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Disruption of sensory gating by the α2 selective noradrenergic antagonist yohimbine
130
BIOL PSYCHIATRY !'~3;33:130-132
Disruption of Sensory Gating by the oL2 Selective Noradrenergic Antagonist Yohimbine Karen E. Stevens, Jeri Meltzer, and Gregory M. Rose
Introduction Schizophrenia is a disease marked by abnormalities in sensory processing that are thought to be involved in the development of the disease. Specifically, it has been suggested that schizophrenics are unable to adequately filter incoming stimuli, which leads to sensory overload or "flooding," and thence to disorganization and decompensation (Venebles 1964). Central filtering mechanisms have been demonstrated in the laboratory in both humans (Fruhstorfer et al 1970) and animals (Knight et al 1985). Additionally, it has been shown that these filtering mechanisms are aberrant in schizophrenics (Adler et al 1982; Braff and Geyer 1990) and in amphetamine-treated or phencyclidine-treated laboratory rats (Adler et al 1986; Stevens et al 1991). Sensory filtering, or "gating," is easily demonstrated using a condition-test auditory paradigm (Braff and Geyer 1990). In this paradigm, click pairs are delivered at a 0.5-sec interval. Normal humans and unmedicated rats show a reduced auditory evoked potential to the second of these closely paired stimuli (Freedman et al 1987; Adler et al 1982; Stevens et al 1991). Previous work has indicated that central noradrenergic pathways are important in the gating process (Adler et al 1988; Stevens et al 1991). To more directly examine the noradrenergic contribution to sensory gating, we have employed the selective or2 antagonist, yohimbine, to enhance noradrenergic tone via the blockade of inhibitory feedback autoreceptors (Fludder and Leonard 1979). Our results demonstrate that this treatment can disrupt sensory gating.
thesia (50 mg/kg, IP) was used with methoxyflurane as auxiliary. Animals recovered at least 1 week prior to recording. The rats were handled for several minutes prior to recording-cable hookup and placement in the recording chamber. After several more minutes of acclimation, the recording session began. Paired click stimuli (10-msec duration, 0.5 sec apart) were presented every 15 sec by a computer. Waveforms were stored by the computer for later averaging and analysis. Recording sessions consisted of 20-30 trials. Only trials where the animal was still and alert were accepted. The accumulated trials were averaged and the waveform amplitudes and latencies were measured. In addition, a condition-test (CT; test amplitude/condition amplitude) ratio was determined; a CT ratio of less than 0.4 indicated gating of the response to the test stimulus. Ten unmedicated sessions were recorded per animal prior to drug testing. Yohimbine hydrochloride (Research Biochemicals Inc., Natwick, MA) was administered at 0.1, ! and 10 mg/kg, IP, with dose-order randomized, and recordings made at 20, 45, and 65 min postinjection. When SCH 23390 (Research Biochemical Inc., Natwick, MA) at 0.5 mg/kg, IP, was coadministered with yohimbine, recordings were made at 20 and 45 min postinjections. All rats received all doses of both drugs, which were dissolved in physiological saline. Data were analyzed with a two-way analysis of variance with repeated measures and a priori orthogonal contrasts.
