Clonidine impairs recovery of beam-walking after a sensorimotor cortex lesion in the rat

doi:10.1016/0006-8993(90)90413-6

Brain Research

Volume 508, Issue 2, 5 February 1990, Pages 305-309

https://doi.org/10.1016/0006-8993(90)90413-6 Get rights and content

Abstract

Beam-walking in the rat is a useful model for studying the effects of drugs on motor recovery following brain injury. In the present experiment, the effect of clonidine HCl on beam-walking recovery was investigated. Groups of rats were first trained to traverse a narrow elevated beam and then subjected to a right sensorimotor cortex suction-ablation injury. After 24 h, each rat received asingle dose of clonidine HCl (20, 60, or 200 μg/kg, i.p., salt weight) or saline. Recovery of beam-walking ability was scored over the next 12 days. Treatment with clonidine significantly slowed the rate of recovery (Kruskal-Wallis H = 8.755,df= 3; 0.02 <P < 0.05). Furthermore, the impairment persisted for at least 5 days after the rats were treated (Kruskal-Wallis H = 8.47,df= 3; 0.02 <P < 0.05). These data are consistent with the hypothesis that norepinephrine, working through central α₂-adrenergic receptors, influences motor recovery after a unilateral sensorimotor cortex lesion in the rat. Since many stroke patients are treated with centrally acting antihypertensive drugs, the potential effects of specific classes of these drugs during the recovery period, should be carefully considered.

References (33)

BrailowskyS. et al.
Phenytoin increases the severity of cortical hemiplegia in rats
Brain Research
(1986)
FeeneyD.M. et al.
Reinstatement of binocular depth perception by amphetamine and visual experience after visual cortex ablation
Brain Research
(1985)
SchallertT. et al.
Recovery of function after brain damage: severe and chronic disruption by diazepam
Brain Research
(1986)
BeyerW.H.
CRC Standard Mathematical Tables
BoyesonM.G. et al.
The role of norepinephrine in recovery from brain injury
Soc. Neurosci. Abstr.
(1984)
BoyesonM.G. et al.
Norepinephrine infusions into cerebellum facilitate recovery from sensorimotor cortex injury in the rat
Soc. Neurosci. Abstr.
(1986)
BraunJ.J. et al.
Sparing of a brightness habit in rats following visual decortication
J. Comp. Physiol. Psychol.
(1986)
BuytendijkF.J.J.
An experimental investigation into the influence of cortical lesions on the behaviour of rats
Arch. Neerl. Physiol. L'Homme Anim.
(1932)
CrisostomoE.A. et al.
Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients
Ann. Neurol.
(1988)
DunbarG.L. et al.
Use of gangliosides and amphetamines to promote behavioral recovery following bilateral caudate nucleus lesions

FeeneyD.M. et al.

Amphetamine restores locomotor function after motor cortex injury in the rat

FeeneyD.M. et al.

Amphetamine haloperidol and experience interact to affect the rate of recovery after motor cortex injury

Science

(1982)

FeeneyD.M. et al.

Amphetamine restores tactile placing after motor cortex lesions

FeeneyD.M. et al.

Pharmacotherapy for recovery of function after brain injury

CRC Crit. Rev. Neurobiol.

(1987)

FeeneyD.M. et al.

The locus-coeruleus and cerebral metabolism: recovery of function after cortical injury

Physiol. Psychol.

(1985)

FuxeK. et al.

