Michael G. Boyeson

Intraventricular norepinephrine facilitates motor recovery following sensorimotor cortex injury

Intraventricular norepinephrine, dopamine, or vehicle was administered to rats 24 hours after a unilateral sensorimotor cortex ablation to determine their potential roles in acceleration of motor recovery as measured by the beam-walking task. Norepinephrine was found to be the critical neurotransmitter in facilitating motor recovery. Blocking norepinephrine synthesis by dopamine-beta-hydroxylase inhibition coupled with dopamine administration failed to accelerate recovery, indicating a more important role for norepinephrine compared to its precursor dopamine in motor recovery after sensorimotor cortex injury.

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

Cerebral metabolic effects of locus coeruleus (LC) lesion or drugs affecting LC were investigated after unilateral injury of sensorimotor cortex in rats. Sensoriomotor cortex ablation produced a widespread depression of cerebral 14C-2-deoxyglucose utilization which was reversed by amphetamine (AMP, 2 mg/kg) and worsened by haloperidol (HAL, 0.4 mg/kg). Lesion of LC alone did not affect cerebral oxidative metabolism, measured by a stain for the enzyme alpha-glycerophosphate dehydrogenase (α-GPDH). Lesion of LC prior to undercut laceration of motor cortex shortened time to onset of α-GPDH cortical paling. Treatment with AMP (2 mg/kg) blocked cortical paling of the enzyme stain at 4 days postinjury, an effect prevented by concomitant HAL (0.3 or 0.6 mg/kg). Apomorphine (1 mg/kg) did not block cortical paling. These data parallel effects of these drugs on recovery of function. The results suggest that a metabolic “remote functional depression” (RFD) is alleviated by catecholamine activation after cortical injury, whereas onset of RFD is accelerated by LC lesions and exacerbated by catecholamine blockade.

Responses to cortical injury: II. Widespread depression of the activity of an enzyme in cortex remote from a focal injury

As a part of a broader study of the reaction of the brain to injury, we report here an interesting loss of the activity of an enzyme in areas quite remote from the site of direct injury. At 36 h following a laceration or contusion injury to the hindpaw area of the motor cortex, a peculiar loss of staining for the enzyme alpha glycerophosphate dehydrogenase (alpha-GPDH) was noted. alpha-GPDH activity was markedly depressed in cortical layers II and III throughout the hemisphere on the side of the injury. The depression of alpha-GPDH activity extended far laterally across the rhinal fissure into the pyriform cortex. The decrease in alpha-GPDH staining was prominent 4 days after the injury: however, the staining pattern had returned to normal at 9 days. Enzyme changes in animals lesioned in the occipital cortex paralleled that seen in animals with a lesion in the motor cortex. Animals which had received an undercut lesion in the motor cortex 56 days earlier were contused in the occipital cortex. The old injury site presented the same sequelae of changes as seen in other lesioned animals. Additionally, a suction ablation injury involving only a small part of motor cortex resulted in the same widespread reduction of staining for alpha-GPDH in layers II and III. The derangement in energy metabolism suggests that cells in layers II and III of the cerebral cortex may be particularly vulnerable to perturbations induced by cortical trauma. These findings may be related to the diffuse and transient functional losses observed after head injury in man.

Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex injury

ABSTRACT A recent investigation of the effects of the antidepressants desipramine and trazodone on behavioral recovery in brain-injured animals suggested that antidepressants, which act to increase noradrenergic activity in the brain, may facilitate the rate of recovery, whereas those that act to increase serotonergic (5-HT) activity may hinder recovery and reinstate deficits in recovered animals. The present study was designed to evaluate these findings further by assessing the effect of a single intraperitoneal injection of fluoxetine (a relatively pure 5-HT reuptake blocker), amitriptyline (a mixed 5-HT and noradreneregic reuptake blocker with α1-adrenergic receptor blocking activity) or a single intraventricular infusion of 5-HT on recovery of beam-walking ability in animals with a unilateral sensorimotor cortex injury. None of the drugs significantly affected the rate of recovery. Although fluoxetine was ineffective in reinstating the motor deficit in recovered animals, amitriptyline reinstated the deficit in a dose-dependent fashion. Infusion of 5-HT resulted in an extremely transient reinstatement of the deficit, which was largely attributable to its short-term sedative properties. These results suggest that 5-HT may be less involved in functional recovery than previously thought. They also add further support to previous findings that indicate that drugs which act to antagonize α1-adrenergic activity (e.g., phenoxybenzamine) may interfere with motor recovery after sensorimotor cortex injury. An appreciation of the potential impact of certain antidepressants on functional recovery in brain-injured patients appears warranted.

Neuroplasticity in the smooth muscle of the myenterically and extrinsically denervated rat jejunum