Results Methods Recording electrodes were stereotaxically implanted into 9 male Sprague-Dawlcy rats (Harlan Laboratories, Indianapolis, IN) at "vertex" on the brain surface (coordinates 4.0 mm posterior to bregma, just lateral to midline); ground wires were placed 3.0 mm anterior to bregma and _+ 1.5 mm lateral of midline. (Details are presented in Stevens et al 1991 .) Sodium pentobarbital anes-
From the Departmentof Pharmacology,Universityof ColoradoHealthSciences Center (KES, JM, GMR); the NeuroscienceTraining Program, Universityof ColoradoHeal~ SciencesCenter(GMR), and the MedicalResearchService, VeteransAdm':aistrationMedicalCenter, Denver,CO (GMR). Address reprint requests to Dr. G. M. Rose, Medical Research Service(151), VeteransAdministrationMedicalCenter, 1055ClermontStreet, Denver,CO 80220. ReceivedFebruary 22, 1992;revisedSeptember19, 1992. © 1993Societyof BiologicalPsychiatry
The following parameters of the N40 waveform were analyzed: condition amplitude (CAMP); test amplitude (TAMP); conditiontest ratio (CT); condition latency (CLAT) and test latency (TLAT). A statistically-significant (p < 0.0001) change in CT ratio (following natural log transformation) was observed after yohimbine (YOH) administration, at both the 20- and 45-min time frames (Figure 1). Only the 1 mg/kg dose showed a significant increase, with no change in CT ratio at ei~ber the 0.1 or 10 mg/kg dose, nor at any dose by 65 min after YOH was injected. No other parameters analyzed yielded significant differences. Previous studies implicating dopamine in the modulation of gating demonstrated a normalization of amphetamine-induced changes in gating through blockage of the DI, but not the D2, receptor (Stevens et al 1991). To assess any dopamine involvement in the changes observed after yohimbine administation, the Dl-selective dopamine antagonist, SCH 23390 (SCH), was co0006-3223/93/$06.00
BIOLPSYCHIATRY
Brief Reports
131
1993;33:130-132
20 MIN
100
CONDITION
4 5 MIN
CONTROL; I ~ L "
i
TEST CTRATIO "-J~l/'~,/ 0.27
lib CAMP
50
0
100
TAMP
i
50
0
i II=
ill
_I_
1.0
3_
CT IIATIO
i
0.5
0.0
i
CONTROL
,i 0.1
1
10
0.1
1
10
DOSE YOHIIIBINE ( M G / K G )
Figure 1. A comparison of the effects of yohimbine (0.1, ! and 10 mg/kg, IP) on condition amplitude (CAMP), test amplitude (TAMP), and CT ratio. There was a significant effect of the 1 mg/kg dose on CT ratio at both 20 and 45 min postinjection. There was no effect of yohimbine at any dose on either condition or test latency, nor were there significant changes observed on any parameter 65 min postinjection (data not shown). Data represent mean --- SEM. n = 9. *p < 0.05 as compared to control.
administered with YOH (! mg/kg) at a dose of 0.5 mg/kg, IP. SCH co-administation had no effect on the increase in CT ratio observed with YOH alone at either time frame (p = 0.73). Figure 2 illustrates averaged waveforms across animals after YOH and YOH + SCH.
Discussion This study sought to further elucidate the role of norepinephrine in the modulation of sensory gating. Previous studies employing both selective depletion of norepinephrine followed by amphetamine administration (Adler et al 1988), and o~-noradrenergic and 13-noradrenergic challenge following amphetamine (Stevens et al 1991), have indicated a role for norepinephrine in the modualtion of auditory gating. The present study employed the selective a2 antagonist, yohimbine, to inhibit presynaptic negative feedback and thus increase endogenous noradrenergic tone (Findder and Leonard 1979). Alterations in the CT ratio displayed an
YOHIMBINE+ r ~ ~ f SCH23390
~/~ i
0.86
Figure 2. Waveforms representing averaged recordings across animals for control (unmedicated), yohimbine (1 mg/kg IP), and yohimbine + SCH 23390 (0.5 mg/kg, IP). Arrows denote stimulus onset, tick marks are the _peak of the waveform. Both a slight decline in condition amplitude and increase in test amplitude are evident after yohimbine or yohimbine plus SCH 23399. These changes combined to produce a significantly greater CT ratio than seen in control sessions. Mean CT ratios ( - SEM) for these conditions, calculated from individual sessions, at the 45 min time frame were: CONTROL 0.34 -4- 0.05, YOHIMBINE (1 mg/kg)0.84 - 0.22, and YOHIMBINE (1 mg/kg) + SCH 23390 (0.5 mg/kg) 1.46 -4- 0.68. Calibration 50 p,V, 50 msec.
