- Email: [email protected]
Noradrenergic modulation of human cortex excitability by the presynaptic α2-antagonist yohimbine
Neuroscience Letters 307 (2001) 41±44
www.elsevier.com/locate/neulet
Noradrenergic modulation of human cortex excitability by the presynaptic a2-antagonist yohimbine Christian Plewnia a, Mathias Bartels a, Leonardo Cohen b, Christian Gerloff c,* a Neurophysiology Section, Department of Psychiatry, University of Tuebingen, Osianderstrasse 24, 72076 Tuebingen, Germany Human Cortical Physiology Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA c Cortical Physiology Research Group, Department of Neurology, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany
b
Received 27 March 2001; received in revised form 10 May 2001; accepted 12 May 2001
Abstract The objective of this study was to determine if yohimbine, a central norepinephrine enhancing drug, increases corticomotoneuronal excitability in intact humans. Transcranial magnetic stimulation was used to assess excitability of the motor system re¯ected in the parameters motor threshold, recruitment curve, intracortical inhibition and intracortical facilitation before and after oral administration of 20 and 40 mg yohimbine. Oral intake of 40 but not 20 mg yohimbine increased slope and plateau of the recruitment curve and intracortical facilitation. Motor threshold and intracortical inhibition remained unchanged. The data show that pharmacological enhancement of central norepinephrine in humans is effective to increase the cortico-motoneuronal excitability. Since cortical excitability is closely linked to neuroplasticity, this observation might be of possible relevance for strategies to enhance rehabilitative processes after cortical lesions by pairing noradrenergic drugs with motor training. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Transcranial magnetic stimulation; Motor cortex; Yohimbine; Motor system excitability; Norepinephrine; Intracortical facilitation; Intracortical inhibition
Motor training results in improvements in performance [1] and recovery of motor function after stroke [12]. Previous studies demonstrated that it is possible to enhance the advantageous effects of motor training on functional recovery that follows cortical lesions by preadministration of d-amphetamine in animals [5,8,13] and humans [3,16,17]. The mechanism of this effect is thought to be alpha-adrenergic [7]. Drugs that modulate alpha-adrenergic neurotransmission like the presynaptic a2-receptor antagonist yohimbine (YOH) appear to be effective in promoting functional recovery in animal models [6,14]. It is possible that these drugs exert this bene®cial effect indirectly by increasing cortical excitability. In turn, increased cortical excitability may play a role in facilitating plasticity. For example, application of the GABAergic antagonist bicuculline that results in decreased intracortical inhibition promotes cortical map reorganization [10] and favors * Corresponding author. Tel.: 149-7071-2980419; fax: 1497071-295260. E-mail address: [email protected] (C. Gerloff).
long-term potentiation (LTP) in vitro and in vivo [2]. LTP, one of the mechanisms involved in learning and memory processes, can be enhanced directly by drugs with noradrenergic properties [9]. Decreased excitability induced by lorazepam (a GABAA receptor positive allosteric modulator) can substantially attenuate use-dependent plasticity in the human motor system [1]. Here we hypothesized that YOH, a presynaptic a2-receptor antagonist that increases brain extracellular norepinephrine (NE) levels by blocking feedback inhibition [15], would enhance cortico-motoneuronal excitability in intact humans. Given the likely association between cortical excitability, cortical plasticity and recovery of function, this information is useful for the evaluation of YOH as a drug that may be a candidate to promote functional recovery of motor function after stroke in humans [6]. Twenty-one healthy male subjects participated in the study and gave written informed consent to an experimental procedure approved by the University of Tuebingen local ethics committee. Subjects received a single oral dose of YOH 20 mg (n 14, 27.1 ^ 4.5 years old) or 40 mg