The objective of this study was to examine the effects of two different denervation procedures on the distribution of nerve fibers and neurotransmitter levels in the rat jejunum. Extrinsic nerves were eliminated by crushing the mesenteric pedicle to a segment of jejunum. The myenteric plexus and extrinsic nerves were eliminated by serosal application of the cationic surfactant benzyldimethyltetradecylammonium chloride (BAC). The effects of these two denervation procedures were evaluated at 15 and 45 days. The level of norepinephrine in whole segments of jejunum was initially reduced by more than 76% after both denervation procedures, but by 45 days the level of norepinephrine was the same as in control tissue. Tyrosine hydroxylase (nor-adrenergic nerve marker) immunostaining was absent at 15 days, but returned by 45 days. However, the pattern of noradrenergic innervating axons was altered in the segment deprived of myenteric neurons. Immunohistochemical studies showed protein gene product 9.5 (PGP 9.5)-immunoreactive fibers in whole-mount preparations of the circular smooth muscle in the absence of the myenteric plexus and extrinsic nerves. At 45 days, the number of nerve fibers in the circular smooth muscle increased. Vasoactive intestinal polypeptide (VIP)-immunoreactive fibers, a subset of the PGP 9.5 nerve fibers, were present in the circular smooth muscle at both time points examined. Choline acetyltransferase (CAT) activity and VIP and leucine enkephalin levels were measured in separated smooth muscle and submucosa-musosal layers of the denervated jejunum. VIP and leucine-enkephalin levels were no different from control in tissue that was extrinsically denervated alone. However, the levels of these peptides were elevated two-fold in the smooth muscle 15 and 45 days after myenteric and extrinsic denervation. In the submucosa-mucosa, VIP and leucine enkephalin levels also were elevated two-fold at 15 days, but comparable to control at 45 days. CAT activity was equal to control in the smooth muscle but elevated two-fold in the submucosa-mucosa at both times. These results provide evidence for innervation of the circular smooth muscle by the submucosal plexus. Moreover, these nerve fibers originating from the submucosal plexus proliferate in the absence of the myenteric plexus. Furthermore, the myenteric neurons appear to be essential for normal innervation of the smooth muscle by the sympathetic nerve fibers. It is speculated that the sprouting of the submucosal plexus induced by myenteric plexus ablation is mediated by increased production of trophic factors in the hyperplastic smooth muscle.

Cerebellar norepinephrine infusions facilitate recovery after sensorimotor cortex injury

This study reports the effects of norepinephrine infusions into cerebellum after unilateral sensorimotor cortex injury. The results demonstrate an immediate and permanent acceleration in motor recovery in awake rats infused with 150 micrograms norepinephrine into the cerebellum contralateral to a right sensorimotor cortex ablation. A vehicle infusion or infusion of norepinephrine into the ipsilateral cerebellum produced no beneficial effects on functional recovery.

Effects of trazodone and desipramine on motor recovery in brain-injured rats.

Rats pretrained to walk a narrow balance beam received unilateral sensorimotor cortex lesions, resulting in a contralateral transient paresis that lasted 14 days. In a dose-dependent manner, a single injection of the antidepressant trazodone given 24 hours after injury transiently slowed motor recovery compared with injured controls. After final recovery level of motor function, a reinjection of trazodone reinstated the hemiparesis for up to 6 hours. In other animals, a single injection of the antidepressant desipramine significantly facilitated motor performance when compared with injured controls. Desipramine had no deleterious motor effect when administered to animals that had recovered on the beam-walking task. These findings would suggest that the predominately noradrenergic neurotransmitter effects of desipramine may facilitate, and those of the predominately serotonergic trazodone may hinder, the recovery of locomotor performance after cortical injury in rats. Further studies appear indicated, including applying these findings to the clinical setting.

The effect of seizures on recovery of function following cortical contusion in the rat

The effect of seizures on recovery of motor function was studied in rats following unilateral contusion of the sensorimotor cortex. Animals receiving two electroconvulsive seizures (ECSs) within the first 24 hours postcontusion showed accelerated recovery of beam-walking ability, reduced volume of necrosis and less spontaneous activity compared to animals receiving only contusions. Animals receiving seven ECSs after contusion had an even smaller volume of necrosis and also reduced spontaneous activity compared to the two ECS group and to controls receiving contusions alone. However, for recovery of beam-walking ability, the seven ECS group did not differ from control rats receiving only contusions. The results are discussed in terms of the effects of seizures on catcholamines, gamma-amino butyric acid, cerebral blood flow and possible effects on remote functional depression after brain injury.

Unilateral, but not bilateral, locus coeruleus lesions facilitate recovery from sensorimotor cortex injury

This study investigates the role of the locus coeruleus in recovery from sensorimotor cortex injury. Unilateral locus coeruleus lesions given 2 weeks prior to unilateral sensorimotor cortex injury facilitate subsequent motor recovery compared to animals with only a sensorimotor cortex injury, while bilateral locus coeruleus lesions severely retard motor recovery. The results suggest that recovery of function from the cortical injury is facilitated as long as a sufficient amount of the noradrenergic system remains intact, perhaps to provide a basis for compensatory sprouting. The results also suggest that recovery does occur in the absence of the locus coeruleus, indicating that the noradrenergic system is not necessary for recovery to occur after the cortical injury.

Adverse effects of catecholaminergic drugs following unilateral cerebellar ablations

The following experiment was designed to examine the effects of unilateral cerebellar cortex lesions and pharmacological postinjury treatments with catecholamine drugs on recovery of beam walking ability in rats. Rats trained on a beam walking task were initially given either amphetamine, haloperidol, or a combination of the drugs at 24 h after injury, and tested at various intervals after drug administration. Six total doses were given to animals at 5d intervals during recovery. All drugs retarded recovery of function on the beam walking task compared to saline controls. Animals with cortical lesions that involved the deep cerebellar nuclei showed no recovery on the beam, regardless of group assignment. Phenoxybenzamine and propranalol were both ineffective in reinstating the beam walking deficit in those animals that demonstrated recovery on the beam walking task. The results indicate that the cerebellum plays a particularly important role in recovery of beam walking ability, and may contribute to beam walking recovery commonly observed after sensorimotor cortex ablations.