inverted-U relationship with dose of yohimbine administered. Significant loss of sensory gating was observed following the 1 mg/kg, but not the 0. ! or 10 mg/kg dose. The lack of effect observed at the higher dose is probably attributable to yohimbine binding postsyiiaptically (Cerrito and Preziosi 1985). Both the increase in CT ratio, and the time frame in which it was observed, correspond well with findings from gating studies performed in normal human subjects administered oral yohimbine (Adler et al 1991). Previous studies (Adler et ai i988, Stevens et ai i99i) have implicated dopamine, as well as norepinephrine, in the modulation of sensory gating. Additionally, it has been shown that yohimbine increases dopaminergic turnover, possibly through inhibition of the postsynaptic D2 receptor (Scatton et al 1980). Blockade of the dopamine Di, but not D2, receptor has demonstrated efficacy in nocrnalizing amphetamine-induced changes in auditory gating; however, neither produces gathlg ~.i,~ges alone (Stevens et al 1991). To ascertain if dopaminergic mechanisms mediated chamzes observed following yohimbine administration, SCH 23390 (0.5 mg/kg, IP) was co-administered with the effective dose of yohimbine ( 1 mg/kg). SCH 23390 had no effect on yohimbine-induced increases in CT ratio, thus demonstrating separation of noradrenergic and dopaminergic mechanisms for modulating sensory gating. The results of the present studies are consistent with the theory
132
BlOL PSYCHIATRY 1993;33:130-132
that norepinephrine is altered in human schizophrenia (Homykiewicz 1986). This theory, based on the binding characteristics of neuroleptic drugs, postulates overactivity of both the adrenergic and dopaminergic systems. If the mechanisms that modulate gating to auditory stimuli in rats are analogous to those in humans, the present data could represent an animal model of the sensory processing deficits observed in schizophrenia, generated by excessive noradrenergic activity. If this assumption is valid,
Brief Reports
these data provide information about the neurobiology of sensory gating, which may be valuable in the study of schizophrenia. The authors wish to thank Dr. David Young for his assistance with the statistical analysis. The work was supported by NIMH grant MH44212 and the Veterans Admin~.strationMedical Research Service. K.E.S. is the recipient of a National Research Service Award, No. MHIO173.
References Adler LE, Hoffer L, Nagamoto HT, Waldo MC, Perkins R, Freedman R (1991): Yohimbine causes a transient impairment in P50 auditory sensory gating. Soc Neurosci Abstr 17:1454. Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R (1982): Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 17:639-654. Adler LE, Pang K, Gerhardt G, Rose GM (1988): Modulation of the gating of auditory evoked potentials by norepinephrine: Pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry 24:179-190. Adler LE, Kose G, Freedman R (1986): Neurophysiological studies of sensory gating in rats: Effects of amphetamine, phencyclidine and haloperidol. Biol Psychiatry 21:787-798. Braff DL, Geyer MA (1990): Sensorimotor gating and schizophrenia. Arch Gen Psychiatry 47:181-188. Cerrito F, Preziosi P (1985): Rat brain alpha 2-pre- and postsynaptic receptors are different or differently modulated? J Neurosci Res 14:423-431. Fludder JM, Leonard BE (1979): Chronic effects of mianserin on noradrenaline metabolism in the rat brain: Evidence for a pre-synaptic alpha-adrenolytic action in vivo. Psychopharmacology 64:329-332.
Freedman R, Adler LE, Gerhardt GA, et al (1987): Neurobiological studies of sensory gating in schizophrenia. Schizophr Bull 13:669-678. Fruhstorfer H, Soveri P, Jarvilehto T (1970): Short term habituation of the auditory-evoked response in man. Eiectroencephalogr Clin Electrophysiol 28: ! 53- ! 6 i. Hornykiewicz O (1986): Brain noradrenaline and schizophrenia. In van Ree JM and Matthysse S (eds), Progress in Brain Research Vol 65. Amsterdam, Elsevier, pp 29-39. Knight RT, Brailowski D~ Scabini D, Simpson GV (1958): Surface evoked potentials in the unrestrained rat: component definition. Electroencephalogr Clin Electrophysiol 61:430439. Scatton B, Zivkovic B, Dedek K (1980). Antidop ,,urninergic properties of yohimine. J Pharmacol Exp Ther 215:49.4-499. Stevens KE, Fuller LL, Rose GM (1991): Dopaminergic and noradrenergic modulation of amphetamine-induced changes in auditory gating. Brain Res 555:91-98. Venebles, P (1964): Input dysfunction in schizophrenia. In Maher BA (ed), Progress in Experimental Personality Research, Orlando, FL: Academic Press, pp 1-7.
