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Effects of amphetamines and small related molecules on recovery after stroke in animals and man
Neuropharmacology 39 (2000) 852–859 www.elsevier.com/locate/neuropharm
Effects of amphetamines and small related molecules on recovery after stroke in animals and man Larry B. Goldstein
*
Box 3651, Duke University Medical Center, Durham, NC 27710, USA Accepted 18 November 1999
Abstract Drugs modulating the levels of specific central neurotransmitters may influence both the rate and amount of functional recovery after focal brain injuries such as stroke. Because such drugs may be effective long after brain injury, the “therapeutic window” may be widened beyond the first few hour after stroke and an entirely new avenue for pharmacological intervention may be possible. The impact of drugs affecting norepinephrine and γ-aminobutyric acid have been among the most extensively studied in the laboratory, and preliminary clinical data suggest similar effects in humans. Published by Elsevier Science Ltd. Keywords: Stroke; Recovery; Norepinephrine; GABA; Amphetamine
1. Introduction Studies in laboratory animals are leading to novel approaches designed to enhance poststroke recovery. New methods of retraining stroke patients such as “forced use” are now being tested in humans (Ostendorf and Wolf, 1981; Taub et al., 1993; Miltner et al., 1999). The potential benefits of a variety of growth factors (Walsh et al., 1994; Kawamata et al., 1997) are being explored and the transplantation of progenitor cells is being investigated (Gage et al., 1995). Another potential avenue of therapy is derived from observations in laboratory animals that certain classes of drugs affecting the levels of specific central neurotransmitters can influence both the rate and ultimate amount of functional recovery after injury to the cerebral cortex (Feeney, 1997; Goldstein, 1993; Goldstein, 1997b). Preliminary clinical studies suggest that similar drug effects occur in humans recovering from stroke (Crisostomo et al., 1988; WalkerBatson et al., 1995; Goldstein et al., 1990; Goldstein, 1995). Although the influence of these drugs on neurological function can often be measured within hours of administration, their impact is prolonged. These observations suggest that relatively rapid drug-induced
* Tel.: +1-919-684-3801; fax: +1-919-684-6514. E-mail address: [email protected] (L.B. Goldstein). 0028-3908/00/$ - see front matter. Published by Elsevier Science Ltd. PII: S 0 0 2 8 - 3 9 0 8 ( 9 9 ) 0 0 2 4 9 - X
physiological changes are followed by a long-lasting functional reorganization.
2. Pharmacological studies 2.1. Sympathomimetic amines and related drugs In a seminal series of experiments, Feeney and coworkers found that, when combined with task-relevant experience, a single dose of d-amphetamine given 24 hr following unilateral sensorimotor cortex ablation in the rat resulted in an enduring enhancement of motor recovery (Feeney et al., 1982). This amphetamine effect extends to functional deficits that occur following focal lesions produced through a variety of mechanisms including ischemic brain injury, to lesions affecting other areas of the cortex, and to other behaviors. For example, in rats, post-lesion administration of amphetamine enhances recovery of sensory function after infarction of the barrel cortex (Hurwitz et al., 1989) improves motor function after middle cerebral artery occlusion (Stroemer et al., 1994) and facilitates motor recovery after focal traumatic brain injury (Prasad et al., 1995). Although the effect of amphetamine is generally to speed the normal recovery process in the rat, in other species, amphetamine results in restitution of function that would otherwise have been permanently lost: post-lesion treatment with
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amphetamine enhances motor recovery in cats with unilateral or bilateral frontal cortex ablations (Hovda and Feeney, 1984; Meyer et al., 1963; Sutton et al., 1989) and reinstates stereoscopic vision in cats with bilateral visual cortex lesions (Feeney and Hovda, 1985; Hovda et al., 1989). Independent laboratories have replicated the amphetamine effect suggesting that it is quite robust (Goldstein, 1990; Dunbar et al., 1989; Feeney and Sutton, 1988; Dietrich et al., 1990) although individual experiments have been negative (Schmanke et al., 1996). Systemic administration of amphetamine may produce raised blood pressure with reflex bradycardia, behavioral arousal, and hypermotility (Innes and Nickerson, 1985). Dextroamphetamine also may induce changes in regional cerebral blood flow (Mathew and Wilson, 1985). Furthermore, amphetamine’s central actions may be mediated through noradrenergic, dopaminergic, or serotonergic neurons (Fuxe and Ungerstedt, 1970). Despite these diverse effects, amphetamine-facilitated recovery is hypothesized to be due to its specific effects on central norepinephrine. Pre-treatment with a neurotoxin that depletes central norepinephrine (N-(2Chloroethyl)-N-ethyl-2-bromobenzylamine; DSP-4) impairs motor recovery after a subsequent injury to the cerebral cortex (Goldstein et al., 1991; Boyeson et al., 1992a,b). Consistent with this result, intraventricular infusion of norepinephrine mimics the effect of amphetamine (Boyeson and Feeney, 1990). In other experiments, bilateral selective lesions of the locus coeruleus, the major source of central noradrenergic projection fibers, was found to impair behavioral recovery as compared to rats with sham locus coeruleus lesions (Boyeson et al., 1992a,b; Goldstein, 1997a). Given the hypothesis that amphetamine acts through norepinephrine, other drugs that enhance norepinephrine release or decrease its metabolism would be expected to be beneficial. Yohimbine and idazoxan (centrally acting α2-adrenergic receptor antagonists) increase norepinephrine release and enhance motor recovery when given to rats as a single dose after unilateral sensorimotor cortex injury (Goldstein, 1989; Goldstein et al., 1989; Weaver et al., 1987; Sutton and Feeney, 1992). Phentermine (Hovda et al., 1983), an amphetamine analog with weaker cardiovascular effects, phenylpropanolamine (Feeney and Sutton, 1987) and methylphenidate (Kline et al., 1994) also accelerate motor recovery after experimental focal brain injury. 2.2. Antihypertensives If drugs that enhance norepinephrine release are beneficial, then drugs that decrease norepinephrine release, increase its metabolism, or block its post-synaptic effects would be hypothesized to be harmful. In experiments designed to test this hypothesis, the α2-adrenergic receptor agonist clonidine was found to impair recovery in a
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dose-dependent fashion (Goldstein and Davis, 1990a) and to reinstate neurological deficits in recovered animals (Sutton and Feeney, 1992; Stephens et al., 1986). Prazosin (Feeney and Westerberg, 1990; Sutton and Feeney, 1992) and phenoxybenzamine (Feeney and Westerberg, 1990), centrally acting α1-adrenergic receptor antagonists, also interfere with recovery. Propranolol, a non-selective β-adrenergic receptor antagonist, has no effect (Feeney and Westerberg, 1990). 2.3. Major tranquilizers Haloperidol blocks amphetamine-promoted motor recovery in rats (Feeney et al., 1982), amphetaminefacilitated recovery of stereoscopic vision in visually decorticated cats (Feeney and Sutton, 1988) and is harmful when given alone. Furthermore, haloperidol and other butyrophenones (i.e., fluanisone, droperidol) transiently reinstate deficits in rats that recovered motor function after cortex injury (Van Hasselt, 1973). Although haloperidol is a dopamine receptor antagonist, it also has antagonist effects at noradrenergic receptors (Davis et al., 1978; Peroutka et al., 1977; Cohen and Lipinski, 1986). Further, intraventricular administration of dopamine does not have a significant beneficial effect on recovery from hemiplegia after sensorimotor cortex injury in rats (Boyeson and Feeney, 1990). Thus, the available pharmacological data suggests that the detrimental effect of haloperidol is mediated noradrenergically rather than through a dopaminergic mechanism. 2.4. Antidepressants Antidepressants affect the reuptake and metabolism of a variety of central neurotransmitters, including norepinephrine. The administration of a single dose of trazodone transiently slows motor recovery in rats with cortical injury and reinstates the hemiparesis in recovered animals (Boyeson and Harmon, 1993). In contrast, a single dose of desimpramine facilitates motor recovery in rats (Boyeson and Harmon, 1993). Fluoxetine and amitriptyline have no demonstrable effect on motor recovery after experimental focal brain injury (Boyeson et al., 1994). 2.5. Anxiolytics Although this discussion has focused on norepinephrine-mediated effects, other neurotransmitters may also affect the recovery process. For example, intracortical infusion of γ-aminobutyric acid (GABA) increases the hemiparesis produced by a small motor cortex lesion in rats (Brailowsky et al., 1986a). The short-term administration of the benzodiazepine diazepam, an indirect GABA agonist, permanently impedes recovery from the sensory asymmetry caused
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by anteromedial neocortex damage in the rat (Schallert et al., 1986). Anxiolytics that do not act through the GABA/benzodiazepine receptor complex such as gepirone do not impair recovery in similar animal models (Schallert et al., 1992). 2.6. Anticonvulsants In addition to being anxiolytics, benzodiazepines are potent anticonvulsants. The deleterious effect of GABA on motor recovery after motor cortex injury is increased by the systemic administration of phenytoin (Brailowsky et al., 1986b), which may act through a GABA-mediated mechanism. Phenobarbital also delays behavioral recovery after injury to the cerebral cortex in laboratory studies (Hernandez and Holling, 1994). In contrast, chronic administration of carbamazepine in anticonvulsant doses does not affect recovery (Schallert et al., 1992).