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 92 1- 8
42
C. Plewnia et al. / Neuroscience Letters 307 (2001) 41±44
(n 7, 30.0 ^ 6.4 years old). All values are given as mean ^ SD. Evaluation of cortico-motoneuronal excitability was performed by measuring motor threshold (MT), recruitment curves (RC), intracortical inhibition (ICI), and intracortical facilitation (ICF) immediately before and 60 min after intake of YOH (tmax 69 ^ 39 min; t1=2 76 ^ 72 min). EMG was recorded from the right abductor pollicis brevis (APB) muscle at rest. TMS was applied to the contralateral motor cortex at the optimal position for stimulation of APB (double circular 70 mm coil, Magstim 200, Magstim Co., Whitland, UK). MT was de®ned as the lowest stimulus intensity that elicited a MEP of more than 50 mV in ®ve out of ten trials. Optimal coil position was determined by moving the coil in 1-cm steps on the scalp overlying the left motor cortex. The magnetic coil was held tangentially to the skull in an angle of 458 to the midline with the handle backwards. For the determination of RC, stimulus intensities were changed in steps of 10% of the individual's MT, between 100 and 200% of MT. Ten MEPs were obtained at each intensity. Intracortical inhibition and intracortical facilitation were tested using a paired-pulse technique described previously [11]. Brie¯y, a suprathreshold test stimulus (TS) is preceded by a subthreshold conditioning stimulus (CS) at various time intervals (ISI, 1, 2, 3, 8, 10, 15 ms). We adjusted the TS intensity to produce a MEP with a peak-to-peak amplitude of approximately 1.0 mV. The intensity of the CS was 80% of resting MT. Ten trials were randomly presented for each ISI and TS alone. In ®ve subjects (three in the 40 mg and two in the 20 mg group), it was necessary to adjust TS slightly (2±6% stimu-
lator output) to compensate for baseline changes in cortical excitability. In three subjects, maximal M-responses and a series of 10 F-waves were elicited by supramaximal electrical stimulation of the median nerve at the wrist before and after oral intake of 40 mg YOH. Separate factorial ANOVAs with contrast analyses were used to compare RC and ICI/ICF under the different conditions. For both parameters, the main factors were CONDITION (two levels; before YOH, after YOH) and DOSE (two levels; 20 mg, 40 mg YOH). In addition, for RC the factor INTENSITY (11 levels; from 100% MT through 200% MT) and for ICI/ICF the factor INHFAC (two levels; pooled inhibitory intervals (1, 2 and 3 ms) and pooled facilitatory intervals (8, 10 and 15 ms)) were added. Multiple comparisons on the same data pool were Bonferroni-corrected. Results were considered signi®cant if P , 0:05 after correction. Oral intake of 20 mg YOH did not modify any measure of cortico-motoneuronal excitability (MT, RC or ICI/ICF). On the contrary, a dose of 40 mg YOH exerted a clear facilitatory effect on RC (F 31:2, P , 0:05) and on ICI/ICF (F 18:0, P , 0:05) (Figs. 1 and 2). ICF was signi®cantly enhanced by 40 mg YOH (F 23:30, P , 0:05), in the absence of signi®cant effects on ICI or MT (44.1 ^ 5.1% and 44.6 ^ 5.7% before and after YOH, respectively). On direct comparison, 40 mg of YOH had a greater effect than 20 mg on RC (CONDITION £ DOSE, F 18:0, P , 0:05) and on ICI/ICF (CONDITION £ DOSE, F 14:4, P , 0:05), with a signi®cant increase of ICF but no effect on ICI, as re¯ected in the signi®cant 3-way interaction CONDITION £ DOSE £ INHFAC (F 5:9, P , 0:05).
Fig. 1. Group average data. Left, recruitment curves (RC) before and after administration of (A) 20 mg YOH (n 14) and (B) 40 mg YOH (n 7). The abscissas show stimulation intensity expressed as a percentage of maximal stimulator output, the ordinates average MEP size relative to the pooled MEP maxima (170±200% MT) in the drug naive condition. Error bars, 1 SEM. Right, effect of (A) 20 mg YOH (n 14) and (B) 40 mg YOH (n 7) on intracortical inhibition (ICI) and intracortical facilitation (ICF) before and 60 min after substance intake. The abscissas represent the interstimulus intervals (ISI) in the paired pulse TMS paradigm, the ordinates the size of the conditioned response expressed as a percentage of the response to the test stimulus alone. Error bars, 1 SEM.