BIOL PSYCHIATRY !'~3;33:130-132
Disruption of Sensory Gating by the oL2 Selective Noradrenergic Antagonist Yohimbine Karen E. Stevens, Jeri Meltzer, and Gregory M. Rose
Introduction Schizophrenia is a disease marked by abnormalities in sensory processing that are thought to be involved in the development of the disease. Specifically, it has been suggested that schizophrenics are unable to adequately filter incoming stimuli, which leads to sensory overload or "flooding," and thence to disorganization and decompensation (Venebles 1964). Central filtering mechanisms have been demonstrated in the laboratory in both humans (Fruhstorfer et al 1970) and animals (Knight et al 1985). Additionally, it has been shown that these filtering mechanisms are aberrant in schizophrenics (Adler et al 1982; Braff and Geyer 1990) and in amphetamine-treated or phencyclidine-treated laboratory rats (Adler et al 1986; Stevens et al 1991). Sensory filtering, or "gating," is easily demonstrated using a condition-test auditory paradigm (Braff and Geyer 1990). In this paradigm, click pairs are delivered at a 0.5-sec interval. Normal humans and unmedicated rats show a reduced auditory evoked potential to the second of these closely paired stimuli (Freedman et al 1987; Adler et al 1982; Stevens et al 1991). Previous work has indicated that central noradrenergic pathways are important in the gating process (Adler et al 1988; Stevens et al 1991). To more directly examine the noradrenergic contribution to sensory gating, we have employed the selective or2 antagonist, yohimbine, to enhance noradrenergic tone via the blockade of inhibitory feedback autoreceptors (Fludder and Leonard 1979). Our results demonstrate that this treatment can disrupt sensory gating.
thesia (50 mg/kg, IP) was used with methoxyflurane as auxiliary. Animals recovered at least 1 week prior to recording. The rats were handled for several minutes prior to recording-cable hookup and placement in the recording chamber. After several more minutes of acclimation, the recording session began. Paired click stimuli (10-msec duration, 0.5 sec apart) were presented every 15 sec by a computer. Waveforms were stored by the computer for later averaging and analysis. Recording sessions consisted of 20-30 trials. Only trials where the animal was still and alert were accepted. The accumulated trials were averaged and the waveform amplitudes and latencies were measured. In addition, a condition-test (CT; test amplitude/condition amplitude) ratio was determined; a CT ratio of less than 0.4 indicated gating of the response to the test stimulus. Ten unmedicated sessions were recorded per animal prior to drug testing. Yohimbine hydrochloride (Research Biochemicals Inc., Natwick, MA) was administered at 0.1, ! and 10 mg/kg, IP, with dose-order randomized, and recordings made at 20, 45, and 65 min postinjection. When SCH 23390 (Research Biochemical Inc., Natwick, MA) at 0.5 mg/kg, IP, was coadministered with yohimbine, recordings were made at 20 and 45 min postinjections. All rats received all doses of both drugs, which were dissolved in physiological saline. Data were analyzed with a two-way analysis of variance with repeated measures and a priori orthogonal contrasts.