3. Possible mechanisms of neurotransmittermodulated recovery As early as Feeney’s original observations (Feeney et al., 1982), it was noted that an improvement in motor function in hemiplegic rats could be measured within one hour after receiving a single dose of amphetamine. This observation suggests that amphetamine has a rapid physiological effect that underlies this initial benefit. Feeney had hypothesized that drugs such as amphetamine might facilitate recovery by reversing the “remote functional depression” of brain regions distant from the site of primary injury. This diaschisis has been found in a variety of laboratory animal models (Jaspers et al., 1990; Theodore et al., 1992; Castella et al., 1989; Feeney et al., 1985; Feeney, 1991). In human stroke patients, diaschisis-like changes in metabolism have been demonstrated by positron emission tomography in the noninjured ipsilateral cerebral hemisphere, the contralateral cerebral hemisphere, and the contralateral cerebellum (Lenzi et al., 1982; Martin and Raichle, 1983; Fiorelli et al., 1991; Tanaka et al., 1992). This observed depression of metabolic activity in distant brain regions might be the direct result of regional changes in cerebral blood flow or the decreased regional cerebral blood flow might be secondary to locally depressed cerebral metabolism. Drugs that prolong or worsen diaschisis would be anticipated to be detrimental whereas those that promote the resolution of diaschisis would be anticipated to facilitate recovery. However, the presence of diaschisis does not add to the clinical deficit after stroke in humans (Bowler et al., 1995). Further, improvement in crossed cerebellar diaschisis does not correlate with recovery after stroke affecting the cerebral hemisphere (Infeld et al., 1995). The primary clinical manifestation of crossed cerebellar diaschisis appears to be a prolonged flaccidity
associated with the hemiparesis related to stroke (Pantano et al., 1993). These observations present a challenge to the diaschisis hypothesis of recovery. A second hypothesis is based on observations that the impact of drugs such as amphetamine are dependent on the animal’s experience during intoxication (Feeney et al., 1982; Feeney and Hovda, 1985; Hovda et al., 1989; Goldstein and Davis, 1990b) suggesting that amphetamine might act by facilitating a “relearning” process. Long-term potentiation (LTP) is the best understood putative cellular mechanism of learning and memory (Bliss and Dolphin, 1982; Bliss and Lomo, 1973; Bliss and Gardner-Medwin, 1973). LTP occurs in diverse brain regions including those not typically associated with memory including hypothalamus (Corbett, 1980) visual cortex (Artola and Singer, 1989; Aroniadou and Teyler, 1991) and motor cortex (Keller et al., 1990). Neurotransmitters such as catecholamines (Stanton and Sarvey, 1985; Dahl and Sarvey, 1989; Swanson et al., 1982; Hopkins and Johnston, 1984) and GABA (Wigstrom and Gustafsson, 1985; Douglas et al. 1982, 1983; Olpe and Karlsson, 1990) can modulate LTP induction. Consistent with this hypothesis, the effects of noradrenergic and other drugs on recovery can frequently be predicted based on their effects on LTP induction (Goldstein, 1996). However, predictions based on a drug’s impact on the induction of LTP are not completely accurate. For example, β-adrenergic receptor antagonists interfere with LTP induction (Dahl and Sarvey, 1990), but propranolol has no effect on motor recovery after sensorimotor cortex injury in rats (Feeney and Westerberg, 1990). The physiologic adaptive responses that underlie the rapid effect of amphetamine and similar drugs must lead to subsequent long-term neuronal reorganization and norepinephrine has been implicated in trophic changes in the central nervous system (Kasamatsu et al., 1979). In addition, norepinephrine released in the cerebral cortex from locus coeruleus projection fibers have been suggested to lead to synaptic plasticity that may encode learning (Crow, 1968). Kasamatsu et al. (1979) used changes in visual cortex ocular dominance that followed brief monocular light deprivation as an index of cortical plasticity in kittens. Local perfusion of the neurotoxin 6-hydroxydopamine blocked the effects whereas infusion of norepinephrine reinstated plasticity in animals that were no longer sensitive to visual deprivation. In order to determine the actual cellular mechanisms underlying amphetamine/norepinephrine-promoted motor recovery, it is first necessary to determine the location in the nervous system that the effect is exerted. Based on the studies previously reviewed, it would be hypothesized that depriving critical brain areas of norepinephrine would impair behavioral improvements in animals recovering from cortical injury. This has been accomplished through selective lesioning of the locus
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coeruleus and its efferent pathways. We found that a prior selective lesion of noradrenergic projection fibers (dorsal noradrenergic bundle) to the cerebral hemisphere contralateral, but not ipsilateral to a subsequent sensorimotor cortex lesion retarded recovery (Goldstein and Bullman, 1997). This critical observation suggests that the norepinephrine effect is mediated in the cerebral hemisphere contralateral to a cortical injury and is interesting to consider in view of the earlier and more recent observations of Stroemer and colleagues (Stroemer et al. 1995, 1998). A significant increase of synaptophysin immunoreactivity in the parietal cortex contralateral to a hemispheric lesion was found by these investigators that correlates with motor recovery in amphetamine treated rats. In addition, Jones and Schallert (Jones and Schallert 1992, 1994; Schallert and Jones, 1993) found time-dependent increases in the dedritic arborization of Layer V pyramidal neurons in the homotypic cerebral cortex contralateral to a forelimb sensorimotor cortex lesion in rats. Interestingly, positron emission tomography studies of humans that had recovered motor function after hemiplegic stroke have shown significant increases in regional cerebral blood flow induced by movement of the recovered limb in the sensorimotor cortex contralateral to the injury (Chollet et al., 1991). Similar changes in the contralateral hemisphere of patients recovering motor function after stroke have now been demonstrated with functional MRI (Cao et al., 1998; Cramer et al., 1997; Silvestrini et al., 1998). Studies employing transcranial magnetic stimulation in humans have also demonstrated significant changes in the motor output of the contralateral hemisphere, including an unmasking of ipsilateral corticospinal projections (Netz et al., 1997) (however, the existence of these ipsilateral pathways did not correlate with clinical improvement). Considered together, these data suggest that amphetamine may exert its impact on recovery through effects on norepinephrine-modulated processes in the hemisphere contralateral to cortical injury. These contralateral effects could secondarily influence ongoing neuronal reorganizations in the ipsilateral hemisphere through direct transcallosal connections (Meyer et al., 1998).
4. Pharmacological effects on poststroke recovery in man 4.1. Enhancement of recovery The first study of amphetamine’s effects on recovery after stroke in humans was carefully designed to simulate the paradigm used in the laboratory. Eight patients with stable motor deficits were randomized to receive either 10 mg of amphetamine or placebo within 10 days of ischemic stroke (Crisostomo et al., 1988). Within three hours of drug administration, all of the patients
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underwent intensive physical therapy (i.e., drug administration was coupled with task-specific experience). The following day, the patients’ abilities to use their affected limbs were reassessed. Overall, the amphetamine-treated group had a significant improvement in motor performance whereas there was little change in the placebotreated group. From a clinical standpoint, the study involved only a small group of highly selected patients, only 2 of the 4 receiving amphetamine had a “dramatic” motor improvement and only very short-term motor recovery was measured. In a second study (Reding et al., 1995), 12 patients were given 10 mg of amphetamine daily for 14 days followed by 5 mg for 3 days; an equal number of patients received placebo. The study began more than one month after the stroke and drug/placebo administration was not tightly linked with physical therapy. This study was negative, but varied in several significant ways from the previous trial. These differences include a different dosing regimen, a longer delay between stroke and treatment, and a lack of a tightly coupled drug-physical therapy regimen. Walker-Batson et al. (1995) performed a third doubleblind, placebo-controlled trial. This study included 5 amphetamine- and 5 placebo-treated patients with treatment given once every 4 days for 10 sessions beginning 15 to 30 days after stroke. Each dose was given in tight conjunction with a session of intensive physical therapy. One week after drug-administration was completed, patients treated with amphetamine had significantly greater improvements in motor scores compared to placebo-treated patients. The difference was still present as long as one year later. Methylphenidate has been used in the treatment of post-stroke depression in patients undergoing rehabilitative therapy (Johnson et al., 1992; Lazarus et al. 1994, 1992). Only two studies are available concerning the drug’s impact on neurological impairments. One did not find any effect of the drug on physical performance despite significant effects on cardiovascular function (Larsson et al., 1988). In a second small study, there were similar improvements in motor function when methylphenidate and placebo-treated patients were compared (Grade et al., 1998) Although both studies were negative, experimental studies suggest a complex relationship between methylphenidate dose and training which would need to be systematically explored in a large number of patients to determine whether a specific regimen might result in a clinically meaningful benefit. Antidepressants are commonly used to treat mood disorders in stroke patients. Trazodone, a drug that impairs recovery from hemiplegia in the rat, was found to reduce disability in depressed stroke patients (Reding et al., 1986). Other studies have found a beneficial effect of fluoxetine (Dam et al., 1996) and no significant effect of the norepinephrine reuptake blockers maprotiline
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(Dam et al., 1996) and nortriptyline (Lipsey et al., 1984). Therefore, unlike amphetamine, the effects of antidepressants on functional recovery appear to be opposite to the effects predicted based on the results of the laboratory studies. These disparate results may have occurred because these drugs were only given in a single dose in the laboratory studies. Acute administration of antidepressants have effects on central neurotransmitters that are quite different from their effects after chronic administration. For example, the concentration of norepinephrine in rat brain is reduced after chronic, but not after acute administration of desipramine (Roffler-Tarlov et al., 1973). Preliminary uncontrolled studies suggested that the administration of bromocriptine, a dopamine agonist, improved fluency in certain aphasics (Albert et al., 1988; Bachman and Morgan, 1988; Sabe et al., 1992). However, two small controlled studies were negative (Gupta et al., 1995; Sabe et al., 1995). These disappointing results may have been due to a variety of factors. Both controlled trials included patients long after stroke and one included several patients with traumatic brain injury. Both studies titrated patients to a maximally tolerated dose. It is unclear whether drug administration was tightly coupled with active speech therapy. Finally, by analogy to the data regarding locomotor function, motor aphasias might respond to a drug that affects norepinephrine rather than dopamine. One preliminary study of the effects of amphetamine on recovery from aphasia resulting from stroke has been completed (Walker-Batson et al., 1992). In this study, six aphasic patients had language function rated between 10 to 30 days after stroke. Based on this initial evaluation, 6 month language scores were predicted for each patient. All patients were then given 10 mg of d-amphetamine followed by speech therapy every 4th day for 10 sessions. The patients actual scores after 3 months were then compared with their 6 month predicted scores. Five of 6 patients achieved or exceeded their 6 month predicted scores by the time of the 3 month evaluation. 4.2. Impairment of recovery An initial retrospective survey found that antihypertensives such as clonidine and prazosin and sedative hypnotics including benzodiazepines were commonly prescribed to patients hospitalized with acute stroke (Goldstein and Davis, 1988). The number of patients prescribed sedative-hypnotic agents more than doubled over the first two days of hospitalization (17% to 44%), including a doubling of the number receiving benzodiazepines (10% to 20%). Thus, several of the drugs that have deleterious effects on recovery of function in laboratory animals are commonly prescribed for stroke patients for the treatment of coincident medical conditions.
In a retrospective cohort study, the motor recoveries of stroke patients who received one or a combination of the antihypertensives clonidine and prazosin, dopamine receptor antagonists, benzodiazepines, and phenytoin were compared to the recoveries of a similar group of patients who were not given any of these medications (Goldstein et al., 1990). Those that received these drugs had poorer recoveries than controls. Multivariate analysis indicated that the effect remained even after correcting for the contributions of other variables including the initial severity of the deficit. The potential deleterious effect of this group of drugs on motor recovery was also found in a separate cohort of patients who were control subjects in a prospective acute interventional stroke trial (Goldstein, 1995). Nearly 40% of the control patients enrolled in this study received one or a combination of drugs hypothesized to impair recovery. As with the previous study, stepwise regression models indicated that drug group had a negative effect on outcome independent of the degree of the initial motor impairment, co-morbid conditions and other patient characteristics. Because both studies involved retrospective analyses, it can not be certain that the reason for the administration of a given drug rather than the drug itself influenced recovery. Another limitation is that these studies did not permit an analysis of the impact of specific “detrimental” drugs, nor did they permit analyses of dose or timing effects.
5. Conclusion These data suggest a consistent effect of drugs affecting central neurotransmitters on functional recovery after focal brain injury in laboratory animal models and in humans recovering from stroke. Although it is reasonable to avoid drugs suspected of impairing recovery when alternatives are available, the available data does not yet conclusively demonstrate a beneficial clinical effect of drugs such as amphetamine. Enthusiasm for the routine use of these drugs should continue to be restrained as only one small study carried out in a highly selected group of patients in a single center has demonstrated long-term benefit. Larger multicenter studies will be required to determine whether this approach will prove feasible in a more diverse population of patients recovering from stroke.