C. Plewnia et al. / Neuroscience Letters 307 (2001) 41±44
43
Fig. 2. Single subject data (A±G). Left, recruitment curves (RC) before and 60 min after oral intake of 40 mg YOH. Right, effect of 40 mg YOH on intracortical inhibition (ICI) and intracortical facilitation (ICF) before and 60 min after substance intake. Representative raw data (5 MEPs superimposed at 100, 150 and 200% of maximum output [RC], 10 MEP superimposed at 2 ms and 10 ms ISI [ICI/ICF]) of one subject (A) are inserted in the graph. For RC (left), ordinates represent individual MEP amplitudes in mV, otherwise same conventions as in Fig. 1.
M-responses and F-waves did not change systematically after intake of 40 mg YOH (three subjects, M-response before YOH (baseline-to-peak, mV): 5.6, 4.2, 6.3, after: 6.1, 4.9, 5.0; F-wave before YOH (peak-to-peak, mV): 249, 663, 249; after: 297, 479, 208). No side effects were reported at the dose of 20 mg. The main side effect reported in all subjects after 40 mg YOH was mild to moderate nervousness. One subject complained about insomnia during the night following the experimental
session. None of the subjects experienced inability to relax during the experimental procedures. Our results demonstrate that oral administration of a single dose of an a2-adrenergic antagonist increases the excitability of the cortico-motoneuronal system in intact humans. The enhancement of RC documents this increase which may be originated at cortical or/and subcortical sites. ICI/ICF assess inhibitory and facilitatory interactions at the cortical level [4,18]. Thus, our ®nding of increased ICF
44
C. Plewnia et al. / Neuroscience Letters 307 (2001) 41±44
suggests that at least a substantial part of the YOH effect takes place at cortical sites. This is further supported by the absence of systematic enhancement of peripheral excitability (M-responses, F-waves). Taken together, our results support the hypothesis that modulation of central NE is a possible way of enhancing human cortico-motoneuronal excitability. These effects were present after intake of 40 mg but not after 20 mg of YOH. This dose-dependent behavior indicates that increased cortical excitability was YOHinduced, and not a result of repeated recording sessions or a `placebo-like' effect. NE appears to be responsible for the bene®cial effect of drugs like amphetamine on the recovery of motor function after cortical lesions [7]. In experimental animals, infusions of NE mimic the effects of amphetamine, whereas dopamine infusions do not. While amphetamine is a drug that acts on multiple neurotransmitter systems (dopamine, serotonin, NE) and may cause cardiovascular side effects and addiction, YOH has a more selective mechanism of action and less adverse effects. YOH is a presynaptic a2adrenergic antagonist that enhances alpha adrenergic neurotransmission and, when paired with motor training, has also bene®cial effects on recovery of motor function after cortical lesions in animal models. Noteworthy, previous studies in animal models have not addressed directly the effects of YOH on cortical excitability, and thus, the possible mode of action of yohimbine at the neurophysiological level was unknown. Also, no physiological data on the action of YOH on the human central nervous system had been available. This lack of information made it dif®cult to propose YOH as a potential supportive means for rehabilitation. Our ®nding that YOH increases cortico-motoneuronal excitability in neurologically healthy subjects brings us one step closer. Together with the results in animal models, it supports the hypothesis that central NE is a crucial player in modulation