Results Methods Recording electrodes were stereotaxically implanted into 9 male Sprague-Dawlcy rats (Harlan Laboratories, Indianapolis, IN) at "vertex" on the brain surface (coordinates 4.0 mm posterior to bregma, just lateral to midline); ground wires were placed 3.0 mm anterior to bregma and _+ 1.5 mm lateral of midline. (Details are presented in Stevens et al 1991 .) Sodium pentobarbital anes-
From the Departmentof Pharmacology,Universityof ColoradoHealthSciences Center (KES, JM, GMR); the NeuroscienceTraining Program, Universityof ColoradoHeal~ SciencesCenter(GMR), and the MedicalResearchService, VeteransAdm':aistrationMedicalCenter, Denver,CO (GMR). Address reprint requests to Dr. G. M. Rose, Medical Research Service(151), VeteransAdministrationMedicalCenter, 1055ClermontStreet, Denver,CO 80220. ReceivedFebruary 22, 1992;revisedSeptember19, 1992. © 1993Societyof BiologicalPsychiatry
The following parameters of the N40 waveform were analyzed: condition amplitude (CAMP); test amplitude (TAMP); conditiontest ratio (CT); condition latency (CLAT) and test latency (TLAT). A statistically-significant (p < 0.0001) change in CT ratio (following natural log transformation) was observed after yohimbine (YOH) administration, at both the 20- and 45-min time frames (Figure 1). Only the 1 mg/kg dose showed a significant increase, with no change in CT ratio at ei~ber the 0.1 or 10 mg/kg dose, nor at any dose by 65 min after YOH was injected. No other parameters analyzed yielded significant differences. Previous studies implicating dopamine in the modulation of gating demonstrated a normalization of amphetamine-induced changes in gating through blockage of the DI, but not the D2, receptor (Stevens et al 1991). To assess any dopamine involvement in the changes observed after yohimbine administation, the Dl-selective dopamine antagonist, SCH 23390 (SCH), was co0006-3223/93/$06.00
BIOLPSYCHIATRY
Brief Reports
131
1993;33:130-132
20 MIN
100
CONDITION
4 5 MIN
CONTROL; I ~ L "
i
TEST CTRATIO "-J~l/'~,/ 0.27
lib CAMP
50
0
100
TAMP
i
50
0
i II=
ill
_I_
1.0
3_
CT IIATIO
i
0.5
0.0
i
CONTROL
,i 0.1
1
10
0.1
1
10
DOSE YOHIIIBINE ( M G / K G )
Figure 1. A comparison of the effects of yohimbine (0.1, ! and 10 mg/kg, IP) on condition amplitude (CAMP), test amplitude (TAMP), and CT ratio. There was a significant effect of the 1 mg/kg dose on CT ratio at both 20 and 45 min postinjection. There was no effect of yohimbine at any dose on either condition or test latency, nor were there significant changes observed on any parameter 65 min postinjection (data not shown). Data represent mean --- SEM. n = 9. *p < 0.05 as compared to control.
administered with YOH (! mg/kg) at a dose of 0.5 mg/kg, IP. SCH co-administation had no effect on the increase in CT ratio observed with YOH alone at either time frame (p = 0.73). Figure 2 illustrates averaged waveforms across animals after YOH and YOH + SCH.
Discussion This study sought to further elucidate the role of norepinephrine in the modulation of sensory gating. Previous studies employing both selective depletion of norepinephrine followed by amphetamine administration (Adler et al 1988), and o~-noradrenergic and 13-noradrenergic challenge following amphetamine (Stevens et al 1991), have indicated a role for norepinephrine in the modualtion of auditory gating. The present study employed the selective a2 antagonist, yohimbine, to inhibit presynaptic negative feedback and thus increase endogenous noradrenergic tone (Findder and Leonard 1979). Alterations in the CT ratio displayed an
YOHIMBINE+ r ~ ~ f SCH23390
~/~ i
0.86
Figure 2. Waveforms representing averaged recordings across animals for control (unmedicated), yohimbine (1 mg/kg IP), and yohimbine + SCH 23390 (0.5 mg/kg, IP). Arrows denote stimulus onset, tick marks are the _peak of the waveform. Both a slight decline in condition amplitude and increase in test amplitude are evident after yohimbine or yohimbine plus SCH 23399. These changes combined to produce a significantly greater CT ratio than seen in control sessions. Mean CT ratios ( - SEM) for these conditions, calculated from individual sessions, at the 45 min time frame were: CONTROL 0.34 -4- 0.05, YOHIMBINE (1 mg/kg)0.84 - 0.22, and YOHIMBINE (1 mg/kg) + SCH 23390 (0.5 mg/kg) 1.46 -4- 0.68. Calibration 50 p,V, 50 msec.