References Albert, M.L., Bachman, D.L., Morgan, A., Helm-Estabrooks, N., 1988. Pharmacotherapy for aphasia. Neurology 38, 877–879. Aroniadou, V.A., Teyler, T.J., 1991. The role of NMDA receptors in long-term potentiation (LTP) and depression (LTD) in rat visual cortex. Brain Res. 562, 136–143. Artola, A., Singer, W., 1989. NMDA receptors and developmental
L.B. Goldstein / Neuropharmacology 39 (2000) 852–859
plasticity in visual neocortex. In: Collingridge, G.L., Watkins, J.C. (Eds.) The NMDA Receptor. Oxford University Press, Oxford, pp. 153–166. Bachman, D.L., Morgan, A., 1988. The role of pharmacotherapy in the treatment of aphasia. Aphasiology 3/4, 225–228. Bliss, T.V.P., Dolphin, A.C., 1982. What is the mechanism of longterm potentiation in the hippocampus? T.I.N.S. 5, 289–290. Bliss, T.V.P., Gardner-Medwin, A.R., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 357–374. Bliss, T.V.P., Lomo, T., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356. Bowler, J.V., Wade, J.P.H., Jones, B.E., Nijran, K., Jewkes, R.F., Cuming, R., Steiner, T.J., 1995. Contribution of diaschisis to the clinical deficit in human cerebral infarction. Stroke 26, 1000–1006. Boyeson, M.G., Feeney, D.M., 1990. Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury. Pharmacol. Biochem. Behav. 35, 497–501. Boyeson, M.G., Callister, T.R., Cavazos, J.E., 1992a. Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4. Behav. Neurosci. 106, 964–973. Boyeson, M.G., Krobert, K.A., Grade, C.M., Scherer, P.J., 1992b. Unilateral, but not bilateral, locus coeruleus lesions facilitate recovery from sensorimotor cortex injury. Pharmacol. Biochem. Behav. 43, 771–777. Boyeson, M.G., Harmon, R.L., 1993. Effects of trazodone and desipramine on motor recovery in brain-injured rats. Am. J. Phys. Med. Rehabil. 72, 286–293. Boyeson, M.G., Harmon, R.L., Jones, J.L., 1994. Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury. Am. J. Phys. Med. Rehabil. 73, 76–83. Brailowsky, S., Knight, R.T., Blood, K., 1986a. γ-aminobutyric acidinduced potentiation of cortical hemiplegia. Brain Res. 362, 322– 330. Brailowsky, S., Knight, R.T., Efron, R., 1986b. Phenytoin increases the severity of cortical hemiplegia in rats. Brain Res. 376, 71–77. Cao, Y., D’Olhaberriague, L., Vikingstad, E.M., Levine, S.R., Welch, K.M.A., 1998. Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis. Stroke 29, 112–122. Castella, Y., Dietrich, W.D., Watson, B.D., Busto, R., 1989. Acute thrombotic infarction suppresses metabolic activation of ipsilateral somatosensory cortex: evidence for functional diaschisis. J. Cereb. Blood Flow Metab. 9, 329–341. Chollet, F., DiPiero, V., Wise, R.J.S., Brooks, D.J., Dolan, R.J., Frackowiak, R.S.J., 1991. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann. Neurol. 29, 63–71. Cohen, B.M., Lipinski, J.F., 1986. In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci. 39, 2571–2580. Corbett, D., 1980. Long term potentiation of lateral hypothalamic selfstimulation following parabrachial lesions in the rat. Brain Res. Bull. 5, 637–642. Cramer, S.C., Nelles, G., Benson, R.R., Kaplan, J.D., Parker, R.A., Kwong, K.K., Kennedy, D.N., Finklestein, S.P., Rosen, B.R., 1997. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 28, 2518–2527. Crisostomo, E.A., Duncan, P.W., Propst, M.A., Dawson, D.B., Davis, J.N., 1988. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann. Neurol. 23, 94–97.
857
Crow, T.J., 1968. Cortical synapses and reinforcement: a hypothesis. Nature 219, 736–737. Dahl, D., Sarvey, J.M., 1989. Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus. Proc. Natl. Acad. Sci., USA 86, 4776–4780. Dahl, D., Sarvey, J.M., 1990. Beta-Adrenergic agonist induced longlasting synaptic modifications in hippocampal dentate gyrus require activation of NMDA receptors, but not electrical activation of afferents. Brain Res. 526, 347–350. Dam, M., Tonin, P., De Boni, A., Pizzolato, G., Casson, S., Ermani, M., Freo, U., Piron, L., Battistin, L., 1996. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 27, 1211–1214. Davis, J.N., Arnett, C.D., Hoyler, E., Stalvey, L.P., Daly, J.W., Skolnick, P., 1978. Brain alpha-adrenergic receptors: comparison of [3H]WB4101 binding with norepinephrine-stimulated cyclic AMP accumulation in rat cerebral cortex. Brain Res. 159, 125–135. Dietrich, W.D., Alonso, O., Busto, R., Ginsberg, M.D., 1990. Influence of amphetamine treatment on somatosensory function of the normal and infarcted rat brain. Stroke 21 (Suppl. III), 147–150. Douglas, R.M., Goddard, G.V., Riives, M., 1982. Inhibitory modulation of long-term potentiation: evidence for a postsynaptic locus of control. Brain Res. 240, 259–272. Douglas, R.M., McNaughton, B.L., Goddard, G.V., 1983. Commissural inhibition and facilitation of granule cell discharge in fascia dentata. J. Comp. Neurol. 219, 285–294. Dunbar, G.L., Smith, G.A., Look, S.K., Whalen, R.J., 1989. d-Amphetamine attenuates learning and motor deficits following cortical injury in rats. Soc. Neurosci. Abstr. 15, 132. Feeney, D.M., 1991. Pharmacologic modulation of recovery after brain injury: a reconsideration of diaschisis. J. Neuro. Rehab. 5, 113–128. Feeney, D.M., 1997. From laboratory to clinic: noradrenergic enhancement of physical therapy for stroke or trauma patients. In: Freund, H.-J., Sabel, B.A., Witte, O.W. (Eds.) Brain Plasticity, Advances in Neurology. Lippincott-Raven Publishers, Philadelphia, pp. 383–394. Feeney, D.M., Gonzalez, A., Law, W.A., 1982. Amphetamine, haloperidol, and experience interact to affect the rate of recovery after motor cortex injury. Science 217, 855–857. Feeney, D.M., Hovda, D.A., 1985. Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation. Brain Res. 342, 352–356. Feeney, D.M., Sutton, R.L., 1987. Pharmacotherapy for recovery of function after brain injury. CRC Crit. Rev. Neurobiol. 3, 135–197. Feeney, D.M., Sutton, R.L., 1988. Catecholamines and recovery of function after brain damage. In: Stein, D.G., Sabel, B.A. (Eds.) Pharmacological Approaches to the Treatment of Brain and Spinal Cord Injury. Plenum Publishing Corporation, New York, pp. 121–142. Feeney, D.M., Sutton, R.L., Boyeson, M.G., Hovda, D.A., Dail, W.G., 1985. The locus-coeruleus and cerebral metabolism: Recovery of function after cortical injury. Physiol. Psych. 13, 197–203. Feeney, D.M., Westerberg, V.S., 1990. Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma. Can. J. Psychol. 44, 233–252. Fiorelli, M., Blin, J., Bakchine, S., Laplane, D., Baron, J.C., 1991. PET studies of cortical diaschisis in patients with motor hemi-neglect. J. Neurol. Sci. 104, 135–142. Fuxe, K., Ungerstedt, U., 1970. Histochemical, biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration. In: Costa, E., Garattini, S. (Eds.) Amphetamines and Related Compounds. Raven Press, New York, pp. 257–288. Gage, F.H., Coates, P.W., Palmer, T.D., Kuhn, H.G., Fisher, L.J., Suhonen, J.O., Suhr, S.T., Ray, J., 1995. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci., USA 92, 11879–11883.
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Goldstein, L.B., 1989. Amphetamine-facilitated functional recovery after stroke. In: Ginsberg, M.D., Dietrich, W.D. (Eds.) Cerebrovascular Diseases. Sixteenth Research (Princeton) Conference. Raven Press, New York, pp. 303–308. Goldstein, L.B., 1990. Pharmacology of recovery after stroke. Stroke 21 (Suppl III), 139–142III. Goldstein, L.B., 1993. Basic and clinical studies of pharmacologic effects on recovery from brain injury. J. Neural Transplant. Plast. 4, 175–192. Goldstein, L.B., 1996. Pharmacologic interventions for improving functional tasks and altering brain behavior. In: Toole, J., Good, D. (Eds.) Imaging in Neurorehabilitation. Demos Vermande, New York, pp. 155–169. Goldstein, L.B., 1997a. Effects of bilateral and unilateral locus coeruleus lesions on beam-walking recovery after subsequent unilateral sensorimotor cortex suction-ablation in the rat. Restor. Neurol. Neurosci. 11, 55–63. Goldstein, L.B., 1997b. Influence of common drugs and related factors on stroke outcome. Current Opinion in Neurology 10, 52–57. Goldstein, L.B., Bullman, S., 1997. Effects of dorsal noradrenergic bundle lesions on recovery after sensorimotor cortex injury. Pharmacol. Biochem. Behav. 58, 1151–1157. Goldstein, L.B., Coviello, A., Miller, G.D., Davis, J.N., 1991. Norepinephrine depletion impairs motor recovery following sensorimotor cortex injury in the rat. Restor. Neurol. Neurosci. 3, 41–47. Goldstein, L.B., Davis, J.N., 1988. Physician prescribing patterns following hospital admission for ischemic cerebrovascular disease. Neurology 38, 1806–1809. Goldstein, L.B., Davis, J.N., 1990a. Clonidine impairs recovery of beam-walking in rats. Brain Res. 508, 305–309. Goldstein, L.B., Davis, J.N., 1990b. Post-lesion practice and amphetamine-facilitated recovery of beam-walking in the rat. Restor. Neurol. Neurosci. 1, 311–314. Goldstein, L.B., Matchar, D.B., Morgenlander, J.C., Davis, J.N., 1990. Influence of drugs on the recovery of sensorimotor function after stroke. J. Neuro. Rehab. 4, 137–144. Goldstein, L.B., Poe, H.V., Davis, J.N., 1989. An animal model of recovery of function after stroke: Facilitation of recovery by an α2adrenergic receptor antagonist. Ann. Neurol. 26, 157. Goldstein, L.B., 1995. Sygen in Acute Stroke Study Investigators, 1995. Common drugs may influence motor recovery after stroke. Neurology 45, 865–871. Grade, C., Redford, B., Chrostowski, J., Toussaint, L., Blackwell, B., 1998. Methylphenidate in early poststroke recovery: a doubleblind, placebo-controlled study. Arch. Phys. Med. Rehabil. 79, 1047–1050. Gupta, S.R., Mlcoch, A.G., Scolaro, C., Moritz, T., 1995. Bromocriptine treatment of nonfluent aphasia. Neurology 45, 2170–2173. Hernandez, T.D., Holling, L.C., 1994. Disruption of behavioral recovery by the anti-convulsant phenobarbital. Brain Res. 635, 300–306. Hopkins, W.F., Johnston, D., 1984. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science 226, 350–352. Hovda, D.A., Bailey, B., Montoya, S., Salo, A.A., Feeney, D.M., 1983. Phentermine accelerates recovery of function after motor cortex injury in rats and cats. Fed. Am. Soc. Exp. Biol. 42, 1157.83. Hovda, D.A., Feeney, D.M., 1984. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res. 298, 358–361. Hovda, D.A., Sutton, R.L., Feeney, D.M., 1989. Amphetamineinduced recovery of visual cliff performance after bilateral visual cortex ablation in cats: Measurements of depth perception thresholds. Behav. Neurosci. 103, 574–584. Hurwitz, B.E., Dietrich, W.D., McCabe, P.M., Watson, B.D., Ginsberg, M.D., Schneiderman, N., 1989. Amphetamine-accelerated recovery from cortical barrel-field infarction: Pharmacological treatment of stroke. In: Ginsberg, M.D., Dietrich, W.D. (Eds.) Cer-