of cortical excitability in humans, and it opens the perspective that YOH may be useful when paired with motor training to facilitate recovery of motor function after stroke in humans. It is now important to evaluate if the lesioned brain (e.g. after stroke) is similarly susceptible to noradrenergic modulation. C.G. was supported by the Deutsche Forschungsgemeinschaft (Research Grant SFB 550-C5) and L.G.C. by a Humboldt Award. [1] Bute®sch, C.M., Davis, B.C., Wise, S.P., Sawaki, L., Kopylev, L., Classen, J. and Cohen, L.G., Mechanisms of use-dependent plasticity in the human motor cortex, Proc. Natl. Acad. Sci. U.S.A., 97 (2000) 3661±3665. [2] Castro-Alamancos, A.M., Donoghue, J.P. and Connors, B.W., Different forms of synaptic plasticity in somatosen-
[3]
[4]
[5] [6] [7] [8]
[9] [10] [11]
[12]
[13]
[14]
[15]
[16] [17]
[18]
sory and motor areas of the neocortex, J. Neurosci., 15 (1995) 5324±5333. Crisostomo, E.A., Duncan, P.W., Propst, M., Dawson, D.V. and Davis, J.N., Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients, Ann. Neurol., 23 (1988) 94±97. Di Lazzarro, V., Oliviero, A., Meglio, M., Cioni, B., Tamburrini, G., Tonali, P. and Rothwell, J.C., Direct demonstration of the effect of lorazepam on the excitability of the human motor cortex, Clin. Neurophysiol., 111 (2000) 794± 799. Feeney, D.M. and Sutton, R.L., Pharmacotherapy for recovery of function after brain injury, Crit. Rev. Neurobiol., 3 (1987) 135±197. Gladstone, D.J. and Black, S.E., Enhancing recovery after stroke with noradrenergic pharmacotherapy: a new frontier? Can. J. Neurol. Sci., 27 (2000) 97±105. Goldstein, L.B., Basic and clinical studies of pharmacologic effects on recovery from brain injury, J. Neural Transplant. Plast., 4 (1993) 175±192. Hovda, D.A., Sutton, R.L. and Feeney, D.M., Amphetamineinduced recovery of visual cliff performance after bilateral visual cortex ablation in cats: measurements of depth perception thresholds, Behav. Neurosci., 103 (1989) 574± 584. Izumi, Y. and Zorumski, C.F., Norepinephrine promotes long-term potentiation in the adult rat hippocampus in vitro, Synapse, 31 (1999) 196±202. Jacobs, K.M. and Donoghue, J.P., Reshaping the cortical motor map by unmasking latent intracortical connections, Science, 251 (1991) 944±947. Kujirai, T., Caramia, M.D., Rothwell, J.C., Day, B.L., Thompson, P.D., Ferbert, A., Wroe, S., Asselman, P. and Marsden, C.D., Corticocortical inhibition in human motor cortex, J. Physiol. (Lond.), 471 (1993) 501±519. Nudo, R.J., Wise, B.M., SiFuentes, F. and Milliken, G.W., Neural substrates for the effects of rehabilitative training on motor recovery after ischemic infarct, Science, 272 (1996) 1791±1794. Stroemer, R.P., Kent, T.A. and Hulsebosch, C.E., Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats, Stroke, 29 (1998) 2381±2393. Sutton, R.L. and Feeney, D.M., a-noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in rat, Restor. Neurol. Neurosci., 4 (1992) 1±11. Szemeredi, K., Komoly, S., Kopin, I.J., Bagdy, G., Keiser, H.R. and Goldstein, D.S., Simultaneous measurement of plasma and brain extracellular ¯uid concentrations of catechols after yohimbine administration in rats, Brain Res., 542 (1991) 8±14. Walker-Batson, D. and Unwin, H., Use of amphetamine in the treatment of aphasia, Restor. Neurol. Neurosci., 4 (1992) 47±50. Walker-Batson, D., Smith, P., Curtis, S., Unwin, H. and Greenlee, R., Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence, Stroke, 26 (1995) 2254±2259. Ziemann, U., Rothwell, J.C. and Ridding, M.C., Interaction between intracortical inhibition and facilitation in human motor cortex, J. Physiol. (Lond.), 496 (1996) 873±881.