Histochemical, biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration

Cited by (90)

Psychopharmacology of traumatic brain injury
2019, Handbook of Clinical Neurology
Citation Excerpt :
More recently, a large RCT aimed to evaluate whether the combined use of propranolol along with clonidine, an α2 agonist, could acutely decrease sympathetic hyperactivity after severe TBI (Patel et al., 2012), but due to unremarkable findings at the interim analysis, this study was terminated early. Of further relevance regarding use of clonidine in TBI is the small number of preclinical and clinical studies suggesting that by reducing catecholaminergic outflow, this medication may adversely affect motor recovery (Goldstein and Davis, 1990; Goldstein, 1995; Feeney et al., 2004). Antiepileptic agents and mood stabilizers can also be used to treat post-TBI agitation, though the evidence on the use of these agents is limited.
The pathophysiology of traumatic brain injury (TBI) can be highly variable, involving functional and/or structural damage to multiple neuroanatomical networks and neurotransmitter systems. This wide-ranging potential for physiologic injury is reflected in the diversity of neurobehavioral and neurocognitive symptoms following TBI. Here, we aim to provide a succinct, clinically relevant, up-to-date review on psychopharmacology for the most common sequelae of TBI in the postacute to chronic period. Specifically, treatment for neurobehavioral symptoms (depression, mania, anxiety, agitation/irritability, psychosis, pseudobulbar affect, and apathy) and neurocognitive symptoms (processing speed, attention, memory, executive dysfunction) will be discussed. Treatment recommendations will reflect general clinical practice patterns and the research literature.
Alpha-methyltyrosine inhibits formation of reactive oxygen species and diminishes apoptosis in PC12 cells
2009, Brain Research
Citation Excerpt :
Aware that increased levels of circulating catecholamines were associated with poorer outcomes following TBI, many investigators have suggested treating laboratory animals with adrenergic receptor antagonists in an effort to mitigate the toxic effects of norepinephrine and epinephrine. However, the results from these types of studies have been inconsistent, with some laboratories reporting improvements, and others noting decrements, in outcomes following treatment of TBI with agents that modify the actions of the catecholamines (Feeny and Westerberg, 1990; Goldstein and Davis, 1990; Inoue et al., 1991). Concurrently, it has become increasingly obvious that in addition to catecholamines, adrenal steroids also play an adverse role in TBI outcomes.
Circulating catecholamines and adrenal steroids are significantly increased following traumatic brain injury, and elevations in plasma catecholamines and cortisol portend a poor outcome. We hypothesize that an increase in the generation of reactive oxygen species from the synthesis of adrenal steroids and catecholamines is responsible for neuronal injury following traumatic brain injury. As a first step in testing this hypothesis, we sought to determine whether or not inhibition of catecholamine synthesis would decrease neuronal damage.
Using PC12 cells as a model of catecholamine synthesizing neurons, and serum deprivation as a method to induce neuronal damage, we show (1) adrenal corticosteroids increase reactive oxygen species formation and apoptosis induced by serum deprivation; (2) the inhibitor of catecholamine synthesis, alpha-methyltyrosine, reduces reactive oxygen species formation and apoptosis in PC12 cells; and (3) that acetazolamide, chlorthalidone, and the neurosteroid, allopregnanolone, which inhibits chloride transport, protect PC12 cells from apoptosis.
It may be possible to protect catecholaminergic neurons from reactive oxygen species-induced apoptotic death by not only blocking catecholamine synthesis, but also, by inhibiting carbonic anhydrase-dependent chloride/bicarbonate exchange with acetazolamide or chlorthalidone. These agents may prove salutary in reducing cell death in patients with traumatic brain injury or stroke.
Reversal of noradrenergic depletion and lipid peroxidation in the pons after brain injury correlates with motor function recovery in rats
2008, Neuroscience Letters
Functional impairment after brain injury (BI) has been attributed to the inhibition of regions that are related to the injured site. Therefore, noradrenaline (NA) is thought to play a critical role in recovery from motor injury. However, the mechanism of this recovery process has not been completely elucidated. Moreover, the locus coeruleus (LC) projects from the pons through the rat sensorimotor cortex, and injury axotomizes LC fibers, depressing NA function. This was tested by measuring lipid peroxidation (LP) in the pons after sensorimotor cortex injury. Depression of function in the pons would be expected to alter areas receiving pontine efferents. Male Wistar rats were divided into three groups: control (n = 16), injured (n = 10) and recovering (n = 16), and they were evaluated using a beam-walking assay between 2 and 20 days after cortical injury. We performed measures of NA and LP in both sides of the pons and cerebellum. We found a decrease of NA in the pons and the cerebellum, and a concomitant increase in the motor deficit and LP in the pons of injured animals. Recovering rats had NA and LP levels that were very similar to those observed in control rats. These observations suggest that the mechanism of remote inhibition after BI involves lipid peroxidation, and that the NA decrease found in the cerebellum of injured animals is mediated by a noradrenergic depression in the pons, or in areas receiving NA projections from the pons.
Voluntary exercise or amphetamine treatment, but not the combination, increases hippocampal brain-derived neurotrophic factor and synapsin I following cortical contusion injury in rats
2008, Neuroscience