ebrovascular Diseases. The Sixteenth Research (Princeton) Conference. Raven Press, New York, pp. 309–318. Infeld, B., Davis, S.M., Lichtenstein, M., Mitchell, P.J., Hopper, J.L., 1995. Crossed cerebellar diaschisis and brain recovery after stroke. Stroke 26, 90–95. Innes, I.R., Nickerson, M., 1985. Norepinephrine, epinephrine, and the sympathomimetic amines. In: Goodman, L.S., Gilman, A.G., Gilman, A., Koelle, G.B. (Eds.) The Pharmacological Basis of Therapeutics. Macmillan Publishing Company, Inc, New York, pp. 477–513. Jaspers, R.M.A., Van Der Sprenkel, J.W.B., Tulleken, C.A.F., Cools, A.R., 1990. Local as well as remote functional and metabolic changes after focal ischemia in cats. Brain Res. Bull. 24, 23–32. Johnson, M.L., Roberts, M.D., Ross, A.R., Witten, C.M., 1992. Methylphenidate in stroke patients with depression. Am. J. Phys. Med. Rehabil. 71, 239–241. Jones, T.A., Schallert, T., 1992. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res. 581, 156–160. Jones, T.A., Schallert, T., 1994. Use-dependent growth of pyramidal neurons after neocortical damage. J. Neurosci. 14, 2140–2152. Kasamatsu, T., Pettigrew, J.D., Ary, M., 1979. Restoration of visual cortical plasticity by local microperfusion of norepinephrine. J. Comp. Neurol. 185, 163–182. Kawamata, T., Speliotes, E.K., Finklestein, S.P., 1997. The role of polypeptide growth factors in recovery from stroke. Adv. Neurol 73, 377–382. Keller, A., Iriki, A., Asanuma, H., 1990. Identification of neurons producing long-term potentiation in the cat motor cortex: Intracellular recordings and labeling. J. Comp. Neurol. 300, 47–60. Kline, A.E., Chen, M.J., Tso-Olivas, D.Y., Feeney, D.M., 1994. Methylphenidate treatment following ablation-induced hemiplegia in rat: Experience during drug action alters effects on recovery of function. Pharmacol. Biochem. Behav. 48, 773–779. Larsson, M., Ervik, M., Lundborg, P., Sundh, V., Svanborg, A., 1988. Comparison between methylphenidate and placebo as adjuvant in care and rehabilitation of geriatric patients. Comp. Gerontol. 2, 53–59. Lazarus, L.W., Moberg, P.J., Langsley, P.R., Lingam, V.R., 1994. Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison. Arch. Phys. Med. Rehabil. 75, 403–406. Lazarus, L.W., Winemiller, D.R., Lingam, V.R., Neyman, I., Hartman, C., Abassian, M., Kartan, U., Groves, L., Fawcett, J., 1992. Efficacy and side effects of methylphenidate for poststroke depression. J. Clin. Psychiatry 53, 447–449. Lenzi, G.L., Frackowiak, R.S.J., Jones, T., 1982. Cerebral oxygen metabolism and blood flow in human cerebral infarction. J. Cereb. Blood Flow Metab. 2, 321–335. Lipsey, J.R., Pearlson, G.D., Robinson, R.G., Rao, K., Price, T.R., 1984. Nortriptyline treatment of post-stroke depression: a doubleblind study. Lancet 1, 297–300. Martin, W.R.W., Raichle, M.E., 1983. Cerebellar blood flow and metabolism in cerebral hemisphere infarction. Ann. Neurol. 14, 168–176. Mathew, R.J., Wilson, W.H., 1985. Dextroamphetamine-induced changes in regional cerebral blood flow. Psychopharmacology 87, 298–302. Meyer, B.-U., Ro¨richt, S., Woiciechowsky, C., 1998. Topography of fibers in the human corpus callosum mediating interhemispheric inhibition between the motor cortices. Ann. Neurol. 43, 360–369. Meyer, P.M., Horel, J.A., Meyer, D.R., 1963. Effects of dl-amphetamine upon placing responses in neodecorticate cats. J. Comp. Physiol. Psych. 56, 402–404. Miltner, W.H.R., Bauder, H., Sommer, M., Dettmers, C., Taub, E., 1999. Effects of constraint-induced movement therapy on patients
L.B. Goldstein / Neuropharmacology 39 (2000) 852–859
with chronic motor deficits after stroke. A replication. Stroke 30, 586–592. Netz, H., Lammers, T., Ho¨mberg, V., 1997. Reorganization of motor output in the non-affected hemisphere after stroke. Brain 120, 1579–1586. Olpe, H.R., Karlsson, G., 1990. The effects of baclofen and two GABA B-receptor antagonists on long-term potentiation. Naunyn. Schmiedebergs. Arch. Pharmacol. 342, 194–197. Ostendorf, C.G., Wolf, S.L., 1981. Effect of forced use of the upper extremity of a hemiplegic patient on changes in function. Phys. Ther. 61, 1022–1028. Pantano, P., Formisano, R., Ricci, M., Barbanti, P., Fiorelli, M., Sabatini, U., DiPiero, V., Lenzi, G.L., 1993. Prolonged muscular flaccidity in stroke patients is associated with crossed cerebellar diaschisis. Cerebrovasc. Dis. 3, 80–85. Peroutka, S.J., U’Pritchard, D.C., Greenberg, D.A., Snyder, S.H., 1977. Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology 16, 549–556. Prasad, R.M., Dose, J.M., Dhillon, H.S., Carbary, T., Kraemer, P.J., 1995. Amphetamine affects the behavioral outcome of lateral fluid percussion brain injury in the rat. Restor. Neurol. Neurosci. 9, 65–75. Reding, M.J., Orto, L.A., Winter, S.W., Fortuna, I.M., Di Ponte, P., McDowell, F.H., 1986. Antidepressant therapy after stroke. A double-blind trial. Arch. Neurol. 43, 763–765. Reding, M.J., Solomon, B., Borucki, S.J., 1995. Effect of dextroamphetamine on motor recovery after stroke. Neurology 45 (suppl 4), A222. Roffler-Tarlov, S., Schildkraut, J.J., Draskoczy, P.R., 1973. Effects of acute and chronic administration of desmethylimipramine on the content of norepinephrine and other monamines in the rat brain. Biochem. Pharmacol. 22, 2923–2926. Sabe, L., Leiguarda, R., Starkstein, S.E., 1992. An open-label trial of bromocriptine in nonfluent aphasia. Neurology 42, 1637–1638. Sabe, L., Salvarezza, F., Cuerva, A.G., Leiguarda, R., Starkstein, S., 1995. A randomized, double-blind, placebo-controlled study of bromocriptine in nonfluent aphasia. Neurology 45, 2272–2274. Schallert, T., Hernandez, T.D., Barth, T.M., 1986. Recovery of function after brain damage: Severe and chronic disruption by diazepam. Brain Res. 379, 104–111. Schallert, T., Jones, T.A., 1993. “Exuberant” neuronal growth after brain damage in adult rats: the essential role of behavioral experience. J. Neural Transplant. Plast. 4, 193–198. Schallert, T., Jones, T.A., Weaver, M.S., Shapiro, L.E., Crippens, D., Fulton, R., 1992. Pharmacologic and anatomic considerations in recovery of function. Physic. Med. Rehab. 6, 375–393. Schmanke, T.D., Avery, R.A., Barth, T.M., 1996. The effects of amphetamine on recovery of function after cortical damage in the rat depend on the behavioral requirements of the task. J. Neurotrauma 13, 293–307. Silvestrini, M., Cupini, L.M., Placidi, F., Diomedi, M., Bernardi, G., 1998. Bilateral hemispheric activation in the early recovery of motor function after stroke. Stroke 29, 1305–1310. Stanton, P.K., Sarvey, J.M., 1985. Blockade of norepinephrine-induced
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long-lasting potentiation in the hippocampal dentate gyrus by an inhibitor of protein synthesis. Brain Res. 361, 276–283. Stephens, J., Goldberg, G., Demopoulos, J.T., 1986. Clonidine reinstates deficits following recovery from sensorimotor cortex lesion in rats. Arch. Phys. Med. Rehabil. 67, 666–667. Stroemer, R.P., Kent, T.A., Hulsebosch, C.E., 1994. Amphetamines permanently promote recovery following cortical infarction. Soc. Neurosci. Abstr. 20, 186.94. Stroemer, R.P., Kent, T.A., Hulsebosch, C.E., 1995. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke 26, 2135–2144. Stroemer, R.P., Kent, T.A., Hulsebosch, C.E., 1998. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 29, 2381–2395. Sutton, R.L., Hovda, D.A., Feeney, D.M., 1989. Amphetamine accelerates recovery of locomotor function following bilateral frontal cortex ablation in cats. Behav. Neurosci. 103, 837–841. Sutton, R.L., Feeney, D.M., 1992. α-Noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in the rat. Restor. Neurol. Neurosci. 4, 1–11. Swanson, L.W., Teyler, T.J., Thompson, R.F., 1982. Hippocampal long-term potentiation: Mechanisms and implications for memory. Neurosci. Res. Prog. Bull. 20, 601–769. Tanaka, M., Kondo, S., Hirai, S., Ishiguro, K., Ishihara, T., Morimatsu, M., 1992. Crossed cerebellar diaschisis accompanied by hemiataxia: a PET study. J. Neurol. Neurosurg. Psychiatry 55, 121–125. Taub, E., Miller, N.E., Novack, T.A., Cook, E.W.I., Fleming, W.C., Nepomuceno, C.S., Connell, J.S., Crago, J.E., 1993. Technique to improve chronic motor deficit after stroke. Arch. Phys. Med. Rehabil. 74, 347–354. Theodore, D.R., Meier-Ruge, W., Abraham, J., 1992. Microvascular morphometry in primate diaschisis. Microvas. Res. 43, 147–155. Van Hasselt, P., 1973. Effect of butyrophenones on motor function in rats after recovery from brain damage. Neuropharmacology 12, 245–247. Walker-Batson, D., Smith, P., Curtis, S., Unwin, H., Greenlee, R., 1995. Amphetamine paired with physical therapy accelerates motor recovery after stroke - Further evidence. Stroke 26, 2254–2259. Walker-Batson, D., Unwin, H., Curtis, S., Allen, E., Wood, M., Smith, P., Devous, M.D., Reynolds, S., Greenlee, R.G., 1992. Use of amphetamine in the treatment of aphasia. Restor. Neurol. Neurosci. 14, 47–50. Walsh, T.J., Kelly, R.M., Stackman, R.W., 1994. Strategies to limit brain injury and promote recovery of function. Neurotoxicology 15, 467–476. Weaver, M.S., Farmer, L.J., Feeney, D.M., 1987. Norepinephrine receptor agonists and antagonists influence rate and maintenance of recovery of function after sensorimotor cortex contusion in the rat. Soc. Neurosci. Abstr. 13, 477. Wigstrom, H., Gustafsson, B., 1985. Facilitation of hippocampal longlasting potentiation by GABA antagonists. Acta Physiol. Scand. 125, 159–172.