www.elsevier.com/locate/neulet
Noradrenergic modulation of human cortex excitability by the presynaptic a2-antagonist yohimbine Christian Plewnia a, Mathias Bartels a, Leonardo Cohen b, Christian Gerloff c,* a Neurophysiology Section, Department of Psychiatry, University of Tuebingen, Osianderstrasse 24, 72076 Tuebingen, Germany Human Cortical Physiology Section, Medical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA c Cortical Physiology Research Group, Department of Neurology, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tuebingen, Germany
b
Received 27 March 2001; received in revised form 10 May 2001; accepted 12 May 2001
Abstract The objective of this study was to determine if yohimbine, a central norepinephrine enhancing drug, increases corticomotoneuronal excitability in intact humans. Transcranial magnetic stimulation was used to assess excitability of the motor system re¯ected in the parameters motor threshold, recruitment curve, intracortical inhibition and intracortical facilitation before and after oral administration of 20 and 40 mg yohimbine. Oral intake of 40 but not 20 mg yohimbine increased slope and plateau of the recruitment curve and intracortical facilitation. Motor threshold and intracortical inhibition remained unchanged. The data show that pharmacological enhancement of central norepinephrine in humans is effective to increase the cortico-motoneuronal excitability. Since cortical excitability is closely linked to neuroplasticity, this observation might be of possible relevance for strategies to enhance rehabilitative processes after cortical lesions by pairing noradrenergic drugs with motor training. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Transcranial magnetic stimulation; Motor cortex; Yohimbine; Motor system excitability; Norepinephrine; Intracortical facilitation; Intracortical inhibition
Motor training results in improvements in performance [1] and recovery of motor function after stroke [12]. Previous studies demonstrated that it is possible to enhance the advantageous effects of motor training on functional recovery that follows cortical lesions by preadministration of d-amphetamine in animals [5,8,13] and humans [3,16,17]. The mechanism of this effect is thought to be alpha-adrenergic [7]. Drugs that modulate alpha-adrenergic neurotransmission like the presynaptic a2-receptor antagonist yohimbine (YOH) appear to be effective in promoting functional recovery in animal models [6,14]. It is possible that these drugs exert this bene®cial effect indirectly by increasing cortical excitability. In turn, increased cortical excitability may play a role in facilitating plasticity. For example, application of the GABAergic antagonist bicuculline that results in decreased intracortical inhibition promotes cortical map reorganization [10] and favors * Corresponding author. Tel.: 149-7071-2980419; fax: 1497071-295260. E-mail address: [email protected] (C. Gerloff).
long-term potentiation (LTP) in vitro and in vivo [2]. LTP, one of the mechanisms involved in learning and memory processes, can be enhanced directly by drugs with noradrenergic properties [9]. Decreased excitability induced by lorazepam (a GABAA receptor positive allosteric modulator) can substantially attenuate use-dependent plasticity in the human motor system [1]. Here we hypothesized that YOH, a presynaptic a2-receptor antagonist that increases brain extracellular norepinephrine (NE) levels by blocking feedback inhibition [15], would enhance cortico-motoneuronal excitability in intact humans. Given the likely association between cortical excitability, cortical plasticity and recovery of function, this information is useful for the evaluation of YOH as a drug that may be a candidate to promote functional recovery of motor function after stroke in humans [6]. Twenty-one healthy male subjects participated in the study and gave written informed consent to an experimental procedure approved by the University of Tuebingen local ethics committee. Subjects received a single oral dose of YOH 20 mg (n 14, 27.1 ^ 4.5 years old) or 40 mg
0304-3940/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 1) 01 92 1- 8