Prior work has shown that d-amphetamine (AMPH) treatment or voluntary exercise improves cognitive functions after traumatic brain injury (TBI). In addition, voluntary exercise increases levels of brain-derived neurotrophic factor (BDNF). The current study was conducted to determine how AMPH and exercise treatments, either alone or in combination, affect molecular events that may underlie recovery following controlled cortical impact (CCI) injury in rats. We also determined if these treatments reduced injury-induced oxidative stress. Following a CCI or sham injury, rats received AMPH (1 mg/kg/day) or saline treatment via an ALZET^® pump and were housed with or without access to a running wheel for 7 days. CCI rats ran significantly less than sham controls, but exercise level was not altered by drug treatment. On day 7 the hippocampus ipsilateral to injury was harvested and BDNF, synapsin I and phosphorylated (P) -synapsin I proteins were quantified. Exercise or AMPH alone significantly increased BDNF protein in sham and CCI rats, but this effect was lost with the combined treatment. In sham-injured rats synapsin I increased significantly after AMPH or exercise, but did not increase after combined treatment. Synapsin levels, including the P-synapsin/total synapsin ratio, were reduced from sham controls in the saline-treated CCI groups, with or without exercise. AMPH treatment significantly increased the P-synapsin/total synapsin ratio after CCI, an effect that was attenuated by combining AMPH with exercise. Exercise or AMPH treatment alone significantly decreased hippocampal carbonyl groups on oxidized proteins in the CCI rats, compared with saline-treated sedentary counterparts, but this reduction in a marker of oxidative stress was not found with the combination of exercise and AMPH treatment. These results indicate that, whereas exercise or AMPH treatment alone may induce plasticity and reduce oxidative stress after TBI, combining these treatments may cancel each other's therapeutic effects.
Abnormal motor function and dopamine neurotransmission in DYT1 ΔGAG transgenic mice
2008, Experimental Neurology
A single GAG deletion in Exon 5 of the TOR1A gene is associated with a form of early-onset primary dystonia showing less than 40% penetrance. To provide a framework for cellular and systems study of DYT1 dystonia, we characterized the genetic, behavioral, morphological and neurochemical features of transgenic mice expressing either human wild-type torsinA (hWT) or mutant torsinA (hMT1 and hMT2) and their wild-type (WT) littermates. Relative to human brain, hMT1 mice showed robust neural expression of human torsinA transcript (3.90×). In comparison with WT littermates, hMT1 mice had prolonged traversal times on both square and round raised-beam tasks and more slips on the round raised-beam task. Although there were no effects of genotype on rotarod performance and rope climbing, hMT1 mice exhibited increased hind-base widths in comparison to WT and hWT mice. In contrast to several other mouse models of DYT1 dystonia, we were unable to identify either torsinA- and ubiquitin-positive cytoplasmic inclusion bodies or nuclear bleb formation in hMT1 mice. High-performance liquid chromatography with electrochemical detection was used to determine cerebral cortical, striatal, and cerebellar levels of dopamine (DA), norepinephrine, epinephrine, serotonin, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindoleacetic acid. Although there were no differences in striatal DA levels between WT and hMT1 mice, DOPAC and HVA concentrations and DA turnover (DOPAC/DA and HVA/DA) were significantly higher in the mutants. Our findings in DYT1 transgenic mice are compatible with previous neuroimaging and postmortem neurochemical studies of human DYT1 dystonia. Increased striatal dopamine turnover in hMT1 mice suggests that the nigrostriatal pathway may be a site of functional neuropathology in DYT1 dystonia.
Chapter 66 Stroke recovery and rehabilitation
2008, Handbook of Clinical Neurology
Citation Excerpt :
The impact of amphetamine and other adrenergic agonists and antagonists on post‐brain injury recovery can be predicted based on their effects on the release of norepinephrine from noradrenergic terminals. Both yohimbine and idazoxan (centrally acting α2‐adrenergic receptor antagonists) increase norepinephrine release and enhance motor recovery (Weaver et al., 1987; Goldstein, 1989; Goldstein et al., 1989; Sutton and Feeney, 1992) whereas clonidine, a centrally acting α2‐adrenergic receptor agonist that decreases norepinephrine release, has a prolonged detrimental effect on motor recovery in rats and reinstates motor deficits when given to animals that had recovered motor function (Stephens et al., 1986; Goldstein and Davis, 1990b; Sutton and Feeney, 1992). Prazosin and phenoxybenzamine, centrally acting α1‐adrenergic receptor antagonists, are also harmful (Hovda et al., 1983; Feeney and Westerberg, 1990; Sutton and Feeney, 1992).
This chapter focuses on the stroke recovery and rehabilitation. The goal of post-stroke rehabilitative interventions is to shift the recovery curve upwards so that patients achieve higher levels of function than they would have “spontaneously.” Stroke patients may be exposed to a variety of activities and experiences that have the potential to influence outcome. Patients can benefit from participation in multidisciplinary rehabilitative interventions. Optimization of functional benefits may be achieved through combinations of new physiotherapeutic approaches aimed at providing more intensive practice, along with pharmacological treatments, avoidance of potentially harmful centrally acting drugs, and possibly incorporation of a progenitor cell transplantation strategy. A variety of polypeptide growth factors have the capacity to support neural outgrowth, synaptogenesis, and neurogenesis after stroke and other brain injuries. These include basic fibroblast growth factor (bFGF), vascular endothelial growth factor (Veg-f), osteogenic protein-1 (OP-1), erythropoietin (EPO), and granulocyte colony stimulating factor (G-CSF). The chapter discusses the data from animal model studies, robot-assisted therapy, supported treadmill training, constraint-induced movement therapy, clinical studies and experimental studies of pharmacotherapy, and various adjunctive therapies.