Effects of amphetamines and small related molecules on recovery after stroke in animals and man Larry B. Goldstein
*
Box 3651, Duke University Medical Center, Durham, NC 27710, USA Accepted 18 November 1999
Abstract Drugs modulating the levels of specific central neurotransmitters may influence both the rate and amount of functional recovery after focal brain injuries such as stroke. Because such drugs may be effective long after brain injury, the “therapeutic window” may be widened beyond the first few hour after stroke and an entirely new avenue for pharmacological intervention may be possible. The impact of drugs affecting norepinephrine and γ-aminobutyric acid have been among the most extensively studied in the laboratory, and preliminary clinical data suggest similar effects in humans. Published by Elsevier Science Ltd. Keywords: Stroke; Recovery; Norepinephrine; GABA; Amphetamine
1. Introduction Studies in laboratory animals are leading to novel approaches designed to enhance poststroke recovery. New methods of retraining stroke patients such as “forced use” are now being tested in humans (Ostendorf and Wolf, 1981; Taub et al., 1993; Miltner et al., 1999). The potential benefits of a variety of growth factors (Walsh et al., 1994; Kawamata et al., 1997) are being explored and the transplantation of progenitor cells is being investigated (Gage et al., 1995). Another potential avenue of therapy is derived from observations in laboratory animals that certain classes of drugs affecting the levels of specific central neurotransmitters can influence both the rate and ultimate amount of functional recovery after injury to the cerebral cortex (Feeney, 1997; Goldstein, 1993; Goldstein, 1997b). Preliminary clinical studies suggest that similar drug effects occur in humans recovering from stroke (Crisostomo et al., 1988; WalkerBatson et al., 1995; Goldstein et al., 1990; Goldstein, 1995). Although the influence of these drugs on neurological function can often be measured within hours of administration, their impact is prolonged. These observations suggest that relatively rapid drug-induced
* Tel.: +1-919-684-3801; fax: +1-919-684-6514. E-mail address: [email protected] (L.B. Goldstein). 0028-3908/00/$ - see front matter. Published by Elsevier Science Ltd. PII: S 0 0 2 8 - 3 9 0 8 ( 9 9 ) 0 0 2 4 9 - X
physiological changes are followed by a long-lasting functional reorganization.
2. Pharmacological studies 2.1. Sympathomimetic amines and related drugs In a seminal series of experiments, Feeney and coworkers found that, when combined with task-relevant experience, a single dose of d-amphetamine given 24 hr following unilateral sensorimotor cortex ablation in the rat resulted in an enduring enhancement of motor recovery (Feeney et al., 1982). This amphetamine effect extends to functional deficits that occur following focal lesions produced through a variety of mechanisms including ischemic brain injury, to lesions affecting other areas of the cortex, and to other behaviors. For example, in rats, post-lesion administration of amphetamine enhances recovery of sensory function after infarction of the barrel cortex (Hurwitz et al., 1989) improves motor function after middle cerebral artery occlusion (Stroemer et al., 1994) and facilitates motor recovery after focal traumatic brain injury (Prasad et al., 1995). Although the effect of amphetamine is generally to speed the normal recovery process in the rat, in other species, amphetamine results in restitution of function that would otherwise have been permanently lost: post-lesion treatment with
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amphetamine enhances motor recovery in cats with unilateral or bilateral frontal cortex ablations (Hovda and Feeney, 1984; Meyer et al., 1963; Sutton et al., 1989) and reinstates stereoscopic vision in cats with bilateral visual cortex lesions (Feeney and Hovda, 1985; Hovda et al., 1989). Independent laboratories have replicated the amphetamine effect suggesting that it is quite robust (Goldstein, 1990; Dunbar et al., 1989; Feeney and Sutton, 1988; Dietrich et al., 1990) although individual experiments have been negative (Schmanke et al., 1996). Systemic administration of amphetamine may produce raised blood pressure with reflex bradycardia, behavioral arousal, and hypermotility (Innes and Nickerson, 1985). Dextroamphetamine also may induce changes in regional cerebral blood flow (Mathew and Wilson, 1985). Furthermore, amphetamine’s central actions may be mediated through noradrenergic, dopaminergic, or serotonergic neurons (Fuxe and Ungerstedt, 1970). Despite these diverse effects, amphetamine-facilitated recovery is hypothesized to be due to its specific effects on central norepinephrine. Pre-treatment with a neurotoxin that depletes central norepinephrine (N-(2Chloroethyl)-N-ethyl-2-bromobenzylamine; DSP-4) impairs motor recovery after a subsequent injury to the cerebral cortex (Goldstein et al., 1991; Boyeson et al., 1992a,b). Consistent with this result, intraventricular infusion of norepinephrine mimics the effect of amphetamine (Boyeson and Feeney, 1990). In other experiments, bilateral selective lesions of the locus coeruleus, the major source of central noradrenergic projection fibers, was found to impair behavioral recovery as compared to rats with sham locus coeruleus lesions (Boyeson et al., 1992a,b; Goldstein, 1997a). Given the hypothesis that amphetamine acts through norepinephrine, other drugs that enhance norepinephrine release or decrease its metabolism would be expected to be beneficial. Yohimbine and idazoxan (centrally acting α2-adrenergic receptor antagonists) increase norepinephrine release and enhance motor recovery when given to rats as a single dose after unilateral sensorimotor cortex injury (Goldstein, 1989; Goldstein et al., 1989; Weaver et al., 1987; Sutton and Feeney, 1992). Phentermine (Hovda et al., 1983), an amphetamine analog with weaker cardiovascular effects, phenylpropanolamine (Feeney and Sutton, 1987) and methylphenidate (Kline et al., 1994) also accelerate motor recovery after experimental focal brain injury. 2.2. Antihypertensives If drugs that enhance norepinephrine release are beneficial, then drugs that decrease norepinephrine release, increase its metabolism, or block its post-synaptic effects would be hypothesized to be harmful. In experiments designed to test this hypothesis, the α2-adrenergic receptor agonist clonidine was found to impair recovery in a
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dose-dependent fashion (Goldstein and Davis, 1990a) and to reinstate neurological deficits in recovered animals (Sutton and Feeney, 1992; Stephens et al., 1986). Prazosin (Feeney and Westerberg, 1990; Sutton and Feeney, 1992) and phenoxybenzamine (Feeney and Westerberg, 1990), centrally acting α1-adrenergic receptor antagonists, also interfere with recovery. Propranolol, a non-selective β-adrenergic receptor antagonist, has no effect (Feeney and Westerberg, 1990). 2.3. Major tranquilizers Haloperidol blocks amphetamine-promoted motor recovery in rats (Feeney et al., 1982), amphetaminefacilitated recovery of stereoscopic vision in visually decorticated cats (Feeney and Sutton, 1988) and is harmful when given alone. Furthermore, haloperidol and other butyrophenones (i.e., fluanisone, droperidol) transiently reinstate deficits in rats that recovered motor function after cortex injury (Van Hasselt, 1973). Although haloperidol is a dopamine receptor antagonist, it also has antagonist effects at noradrenergic receptors (Davis et al., 1978; Peroutka et al., 1977; Cohen and Lipinski, 1986). Further, intraventricular administration of dopamine does not have a significant beneficial effect on recovery from hemiplegia after sensorimotor cortex injury in rats (Boyeson and Feeney, 1990). Thus, the available pharmacological data suggests that the detrimental effect of haloperidol is mediated noradrenergically rather than through a dopaminergic mechanism. 2.4. Antidepressants Antidepressants affect the reuptake and metabolism of a variety of central neurotransmitters, including norepinephrine. The administration of a single dose of trazodone transiently slows motor recovery in rats with cortical injury and reinstates the hemiparesis in recovered animals (Boyeson and Harmon, 1993). In contrast, a single dose of desimpramine facilitates motor recovery in rats (Boyeson and Harmon, 1993). Fluoxetine and amitriptyline have no demonstrable effect on motor recovery after experimental focal brain injury (Boyeson et al., 1994). 2.5. Anxiolytics Although this discussion has focused on norepinephrine-mediated effects, other neurotransmitters may also affect the recovery process. For example, intracortical infusion of γ-aminobutyric acid (GABA) increases the hemiparesis produced by a small motor cortex lesion in rats (Brailowsky et al., 1986a). The short-term administration of the benzodiazepine diazepam, an indirect GABA agonist, permanently impedes recovery from the sensory asymmetry caused
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by anteromedial neocortex damage in the rat (Schallert et al., 1986). Anxiolytics that do not act through the GABA/benzodiazepine receptor complex such as gepirone do not impair recovery in similar animal models (Schallert et al., 1992). 2.6. Anticonvulsants In addition to being anxiolytics, benzodiazepines are potent anticonvulsants. The deleterious effect of GABA on motor recovery after motor cortex injury is increased by the systemic administration of phenytoin (Brailowsky et al., 1986b), which may act through a GABA-mediated mechanism. Phenobarbital also delays behavioral recovery after injury to the cerebral cortex in laboratory studies (Hernandez and Holling, 1994). In contrast, chronic administration of carbamazepine in anticonvulsant doses does not affect recovery (Schallert et al., 1992).
3. Possible mechanisms of neurotransmittermodulated recovery As early as Feeney’s original observations (Feeney et al., 1982), it was noted that an improvement in motor function in hemiplegic rats could be measured within one hour after receiving a single dose of amphetamine. This observation suggests that amphetamine has a rapid physiological effect that underlies this initial benefit. Feeney had hypothesized that drugs such as amphetamine might facilitate recovery by reversing the “remote functional depression” of brain regions distant from the site of primary injury. This diaschisis has been found in a variety of laboratory animal models (Jaspers et al., 1990; Theodore et al., 1992; Castella et al., 1989; Feeney et al., 1985; Feeney, 1991). In human stroke patients, diaschisis-like changes in metabolism have been demonstrated by positron emission tomography in the noninjured ipsilateral cerebral hemisphere, the contralateral cerebral hemisphere, and the contralateral cerebellum (Lenzi et al., 1982; Martin and Raichle, 1983; Fiorelli et al., 1991; Tanaka et al., 1992). This observed depression of metabolic activity in distant brain regions might be the direct result of regional changes in cerebral blood flow or the decreased regional cerebral blood flow might be secondary to locally depressed cerebral metabolism. Drugs that prolong or worsen diaschisis would be anticipated to be detrimental whereas those that promote the resolution of diaschisis would be anticipated to facilitate recovery. However, the presence of diaschisis does not add to the clinical deficit after stroke in humans (Bowler et al., 1995). Further, improvement in crossed cerebellar diaschisis does not correlate with recovery after stroke affecting the cerebral hemisphere (Infeld et al., 1995). The primary clinical manifestation of crossed cerebellar diaschisis appears to be a prolonged flaccidity
associated with the hemiparesis related to stroke (Pantano et al., 1993). These observations present a challenge to the diaschisis hypothesis of recovery. A second hypothesis is based on observations that the impact of drugs such as amphetamine are dependent on the animal’s experience during intoxication (Feeney et al., 1982; Feeney and Hovda, 1985; Hovda et al., 1989; Goldstein and Davis, 1990b) suggesting that amphetamine might act by facilitating a “relearning” process. Long-term potentiation (LTP) is the best understood putative cellular mechanism of learning and memory (Bliss and Dolphin, 1982; Bliss and Lomo, 1973; Bliss and Gardner-Medwin, 1973). LTP occurs in diverse brain regions including those not typically associated with memory including hypothalamus (Corbett, 1980) visual cortex (Artola and Singer, 1989; Aroniadou and Teyler, 1991) and motor cortex (Keller et al., 1990). Neurotransmitters such as catecholamines (Stanton and Sarvey, 1985; Dahl and Sarvey, 1989; Swanson et al., 1982; Hopkins and Johnston, 1984) and GABA (Wigstrom and Gustafsson, 1985; Douglas et al. 1982, 1983; Olpe and Karlsson, 1990) can modulate LTP induction. Consistent with this hypothesis, the effects of noradrenergic and other drugs on recovery can frequently be predicted based on their effects on LTP induction (Goldstein, 1996). However, predictions based on a drug’s impact on the induction of LTP are not completely accurate. For example, β-adrenergic receptor antagonists interfere with LTP induction (Dahl and Sarvey, 1990), but propranolol has no effect on motor recovery after sensorimotor cortex injury in rats (Feeney and Westerberg, 1990). The physiologic adaptive responses that underlie the rapid effect of amphetamine and similar drugs must lead to subsequent long-term neuronal reorganization and norepinephrine has been implicated in trophic changes in the central nervous system (Kasamatsu et al., 1979). In addition, norepinephrine released in the cerebral cortex from locus coeruleus projection fibers have been suggested to lead to synaptic plasticity that may encode learning (Crow, 1968). Kasamatsu et al. (1979) used changes in visual cortex ocular dominance that followed brief monocular light deprivation as an index of cortical plasticity in kittens. Local perfusion of the neurotoxin 6-hydroxydopamine blocked the effects whereas infusion of norepinephrine reinstated plasticity in animals that were no longer sensitive to visual deprivation. In order to determine the actual cellular mechanisms underlying amphetamine/norepinephrine-promoted motor recovery, it is first necessary to determine the location in the nervous system that the effect is exerted. Based on the studies previously reviewed, it would be hypothesized that depriving critical brain areas of norepinephrine would impair behavioral improvements in animals recovering from cortical injury. This has been accomplished through selective lesioning of the locus
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coeruleus and its efferent pathways. We found that a prior selective lesion of noradrenergic projection fibers (dorsal noradrenergic bundle) to the cerebral hemisphere contralateral, but not ipsilateral to a subsequent sensorimotor cortex lesion retarded recovery (Goldstein and Bullman, 1997). This critical observation suggests that the norepinephrine effect is mediated in the cerebral hemisphere contralateral to a cortical injury and is interesting to consider in view of the earlier and more recent observations of Stroemer and colleagues (Stroemer et al. 1995, 1998). A significant increase of synaptophysin immunoreactivity in the parietal cortex contralateral to a hemispheric lesion was found by these investigators that correlates with motor recovery in amphetamine treated rats. In addition, Jones and Schallert (Jones and Schallert 1992, 1994; Schallert and Jones, 1993) found time-dependent increases in the dedritic arborization of Layer V pyramidal neurons in the homotypic cerebral cortex contralateral to a forelimb sensorimotor cortex lesion in rats. Interestingly, positron emission tomography studies of humans that had recovered motor function after hemiplegic stroke have shown significant increases in regional cerebral blood flow induced by movement of the recovered limb in the sensorimotor cortex contralateral to the injury (Chollet et al., 1991). Similar changes in the contralateral hemisphere of patients recovering motor function after stroke have now been demonstrated with functional MRI (Cao et al., 1998; Cramer et al., 1997; Silvestrini et al., 1998). Studies employing transcranial magnetic stimulation in humans have also demonstrated significant changes in the motor output of the contralateral hemisphere, including an unmasking of ipsilateral corticospinal projections (Netz et al., 1997) (however, the existence of these ipsilateral pathways did not correlate with clinical improvement). Considered together, these data suggest that amphetamine may exert its impact on recovery through effects on norepinephrine-modulated processes in the hemisphere contralateral to cortical injury. These contralateral effects could secondarily influence ongoing neuronal reorganizations in the ipsilateral hemisphere through direct transcallosal connections (Meyer et al., 1998).