inverted-U relationship with dose of yohimbine administered. Significant loss of sensory gating was observed following the 1 mg/kg, but not the 0. ! or 10 mg/kg dose. The lack of effect observed at the higher dose is probably attributable to yohimbine binding postsyiiaptically (Cerrito and Preziosi 1985). Both the increase in CT ratio, and the time frame in which it was observed, correspond well with findings from gating studies performed in normal human subjects administered oral yohimbine (Adler et al 1991). Previous studies (Adler et ai i988, Stevens et ai i99i) have implicated dopamine, as well as norepinephrine, in the modulation of sensory gating. Additionally, it has been shown that yohimbine increases dopaminergic turnover, possibly through inhibition of the postsynaptic D2 receptor (Scatton et al 1980). Blockade of the dopamine Di, but not D2, receptor has demonstrated efficacy in nocrnalizing amphetamine-induced changes in auditory gating; however, neither produces gathlg ~.i,~ges alone (Stevens et al 1991). To ascertain if dopaminergic mechanisms mediated chamzes observed following yohimbine administration, SCH 23390 (0.5 mg/kg, IP) was co-administered with the effective dose of yohimbine ( 1 mg/kg). SCH 23390 had no effect on yohimbine-induced increases in CT ratio, thus demonstrating separation of noradrenergic and dopaminergic mechanisms for modulating sensory gating. The results of the present studies are consistent with the theory
132
BlOL PSYCHIATRY 1993;33:130-132
that norepinephrine is altered in human schizophrenia (Homykiewicz 1986). This theory, based on the binding characteristics of neuroleptic drugs, postulates overactivity of both the adrenergic and dopaminergic systems. If the mechanisms that modulate gating to auditory stimuli in rats are analogous to those in humans, the present data could represent an animal model of the sensory processing deficits observed in schizophrenia, generated by excessive noradrenergic activity. If this assumption is valid,
Brief Reports
these data provide information about the neurobiology of sensory gating, which may be valuable in the study of schizophrenia. The authors wish to thank Dr. David Young for his assistance with the statistical analysis. The work was supported by NIMH grant MH44212 and the Veterans Admin~.strationMedical Research Service. K.E.S. is the recipient of a National Research Service Award, No. MHIO173.
References Adler LE, Hoffer L, Nagamoto HT, Waldo MC, Perkins R, Freedman R (1991): Yohimbine causes a transient impairment in P50 auditory sensory gating. Soc Neurosci Abstr 17:1454. Adler LE, Pachtman E, Franks RD, Pecevich M, Waldo MC, Freedman R (1982): Neurophysiological evidence for a defect in neuronal mechanisms involved in sensory gating in schizophrenia. Biol Psychiatry 17:639-654. Adler LE, Pang K, Gerhardt G, Rose GM (1988): Modulation of the gating of auditory evoked potentials by norepinephrine: Pharmacological evidence obtained using a selective neurotoxin. Biol Psychiatry 24:179-190. Adler LE, Kose G, Freedman R (1986): Neurophysiological studies of sensory gating in rats: Effects of amphetamine, phencyclidine and haloperidol. Biol Psychiatry 21:787-798. Braff DL, Geyer MA (1990): Sensorimotor gating and schizophrenia. Arch Gen Psychiatry 47:181-188. Cerrito F, Preziosi P (1985): Rat brain alpha 2-pre- and postsynaptic receptors are different or differently modulated? J Neurosci Res 14:423-431. Fludder JM, Leonard BE (1979): Chronic effects of mianserin on noradrenaline metabolism in the rat brain: Evidence for a pre-synaptic alpha-adrenolytic action in vivo. Psychopharmacology 64:329-332.
Freedman R, Adler LE, Gerhardt GA, et al (1987): Neurobiological studies of sensory gating in schizophrenia. Schizophr Bull 13:669-678. Fruhstorfer H, Soveri P, Jarvilehto T (1970): Short term habituation of the auditory-evoked response in man. Eiectroencephalogr Clin Electrophysiol 28: ! 53- ! 6 i. Hornykiewicz O (1986): Brain noradrenaline and schizophrenia. In van Ree JM and Matthysse S (eds), Progress in Brain Research Vol 65. Amsterdam, Elsevier, pp 29-39. Knight RT, Brailowski D~ Scabini D, Simpson GV (1958): Surface evoked potentials in the unrestrained rat: component definition. Electroencephalogr Clin Electrophysiol 61:430439. Scatton B, Zivkovic B, Dedek K (1980). Antidop ,,urninergic properties of yohimine. J Pharmacol Exp Ther 215:49.4-499. Stevens KE, Fuller LL, Rose GM (1991): Dopaminergic and noradrenergic modulation of amphetamine-induced changes in auditory gating. Brain Res 555:91-98. Venebles, P (1964): Input dysfunction in schizophrenia. In Maher BA (ed), Progress in Experimental Personality Research, Orlando, FL: Academic Press, pp 1-7.