42
C. Plewnia et al. / Neuroscience Letters 307 (2001) 41±44
(n 7, 30.0 ^ 6.4 years old). All values are given as mean ^ SD. Evaluation of cortico-motoneuronal excitability was performed by measuring motor threshold (MT), recruitment curves (RC), intracortical inhibition (ICI), and intracortical facilitation (ICF) immediately before and 60 min after intake of YOH (tmax 69 ^ 39 min; t1=2 76 ^ 72 min). EMG was recorded from the right abductor pollicis brevis (APB) muscle at rest. TMS was applied to the contralateral motor cortex at the optimal position for stimulation of APB (double circular 70 mm coil, Magstim 200, Magstim Co., Whitland, UK). MT was de®ned as the lowest stimulus intensity that elicited a MEP of more than 50 mV in ®ve out of ten trials. Optimal coil position was determined by moving the coil in 1-cm steps on the scalp overlying the left motor cortex. The magnetic coil was held tangentially to the skull in an angle of 458 to the midline with the handle backwards. For the determination of RC, stimulus intensities were changed in steps of 10% of the individual's MT, between 100 and 200% of MT. Ten MEPs were obtained at each intensity. Intracortical inhibition and intracortical facilitation were tested using a paired-pulse technique described previously [11]. Brie¯y, a suprathreshold test stimulus (TS) is preceded by a subthreshold conditioning stimulus (CS) at various time intervals (ISI, 1, 2, 3, 8, 10, 15 ms). We adjusted the TS intensity to produce a MEP with a peak-to-peak amplitude of approximately 1.0 mV. The intensity of the CS was 80% of resting MT. Ten trials were randomly presented for each ISI and TS alone. In ®ve subjects (three in the 40 mg and two in the 20 mg group), it was necessary to adjust TS slightly (2±6% stimu-
lator output) to compensate for baseline changes in cortical excitability. In three subjects, maximal M-responses and a series of 10 F-waves were elicited by supramaximal electrical stimulation of the median nerve at the wrist before and after oral intake of 40 mg YOH. Separate factorial ANOVAs with contrast analyses were used to compare RC and ICI/ICF under the different conditions. For both parameters, the main factors were CONDITION (two levels; before YOH, after YOH) and DOSE (two levels; 20 mg, 40 mg YOH). In addition, for RC the factor INTENSITY (11 levels; from 100% MT through 200% MT) and for ICI/ICF the factor INHFAC (two levels; pooled inhibitory intervals (1, 2 and 3 ms) and pooled facilitatory intervals (8, 10 and 15 ms)) were added. Multiple comparisons on the same data pool were Bonferroni-corrected. Results were considered signi®cant if P , 0:05 after correction. Oral intake of 20 mg YOH did not modify any measure of cortico-motoneuronal excitability (MT, RC or ICI/ICF). On the contrary, a dose of 40 mg YOH exerted a clear facilitatory effect on RC (F 31:2, P , 0:05) and on ICI/ICF (F 18:0, P , 0:05) (Figs. 1 and 2). ICF was signi®cantly enhanced by 40 mg YOH (F 23:30, P , 0:05), in the absence of signi®cant effects on ICI or MT (44.1 ^ 5.1% and 44.6 ^ 5.7% before and after YOH, respectively). On direct comparison, 40 mg of YOH had a greater effect than 20 mg on RC (CONDITION £ DOSE, F 18:0, P , 0:05) and on ICI/ICF (CONDITION £ DOSE, F 14:4, P , 0:05), with a signi®cant increase of ICF but no effect on ICI, as re¯ected in the signi®cant 3-way interaction CONDITION £ DOSE £ INHFAC (F 5:9, P , 0:05).
Fig. 1. Group average data. Left, recruitment curves (RC) before and after administration of (A) 20 mg YOH (n 14) and (B) 40 mg YOH (n 7). The abscissas show stimulation intensity expressed as a percentage of maximal stimulator output, the ordinates average MEP size relative to the pooled MEP maxima (170±200% MT) in the drug naive condition. Error bars, 1 SEM. Right, effect of (A) 20 mg YOH (n 14) and (B) 40 mg YOH (n 7) on intracortical inhibition (ICI) and intracortical facilitation (ICF) before and 60 min after substance intake. The abscissas represent the interstimulus intervals (ISI) in the paired pulse TMS paradigm, the ordinates the size of the conditioned response expressed as a percentage of the response to the test stimulus alone. Error bars, 1 SEM.