4. Pharmacological effects on poststroke recovery in man 4.1. Enhancement of recovery The first study of amphetamine’s effects on recovery after stroke in humans was carefully designed to simulate the paradigm used in the laboratory. Eight patients with stable motor deficits were randomized to receive either 10 mg of amphetamine or placebo within 10 days of ischemic stroke (Crisostomo et al., 1988). Within three hours of drug administration, all of the patients
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underwent intensive physical therapy (i.e., drug administration was coupled with task-specific experience). The following day, the patients’ abilities to use their affected limbs were reassessed. Overall, the amphetamine-treated group had a significant improvement in motor performance whereas there was little change in the placebotreated group. From a clinical standpoint, the study involved only a small group of highly selected patients, only 2 of the 4 receiving amphetamine had a “dramatic” motor improvement and only very short-term motor recovery was measured. In a second study (Reding et al., 1995), 12 patients were given 10 mg of amphetamine daily for 14 days followed by 5 mg for 3 days; an equal number of patients received placebo. The study began more than one month after the stroke and drug/placebo administration was not tightly linked with physical therapy. This study was negative, but varied in several significant ways from the previous trial. These differences include a different dosing regimen, a longer delay between stroke and treatment, and a lack of a tightly coupled drug-physical therapy regimen. Walker-Batson et al. (1995) performed a third doubleblind, placebo-controlled trial. This study included 5 amphetamine- and 5 placebo-treated patients with treatment given once every 4 days for 10 sessions beginning 15 to 30 days after stroke. Each dose was given in tight conjunction with a session of intensive physical therapy. One week after drug-administration was completed, patients treated with amphetamine had significantly greater improvements in motor scores compared to placebo-treated patients. The difference was still present as long as one year later. Methylphenidate has been used in the treatment of post-stroke depression in patients undergoing rehabilitative therapy (Johnson et al., 1992; Lazarus et al. 1994, 1992). Only two studies are available concerning the drug’s impact on neurological impairments. One did not find any effect of the drug on physical performance despite significant effects on cardiovascular function (Larsson et al., 1988). In a second small study, there were similar improvements in motor function when methylphenidate and placebo-treated patients were compared (Grade et al., 1998) Although both studies were negative, experimental studies suggest a complex relationship between methylphenidate dose and training which would need to be systematically explored in a large number of patients to determine whether a specific regimen might result in a clinically meaningful benefit. Antidepressants are commonly used to treat mood disorders in stroke patients. Trazodone, a drug that impairs recovery from hemiplegia in the rat, was found to reduce disability in depressed stroke patients (Reding et al., 1986). Other studies have found a beneficial effect of fluoxetine (Dam et al., 1996) and no significant effect of the norepinephrine reuptake blockers maprotiline
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(Dam et al., 1996) and nortriptyline (Lipsey et al., 1984). Therefore, unlike amphetamine, the effects of antidepressants on functional recovery appear to be opposite to the effects predicted based on the results of the laboratory studies. These disparate results may have occurred because these drugs were only given in a single dose in the laboratory studies. Acute administration of antidepressants have effects on central neurotransmitters that are quite different from their effects after chronic administration. For example, the concentration of norepinephrine in rat brain is reduced after chronic, but not after acute administration of desipramine (Roffler-Tarlov et al., 1973). Preliminary uncontrolled studies suggested that the administration of bromocriptine, a dopamine agonist, improved fluency in certain aphasics (Albert et al., 1988; Bachman and Morgan, 1988; Sabe et al., 1992). However, two small controlled studies were negative (Gupta et al., 1995; Sabe et al., 1995). These disappointing results may have been due to a variety of factors. Both controlled trials included patients long after stroke and one included several patients with traumatic brain injury. Both studies titrated patients to a maximally tolerated dose. It is unclear whether drug administration was tightly coupled with active speech therapy. Finally, by analogy to the data regarding locomotor function, motor aphasias might respond to a drug that affects norepinephrine rather than dopamine. One preliminary study of the effects of amphetamine on recovery from aphasia resulting from stroke has been completed (Walker-Batson et al., 1992). In this study, six aphasic patients had language function rated between 10 to 30 days after stroke. Based on this initial evaluation, 6 month language scores were predicted for each patient. All patients were then given 10 mg of d-amphetamine followed by speech therapy every 4th day for 10 sessions. The patients actual scores after 3 months were then compared with their 6 month predicted scores. Five of 6 patients achieved or exceeded their 6 month predicted scores by the time of the 3 month evaluation. 4.2. Impairment of recovery An initial retrospective survey found that antihypertensives such as clonidine and prazosin and sedative hypnotics including benzodiazepines were commonly prescribed to patients hospitalized with acute stroke (Goldstein and Davis, 1988). The number of patients prescribed sedative-hypnotic agents more than doubled over the first two days of hospitalization (17% to 44%), including a doubling of the number receiving benzodiazepines (10% to 20%). Thus, several of the drugs that have deleterious effects on recovery of function in laboratory animals are commonly prescribed for stroke patients for the treatment of coincident medical conditions.
In a retrospective cohort study, the motor recoveries of stroke patients who received one or a combination of the antihypertensives clonidine and prazosin, dopamine receptor antagonists, benzodiazepines, and phenytoin were compared to the recoveries of a similar group of patients who were not given any of these medications (Goldstein et al., 1990). Those that received these drugs had poorer recoveries than controls. Multivariate analysis indicated that the effect remained even after correcting for the contributions of other variables including the initial severity of the deficit. The potential deleterious effect of this group of drugs on motor recovery was also found in a separate cohort of patients who were control subjects in a prospective acute interventional stroke trial (Goldstein, 1995). Nearly 40% of the control patients enrolled in this study received one or a combination of drugs hypothesized to impair recovery. As with the previous study, stepwise regression models indicated that drug group had a negative effect on outcome independent of the degree of the initial motor impairment, co-morbid conditions and other patient characteristics. Because both studies involved retrospective analyses, it can not be certain that the reason for the administration of a given drug rather than the drug itself influenced recovery. Another limitation is that these studies did not permit an analysis of the impact of specific “detrimental” drugs, nor did they permit analyses of dose or timing effects.
5. Conclusion These data suggest a consistent effect of drugs affecting central neurotransmitters on functional recovery after focal brain injury in laboratory animal models and in humans recovering from stroke. Although it is reasonable to avoid drugs suspected of impairing recovery when alternatives are available, the available data does not yet conclusively demonstrate a beneficial clinical effect of drugs such as amphetamine. Enthusiasm for the routine use of these drugs should continue to be restrained as only one small study carried out in a highly selected group of patients in a single center has demonstrated long-term benefit. Larger multicenter studies will be required to determine whether this approach will prove feasible in a more diverse population of patients recovering from stroke.