View all citing articles on Scopus

View full text

Clonidine impairs recovery of beam-walking after a sensorimotor cortex lesion in the rat

Abstract

Brain Research

Brain Research

Brain Research

CRC Standard Mathematical Tables

The role of norepinephrine in recovery from brain injury

Soc. Neurosci. Abstr.

Norepinephrine infusions into cerebellum facilitate recovery from sensorimotor cortex injury in the rat

Soc. Neurosci. Abstr.

Sparing of a brightness habit in rats following visual decortication

J. Comp. Physiol. Psychol.

An experimental investigation into the influence of cortical lesions on the behaviour of rats

Arch. Neerl. Physiol. L'Homme Anim.

Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients

Ann. Neurol.

Use of gangliosides and amphetamines to promote behavioral recovery following bilateral caudate nucleus lesions

Amphetamine restores locomotor function after motor cortex injury in the rat

Amphetamine haloperidol and experience interact to affect the rate of recovery after motor cortex injury

Science

Amphetamine restores tactile placing after motor cortex lesions

Pharmacotherapy for recovery of function after brain injury

CRC Crit. Rev. Neurobiol.

The locus-coeruleus and cerebral metabolism: recovery of function after cortical injury

Physiol. Psychol.

Histochemical, biochemical and functional studies on central monoamine neurons after acute and chronic amphetamine administration