C. Plewnia et al. / Neuroscience Letters 307 (2001) 41±44
43
Fig. 2. Single subject data (A±G). Left, recruitment curves (RC) before and 60 min after oral intake of 40 mg YOH. Right, effect of 40 mg YOH on intracortical inhibition (ICI) and intracortical facilitation (ICF) before and 60 min after substance intake. Representative raw data (5 MEPs superimposed at 100, 150 and 200% of maximum output [RC], 10 MEP superimposed at 2 ms and 10 ms ISI [ICI/ICF]) of one subject (A) are inserted in the graph. For RC (left), ordinates represent individual MEP amplitudes in mV, otherwise same conventions as in Fig. 1.
M-responses and F-waves did not change systematically after intake of 40 mg YOH (three subjects, M-response before YOH (baseline-to-peak, mV): 5.6, 4.2, 6.3, after: 6.1, 4.9, 5.0; F-wave before YOH (peak-to-peak, mV): 249, 663, 249; after: 297, 479, 208). No side effects were reported at the dose of 20 mg. The main side effect reported in all subjects after 40 mg YOH was mild to moderate nervousness. One subject complained about insomnia during the night following the experimental
session. None of the subjects experienced inability to relax during the experimental procedures. Our results demonstrate that oral administration of a single dose of an a2-adrenergic antagonist increases the excitability of the cortico-motoneuronal system in intact humans. The enhancement of RC documents this increase which may be originated at cortical or/and subcortical sites. ICI/ICF assess inhibitory and facilitatory interactions at the cortical level [4,18]. Thus, our ®nding of increased ICF
44
C. Plewnia et al. / Neuroscience Letters 307 (2001) 41±44
suggests that at least a substantial part of the YOH effect takes place at cortical sites. This is further supported by the absence of systematic enhancement of peripheral excitability (M-responses, F-waves). Taken together, our results support the hypothesis that modulation of central NE is a possible way of enhancing human cortico-motoneuronal excitability. These effects were present after intake of 40 mg but not after 20 mg of YOH. This dose-dependent behavior indicates that increased cortical excitability was YOHinduced, and not a result of repeated recording sessions or a `placebo-like' effect. NE appears to be responsible for the bene®cial effect of drugs like amphetamine on the recovery of motor function after cortical lesions [7]. In experimental animals, infusions of NE mimic the effects of amphetamine, whereas dopamine infusions do not. While amphetamine is a drug that acts on multiple neurotransmitter systems (dopamine, serotonin, NE) and may cause cardiovascular side effects and addiction, YOH has a more selective mechanism of action and less adverse effects. YOH is a presynaptic a2adrenergic antagonist that enhances alpha adrenergic neurotransmission and, when paired with motor training, has also bene®cial effects on recovery of motor function after cortical lesions in animal models. Noteworthy, previous studies in animal models have not addressed directly the effects of YOH on cortical excitability, and thus, the possible mode of action of yohimbine at the neurophysiological level was unknown. Also, no physiological data on the action of YOH on the human central nervous system had been available. This lack of information made it dif®cult to propose YOH as a potential supportive means for rehabilitation. Our ®nding that YOH increases cortico-motoneuronal excitability in neurologically healthy subjects brings us one step closer. Together with the results in animal models, it supports the hypothesis that central NE is a crucial player in modulation of cortical excitability in humans, and it opens the perspective that YOH may be useful when paired with motor training to facilitate recovery of motor function after stroke in humans. It is now important to evaluate if the lesioned brain (e.g. after stroke) is similarly susceptible to noradrenergic modulation. C.G. was supported by the Deutsche Forschungsgemeinschaft (Research Grant SFB 550-C5) and L.G.C. by a Humboldt Award. [1] Bute®sch, C.M., Davis, B.C., Wise, S.P., Sawaki, L., Kopylev, L., Classen, J. and Cohen, L.G., Mechanisms of use-dependent plasticity in the human motor cortex, Proc. Natl. Acad. Sci. U.S.A., 97 (2000) 3661±3665. [2] Castro-Alamancos, A.M., Donoghue, J.P. and Connors, B.W., Different forms of synaptic plasticity in somatosen-
[3]
[4]
[5] [6] [7] [8]
[9] [10] [11]
[12]
[13]
[14]
[15]
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[18]
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