References Albert, M.L., Bachman, D.L., Morgan, A., Helm-Estabrooks, N., 1988. Pharmacotherapy for aphasia. Neurology 38, 877–879. Aroniadou, V.A., Teyler, T.J., 1991. The role of NMDA receptors in long-term potentiation (LTP) and depression (LTD) in rat visual cortex. Brain Res. 562, 136–143. Artola, A., Singer, W., 1989. NMDA receptors and developmental
L.B. Goldstein / Neuropharmacology 39 (2000) 852–859
plasticity in visual neocortex. In: Collingridge, G.L., Watkins, J.C. (Eds.) The NMDA Receptor. Oxford University Press, Oxford, pp. 153–166. Bachman, D.L., Morgan, A., 1988. The role of pharmacotherapy in the treatment of aphasia. Aphasiology 3/4, 225–228. Bliss, T.V.P., Dolphin, A.C., 1982. What is the mechanism of longterm potentiation in the hippocampus? T.I.N.S. 5, 289–290. Bliss, T.V.P., Gardner-Medwin, A.R., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the unanaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 357–374. Bliss, T.V.P., Lomo, T., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356. Bowler, J.V., Wade, J.P.H., Jones, B.E., Nijran, K., Jewkes, R.F., Cuming, R., Steiner, T.J., 1995. Contribution of diaschisis to the clinical deficit in human cerebral infarction. Stroke 26, 1000–1006. Boyeson, M.G., Feeney, D.M., 1990. Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury. Pharmacol. Biochem. Behav. 35, 497–501. Boyeson, M.G., Callister, T.R., Cavazos, J.E., 1992a. Biochemical and behavioral effects of a sensorimotor cortex injury in rats pretreated with the noradrenergic neurotoxin DSP-4. Behav. Neurosci. 106, 964–973. Boyeson, M.G., Krobert, K.A., Grade, C.M., Scherer, P.J., 1992b. Unilateral, but not bilateral, locus coeruleus lesions facilitate recovery from sensorimotor cortex injury. Pharmacol. Biochem. Behav. 43, 771–777. Boyeson, M.G., Harmon, R.L., 1993. Effects of trazodone and desipramine on motor recovery in brain-injured rats. Am. J. Phys. Med. Rehabil. 72, 286–293. Boyeson, M.G., Harmon, R.L., Jones, J.L., 1994. Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury. Am. J. Phys. Med. Rehabil. 73, 76–83. Brailowsky, S., Knight, R.T., Blood, K., 1986a. γ-aminobutyric acidinduced potentiation of cortical hemiplegia. Brain Res. 362, 322– 330. Brailowsky, S., Knight, R.T., Efron, R., 1986b. Phenytoin increases the severity of cortical hemiplegia in rats. Brain Res. 376, 71–77. Cao, Y., D’Olhaberriague, L., Vikingstad, E.M., Levine, S.R., Welch, K.M.A., 1998. Pilot study of functional MRI to assess cerebral activation of motor function after poststroke hemiparesis. Stroke 29, 112–122. Castella, Y., Dietrich, W.D., Watson, B.D., Busto, R., 1989. Acute thrombotic infarction suppresses metabolic activation of ipsilateral somatosensory cortex: evidence for functional diaschisis. J. Cereb. Blood Flow Metab. 9, 329–341. Chollet, F., DiPiero, V., Wise, R.J.S., Brooks, D.J., Dolan, R.J., Frackowiak, R.S.J., 1991. The functional anatomy of motor recovery after stroke in humans: a study with positron emission tomography. Ann. Neurol. 29, 63–71. Cohen, B.M., Lipinski, J.F., 1986. In vivo potencies of antipsychotic drugs in blocking alpha 1 noradrenergic and dopamine D2 receptors: implications for drug mechanisms of action. Life Sci. 39, 2571–2580. Corbett, D., 1980. Long term potentiation of lateral hypothalamic selfstimulation following parabrachial lesions in the rat. Brain Res. Bull. 5, 637–642. Cramer, S.C., Nelles, G., Benson, R.R., Kaplan, J.D., Parker, R.A., Kwong, K.K., Kennedy, D.N., Finklestein, S.P., Rosen, B.R., 1997. A functional MRI study of subjects recovered from hemiparetic stroke. Stroke 28, 2518–2527. Crisostomo, E.A., Duncan, P.W., Propst, M.A., Dawson, D.B., Davis, J.N., 1988. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Ann. Neurol. 23, 94–97.
857
Crow, T.J., 1968. Cortical synapses and reinforcement: a hypothesis. Nature 219, 736–737. Dahl, D., Sarvey, J.M., 1989. Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus. Proc. Natl. Acad. Sci., USA 86, 4776–4780. Dahl, D., Sarvey, J.M., 1990. Beta-Adrenergic agonist induced longlasting synaptic modifications in hippocampal dentate gyrus require activation of NMDA receptors, but not electrical activation of afferents. Brain Res. 526, 347–350. Dam, M., Tonin, P., De Boni, A., Pizzolato, G., Casson, S., Ermani, M., Freo, U., Piron, L., Battistin, L., 1996. Effects of fluoxetine and maprotiline on functional recovery in poststroke hemiplegic patients undergoing rehabilitation therapy. Stroke 27, 1211–1214. Davis, J.N., Arnett, C.D., Hoyler, E., Stalvey, L.P., Daly, J.W., Skolnick, P., 1978. Brain alpha-adrenergic receptors: comparison of [3H]WB4101 binding with norepinephrine-stimulated cyclic AMP accumulation in rat cerebral cortex. Brain Res. 159, 125–135. Dietrich, W.D., Alonso, O., Busto, R., Ginsberg, M.D., 1990. Influence of amphetamine treatment on somatosensory function of the normal and infarcted rat brain. Stroke 21 (Suppl. III), 147–150. Douglas, R.M., Goddard, G.V., Riives, M., 1982. Inhibitory modulation of long-term potentiation: evidence for a postsynaptic locus of control. Brain Res. 240, 259–272. Douglas, R.M., McNaughton, B.L., Goddard, G.V., 1983. Commissural inhibition and facilitation of granule cell discharge in fascia dentata. J. Comp. Neurol. 219, 285–294. Dunbar, G.L., Smith, G.A., Look, S.K., Whalen, R.J., 1989. d-Amphetamine attenuates learning and motor deficits following cortical injury in rats. Soc. Neurosci. Abstr. 15, 132. Feeney, D.M., 1991. Pharmacologic modulation of recovery after brain injury: a reconsideration of diaschisis. J. Neuro. Rehab. 5, 113–128. Feeney, D.M., 1997. From laboratory to clinic: noradrenergic enhancement of physical therapy for stroke or trauma patients. In: Freund, H.-J., Sabel, B.A., Witte, O.W. (Eds.) Brain Plasticity, Advances in Neurology. Lippincott-Raven Publishers, Philadelphia, pp. 383–394. Feeney, D.M., Gonzalez, A., Law, W.A., 1982. Amphetamine, haloperidol, and experience interact to affect the rate of recovery after motor cortex injury. Science 217, 855–857. Feeney, D.M., Hovda, D.A., 1985. Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation. Brain Res. 342, 352–356. Feeney, D.M., Sutton, R.L., 1987. Pharmacotherapy for recovery of function after brain injury. CRC Crit. Rev. Neurobiol. 3, 135–197. Feeney, D.M., Sutton, R.L., 1988. Catecholamines and recovery of function after brain damage. In: Stein, D.G., Sabel, B.A. (Eds.) Pharmacological Approaches to the Treatment of Brain and Spinal Cord Injury. Plenum Publishing Corporation, New York, pp. 121–142. Feeney, D.M., Sutton, R.L., Boyeson, M.G., Hovda, D.A., Dail, W.G., 1985. The locus-coeruleus and cerebral metabolism: Recovery of function after cortical injury. Physiol. Psych. 13, 197–203. Feeney, D.M., Westerberg, V.S., 1990. Norepinephrine and brain damage: alpha noradrenergic pharmacology alters functional recovery after cortical trauma. Can. J. Psychol. 44, 233–252. Fiorelli, M., Blin, J., Bakchine, S., Laplane, D., Baron, J.C., 1991. PET studies of cortical diaschisis in patients with motor hemi-neglect. J. Neurol. Sci. 104, 135–142. Fuxe, K., Ungerstedt, U., 1970. Histochemical, biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration. In: Costa, E., Garattini, S. (Eds.) Amphetamines and Related Compounds. Raven Press, New York, pp. 257–288. Gage, F.H., Coates, P.W., Palmer, T.D., Kuhn, H.G., Fisher, L.J., Suhonen, J.O., Suhr, S.T., Ray, J., 1995. Survival and differentiation of adult neuronal progenitor cells transplanted to the adult brain. Proc. Natl. Acad. Sci., USA 92, 11879–11883.
858
L.B. Goldstein / Neuropharmacology 39 (2000) 852–859
Goldstein, L.B., 1989. Amphetamine-facilitated functional recovery after stroke. In: Ginsberg, M.D., Dietrich, W.D. (Eds.) Cerebrovascular Diseases. Sixteenth Research (Princeton) Conference. Raven Press, New York, pp. 303–308. Goldstein, L.B., 1990. Pharmacology of recovery after stroke. Stroke 21 (Suppl III), 139–142III. Goldstein, L.B., 1993. Basic and clinical studies of pharmacologic effects on recovery from brain injury. J. Neural Transplant. Plast. 4, 175–192. Goldstein, L.B., 1996. Pharmacologic interventions for improving functional tasks and altering brain behavior. In: Toole, J., Good, D. (Eds.) Imaging in Neurorehabilitation. Demos Vermande, New York, pp. 155–169. Goldstein, L.B., 1997a. Effects of bilateral and unilateral locus coeruleus lesions on beam-walking recovery after subsequent unilateral sensorimotor cortex suction-ablation in the rat. Restor. Neurol. Neurosci. 11, 55–63. Goldstein, L.B., 1997b. Influence of common drugs and related factors on stroke outcome. Current Opinion in Neurology 10, 52–57. Goldstein, L.B., Bullman, S., 1997. Effects of dorsal noradrenergic bundle lesions on recovery after sensorimotor cortex injury. Pharmacol. Biochem. Behav. 58, 1151–1157. Goldstein, L.B., Coviello, A., Miller, G.D., Davis, J.N., 1991. Norepinephrine depletion impairs motor recovery following sensorimotor cortex injury in the rat. Restor. Neurol. Neurosci. 3, 41–47. Goldstein, L.B., Davis, J.N., 1988. Physician prescribing patterns following hospital admission for ischemic cerebrovascular disease. Neurology 38, 1806–1809. Goldstein, L.B., Davis, J.N., 1990a. Clonidine impairs recovery of beam-walking in rats. Brain Res. 508, 305–309. Goldstein, L.B., Davis, J.N., 1990b. Post-lesion practice and amphetamine-facilitated recovery of beam-walking in the rat. Restor. Neurol. Neurosci. 1, 311–314. Goldstein, L.B., Matchar, D.B., Morgenlander, J.C., Davis, J.N., 1990. Influence of drugs on the recovery of sensorimotor function after stroke. J. Neuro. Rehab. 4, 137–144. Goldstein, L.B., Poe, H.V., Davis, J.N., 1989. An animal model of recovery of function after stroke: Facilitation of recovery by an α2adrenergic receptor antagonist. Ann. Neurol. 26, 157. Goldstein, L.B., 1995. Sygen in Acute Stroke Study Investigators, 1995. Common drugs may influence motor recovery after stroke. Neurology 45, 865–871. Grade, C., Redford, B., Chrostowski, J., Toussaint, L., Blackwell, B., 1998. Methylphenidate in early poststroke recovery: a doubleblind, placebo-controlled study. Arch. Phys. Med. Rehabil. 79, 1047–1050. Gupta, S.R., Mlcoch, A.G., Scolaro, C., Moritz, T., 1995. Bromocriptine treatment of nonfluent aphasia. Neurology 45, 2170–2173. Hernandez, T.D., Holling, L.C., 1994. Disruption of behavioral recovery by the anti-convulsant phenobarbital. Brain Res. 635, 300–306. Hopkins, W.F., Johnston, D., 1984. Frequency-dependent noradrenergic modulation of long-term potentiation in the hippocampus. Science 226, 350–352. Hovda, D.A., Bailey, B., Montoya, S., Salo, A.A., Feeney, D.M., 1983. Phentermine accelerates recovery of function after motor cortex injury in rats and cats. Fed. Am. Soc. Exp. Biol. 42, 1157.83. Hovda, D.A., Feeney, D.M., 1984. Amphetamine with experience promotes recovery of locomotor function after unilateral frontal cortex injury in the cat. Brain Res. 298, 358–361. Hovda, D.A., Sutton, R.L., Feeney, D.M., 1989. Amphetamineinduced recovery of visual cliff performance after bilateral visual cortex ablation in cats: Measurements of depth perception thresholds. Behav. Neurosci. 103, 574–584. Hurwitz, B.E., Dietrich, W.D., McCabe, P.M., Watson, B.D., Ginsberg, M.D., Schneiderman, N., 1989. Amphetamine-accelerated recovery from cortical barrel-field infarction: Pharmacological treatment of stroke. In: Ginsberg, M.D., Dietrich, W.D. (Eds.) Cer-
