentiation in the FPS and severely disrupted LES in female, but not male rats. The observed sex differences add to the validity of the FPS and LES as animal paradigms of fear and anxiety. The findings indicate that these paradigms can be used to study the biological basis of sex differences in fear and anxiety. In contrast, the effects of MS on startle potentiation argue against the idea that MS provides a robust model for the predicted influences of early adverse effects on these startle potentiation measures of fear and anxiety.

Age Factors↗

PubMed2005

On the waveform of the acoustic startle blink in the paradigm of prepulse inhibition - methodological and physiological aspects.

Recent studies suggest that the eye blink response to intense acoustic stimuli consists of two components that may occasionally result in waveforms with two peaks. In the present study, the prevalence, peak latencies, and peak magnitudes in responses exhibiting one or two peaks were investigated in healthy subjects in 25 pulse-alone and 25 prepulse-pulse trials using an interstimulus interval of 60 ms. Electromyographic activity was recorded simultaneously from the orbicularis oculi muscle (OOM) and from the sternocleidomastoid muscle (SCM) to explore the temporal relationship of the peaks to the generalized startle reaction. Responses in the OOM occurred with shorter onset and peak latencies than the responses in the SCM. In about 30% of pulse-alone trials, OOM responses exhibited two peaks that showed similar prepulse inhibition. These findings support the view that both components of the acoustically evoked OOM response exhibit similar plasticity in the paradigm of prepulse inhibition.

Acoustic Stimulation↗

PubMed2005

A developmental influence of the N-methyl-D-aspartate receptor NR3A subunit on prepulse inhibition of startle.

BACKGROUND: The N-methyl-D-aspartate (NMDA) receptor is composed of various conformations of multiple subunits (including NR1, NR2A-D, and NR3A-B). Peak expression of the NR3A subunit occurs approximately 2-3 weeks postnatal, with low levels in adulthood. In the brain, the NR3A subunit is localized primarily in the amygdala, hippocampus, striatum, and cortex. These regions are involved in the modulation of prepulse inhibition of startle (PPI), an operational measure of sensorimotor gating that is modulated by NMDA receptors. NR3A reduces NMDA current in native neurons expressing NR1 and NR2 subunits and forms glycine receptors when expressed with NR1 in the absence of NR2 in both oocyte and mammalian expression systems. METHODS: To examine the role of NR3A in vivo, NR3A knockout (KO), and overexpressing transgenic mice were generated. Adult NR3A overexpressing mice exhibited normal PPI; PPI in NR3A KO mice was tested repeatedly from weaning through adulthood. RESULTS: Male NR3A KO mice exhibited an increase in PPI at 3 and 4 weeks postnatal, whereas female NR3A KO mice did not differ from their WT counterparts at any age tested. CONCLUSIONS: This sex-specific increase in PPI is consistent with the antagonistic role of the NR3A subunit in NMDA receptor function and with the observation that estrogen modulates NMDA receptor function.

Aging↗

PubMed2005

Yohimbine disrupts prepulse inhibition in rats via action at 5-HT1A receptors, not alpha2-adrenoceptors.

RATIONALE: Prepulse inhibition (PPI) of the acoustic startle response is an operational measure of sensorimotor gating that can be assessed in both humans and animals. The noradrenergic system appears to play a role in PPI as the alpha1 agonist cirazoline disrupts PPI and the alpha1 antagonist prazosin blocks the disruptions in PPI produced by phencyclidine. OBJECTIVES: To better understand the role of adrenergic receptors in the modulation of PPI, we assessed the effects of the alpha2 adrenergic antagonist yohimbine (2.5, 5.0, and 7.5 mg/kg) on PPI. RESULTS: Yohimbine reduced PPI at the 5.0 and 7.5 mg/kg doses, without significantly affecting startle magnitude. In separate experiments, we examined whether adrenergic or serotonergic compounds blocked this disruption in PPI produced by yohimbine. There was a trend for the alpha2 agonist clonidine (0.01, 0.02 mg/kg) to attenuate the PPI disruption produced by yohimbine. However, other alpha2 agonists (guanfacine, medetomidine) and an alpha1 antagonist (prazosin) failed to prevent the disruption. The alpha2 antagonist atipamezole weakly decreased PPI in a narrow dose range (0.3-1.0 mg/kg). The 5-HT1A antagonist WAY100,635 (0.1, 0.3 mg/kg) significantly prevented the yohimbine-induced disruption of PPI. CONCLUSIONS: These findings indicate that (1) yohimbine disrupts PPI in rats and (2) the yohimbine-induced disruption of PPI is largely due to the 5-HT1A partial agonist properties of yohimbine.

Adrenergic alpha-2 Receptor Agonists↗