ebrovascular Diseases. The Sixteenth Research (Princeton) Conference. Raven Press, New York, pp. 309–318. Infeld, B., Davis, S.M., Lichtenstein, M., Mitchell, P.J., Hopper, J.L., 1995. Crossed cerebellar diaschisis and brain recovery after stroke. Stroke 26, 90–95. Innes, I.R., Nickerson, M., 1985. Norepinephrine, epinephrine, and the sympathomimetic amines. In: Goodman, L.S., Gilman, A.G., Gilman, A., Koelle, G.B. (Eds.) The Pharmacological Basis of Therapeutics. Macmillan Publishing Company, Inc, New York, pp. 477–513. Jaspers, R.M.A., Van Der Sprenkel, J.W.B., Tulleken, C.A.F., Cools, A.R., 1990. Local as well as remote functional and metabolic changes after focal ischemia in cats. Brain Res. Bull. 24, 23–32. Johnson, M.L., Roberts, M.D., Ross, A.R., Witten, C.M., 1992. Methylphenidate in stroke patients with depression. Am. J. Phys. Med. Rehabil. 71, 239–241. Jones, T.A., Schallert, T., 1992. Overgrowth and pruning of dendrites in adult rats recovering from neocortical damage. Brain Res. 581, 156–160. Jones, T.A., Schallert, T., 1994. Use-dependent growth of pyramidal neurons after neocortical damage. J. Neurosci. 14, 2140–2152. Kasamatsu, T., Pettigrew, J.D., Ary, M., 1979. Restoration of visual cortical plasticity by local microperfusion of norepinephrine. J. Comp. Neurol. 185, 163–182. Kawamata, T., Speliotes, E.K., Finklestein, S.P., 1997. The role of polypeptide growth factors in recovery from stroke. Adv. Neurol 73, 377–382. Keller, A., Iriki, A., Asanuma, H., 1990. Identification of neurons producing long-term potentiation in the cat motor cortex: Intracellular recordings and labeling. J. Comp. Neurol. 300, 47–60. Kline, A.E., Chen, M.J., Tso-Olivas, D.Y., Feeney, D.M., 1994. Methylphenidate treatment following ablation-induced hemiplegia in rat: Experience during drug action alters effects on recovery of function. Pharmacol. Biochem. Behav. 48, 773–779. Larsson, M., Ervik, M., Lundborg, P., Sundh, V., Svanborg, A., 1988. Comparison between methylphenidate and placebo as adjuvant in care and rehabilitation of geriatric patients. Comp. Gerontol. 2, 53–59. Lazarus, L.W., Moberg, P.J., Langsley, P.R., Lingam, V.R., 1994. Methylphenidate and nortriptyline in the treatment of poststroke depression: a retrospective comparison. Arch. Phys. Med. Rehabil. 75, 403–406. Lazarus, L.W., Winemiller, D.R., Lingam, V.R., Neyman, I., Hartman, C., Abassian, M., Kartan, U., Groves, L., Fawcett, J., 1992. Efficacy and side effects of methylphenidate for poststroke depression. J. Clin. Psychiatry 53, 447–449. Lenzi, G.L., Frackowiak, R.S.J., Jones, T., 1982. Cerebral oxygen metabolism and blood flow in human cerebral infarction. J. Cereb. Blood Flow Metab. 2, 321–335. Lipsey, J.R., Pearlson, G.D., Robinson, R.G., Rao, K., Price, T.R., 1984. Nortriptyline treatment of post-stroke depression: a doubleblind study. Lancet 1, 297–300. Martin, W.R.W., Raichle, M.E., 1983. Cerebellar blood flow and metabolism in cerebral hemisphere infarction. Ann. Neurol. 14, 168–176. Mathew, R.J., Wilson, W.H., 1985. Dextroamphetamine-induced changes in regional cerebral blood flow. Psychopharmacology 87, 298–302. Meyer, B.-U., Ro¨richt, S., Woiciechowsky, C., 1998. Topography of fibers in the human corpus callosum mediating interhemispheric inhibition between the motor cortices. Ann. Neurol. 43, 360–369. Meyer, P.M., Horel, J.A., Meyer, D.R., 1963. Effects of dl-amphetamine upon placing responses in neodecorticate cats. J. Comp. Physiol. Psych. 56, 402–404. Miltner, W.H.R., Bauder, H., Sommer, M., Dettmers, C., Taub, E., 1999. Effects of constraint-induced movement therapy on patients
L.B. Goldstein / Neuropharmacology 39 (2000) 852–859
with chronic motor deficits after stroke. A replication. Stroke 30, 586–592. Netz, H., Lammers, T., Ho¨mberg, V., 1997. Reorganization of motor output in the non-affected hemisphere after stroke. Brain 120, 1579–1586. Olpe, H.R., Karlsson, G., 1990. The effects of baclofen and two GABA B-receptor antagonists on long-term potentiation. Naunyn. Schmiedebergs. Arch. Pharmacol. 342, 194–197. Ostendorf, C.G., Wolf, S.L., 1981. Effect of forced use of the upper extremity of a hemiplegic patient on changes in function. Phys. Ther. 61, 1022–1028. Pantano, P., Formisano, R., Ricci, M., Barbanti, P., Fiorelli, M., Sabatini, U., DiPiero, V., Lenzi, G.L., 1993. Prolonged muscular flaccidity in stroke patients is associated with crossed cerebellar diaschisis. Cerebrovasc. Dis. 3, 80–85. Peroutka, S.J., U’Pritchard, D.C., Greenberg, D.A., Snyder, S.H., 1977. Neuroleptic drug interactions with norepinephrine alpha receptor binding sites in rat brain. Neuropharmacology 16, 549–556. Prasad, R.M., Dose, J.M., Dhillon, H.S., Carbary, T., Kraemer, P.J., 1995. Amphetamine affects the behavioral outcome of lateral fluid percussion brain injury in the rat. Restor. Neurol. Neurosci. 9, 65–75. Reding, M.J., Orto, L.A., Winter, S.W., Fortuna, I.M., Di Ponte, P., McDowell, F.H., 1986. Antidepressant therapy after stroke. A double-blind trial. Arch. Neurol. 43, 763–765. Reding, M.J., Solomon, B., Borucki, S.J., 1995. Effect of dextroamphetamine on motor recovery after stroke. Neurology 45 (suppl 4), A222. Roffler-Tarlov, S., Schildkraut, J.J., Draskoczy, P.R., 1973. Effects of acute and chronic administration of desmethylimipramine on the content of norepinephrine and other monamines in the rat brain. Biochem. Pharmacol. 22, 2923–2926. Sabe, L., Leiguarda, R., Starkstein, S.E., 1992. An open-label trial of bromocriptine in nonfluent aphasia. Neurology 42, 1637–1638. Sabe, L., Salvarezza, F., Cuerva, A.G., Leiguarda, R., Starkstein, S., 1995. A randomized, double-blind, placebo-controlled study of bromocriptine in nonfluent aphasia. Neurology 45, 2272–2274. Schallert, T., Hernandez, T.D., Barth, T.M., 1986. Recovery of function after brain damage: Severe and chronic disruption by diazepam. Brain Res. 379, 104–111. Schallert, T., Jones, T.A., 1993. “Exuberant” neuronal growth after brain damage in adult rats: the essential role of behavioral experience. J. Neural Transplant. Plast. 4, 193–198. Schallert, T., Jones, T.A., Weaver, M.S., Shapiro, L.E., Crippens, D., Fulton, R., 1992. Pharmacologic and anatomic considerations in recovery of function. Physic. Med. Rehab. 6, 375–393. Schmanke, T.D., Avery, R.A., Barth, T.M., 1996. The effects of amphetamine on recovery of function after cortical damage in the rat depend on the behavioral requirements of the task. J. Neurotrauma 13, 293–307. Silvestrini, M., Cupini, L.M., Placidi, F., Diomedi, M., Bernardi, G., 1998. Bilateral hemispheric activation in the early recovery of motor function after stroke. Stroke 29, 1305–1310. Stanton, P.K., Sarvey, J.M., 1985. Blockade of norepinephrine-induced
859
long-lasting potentiation in the hippocampal dentate gyrus by an inhibitor of protein synthesis. Brain Res. 361, 276–283. Stephens, J., Goldberg, G., Demopoulos, J.T., 1986. Clonidine reinstates deficits following recovery from sensorimotor cortex lesion in rats. Arch. Phys. Med. Rehabil. 67, 666–667. Stroemer, R.P., Kent, T.A., Hulsebosch, C.E., 1994. Amphetamines permanently promote recovery following cortical infarction. Soc. Neurosci. Abstr. 20, 186.94. Stroemer, R.P., Kent, T.A., Hulsebosch, C.E., 1995. Neocortical neural sprouting, synaptogenesis, and behavioral recovery after neocortical infarction in rats. Stroke 26, 2135–2144. Stroemer, R.P., Kent, T.A., Hulsebosch, C.E., 1998. Enhanced neocortical neural sprouting, synaptogenesis, and behavioral recovery with D-amphetamine therapy after neocortical infarction in rats. Stroke 29, 2381–2395. Sutton, R.L., Hovda, D.A., Feeney, D.M., 1989. Amphetamine accelerates recovery of locomotor function following bilateral frontal cortex ablation in cats. Behav. Neurosci. 103, 837–841. Sutton, R.L., Feeney, D.M., 1992. α-Noradrenergic agonists and antagonists affect recovery and maintenance of beam-walking ability after sensorimotor cortex ablation in the rat. Restor. Neurol. Neurosci. 4, 1–11. Swanson, L.W., Teyler, T.J., Thompson, R.F., 1982. Hippocampal long-term potentiation: Mechanisms and implications for memory. Neurosci. Res. Prog. Bull. 20, 601–769. Tanaka, M., Kondo, S., Hirai, S., Ishiguro, K., Ishihara, T., Morimatsu, M., 1992. Crossed cerebellar diaschisis accompanied by hemiataxia: a PET study. J. Neurol. Neurosurg. Psychiatry 55, 121–125. Taub, E., Miller, N.E., Novack, T.A., Cook, E.W.I., Fleming, W.C., Nepomuceno, C.S., Connell, J.S., Crago, J.E., 1993. Technique to improve chronic motor deficit after stroke. Arch. Phys. Med. Rehabil. 74, 347–354. Theodore, D.R., Meier-Ruge, W., Abraham, J., 1992. Microvascular morphometry in primate diaschisis. Microvas. Res. 43, 147–155. Van Hasselt, P., 1973. Effect of butyrophenones on motor function in rats after recovery from brain damage. Neuropharmacology 12, 245–247. Walker-Batson, D., Smith, P., Curtis, S., Unwin, H., Greenlee, R., 1995. Amphetamine paired with physical therapy accelerates motor recovery after stroke - Further evidence. Stroke 26, 2254–2259. Walker-Batson, D., Unwin, H., Curtis, S., Allen, E., Wood, M., Smith, P., Devous, M.D., Reynolds, S., Greenlee, R.G., 1992. Use of amphetamine in the treatment of aphasia. Restor. Neurol. Neurosci. 14, 47–50. Walsh, T.J., Kelly, R.M., Stackman, R.W., 1994. Strategies to limit brain injury and promote recovery of function. Neurotoxicology 15, 467–476. Weaver, M.S., Farmer, L.J., Feeney, D.M., 1987. Norepinephrine receptor agonists and antagonists influence rate and maintenance of recovery of function after sensorimotor cortex contusion in the rat. Soc. Neurosci. Abstr. 13, 477. Wigstrom, H., Gustafsson, B., 1985. Facilitation of hippocampal longlasting potentiation by GABA antagonists. Acta Physiol. Scand. 125, 159–172.