Darrin P.D. Gilchrist
University of Otago
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Neuroscience Letters | 1990
Darrin P.D. Gilchrist; Paul F. Smith; Cynthia L. Darlington
Neuropeptide hormones such as adrenocorticotropic hormone, fragment 4-10 (ACTH(4-10], have been shown to facilitate various kinds of CNS plasticity, including recovery from deafferentation of the inner ear (vestibular compensation). The purpose of the present experiment was to determine whether the rapid compensation of spontaneous nystagmus (SN), which occurs over 2-3 days post-unilateral labyrinthectomy (UL) in the guinea pig, could be accelerated by administration of ACTH(4-10). Because of the short half-life of ACTH(4-10), injections of 200 micrograms/kg i.m. were given every 4 h for 48 h post-UL, and SN was measured every 2 h for 52 h post-UL. The results were compared with SN measurements from guinea pigs which received saline injections of the same volume, at the same times. ACTH(4-10) injections were found to significantly accelerate the rate of compensation of SN following UL. This result suggests that ACTH(4-10) may be useful in facilitating compensation when the symptoms of UL are most severe, during the first 2-3 days post-UL.
British Journal of Pharmacology | 1994
Darrin P.D. Gilchrist; Cynthia L. Darlington; Paul F. Smith
1 After removal of the peripheral vestibular receptors in one inner ear (unilateral labyrinthectomy, UL), oculo‐motor and postural symptoms occur but disappear over time in a process of recovery known as vestibular compensation. 2 ACTH‐(4–10), a fragment of the adrenocorticotrophic hormone (ACTH) molecule, which is devoid of corticotrophic activity, has been shown to enhance vestibular compensation. The present study investigated the effect of the ACTH‐(4–9) analogue, Org 2766, on vestibular compensation in guinea‐pig. Org 2766 is reported to be more potent behaviourally than ACTH‐(4–10). 3 After UL, Org 2766 was delivered via an osmotic minipump implanted s.c. to 30 animals randomly assigned to one of five conditions: 1, 5, 10, 20 or 40 nmol kg−1 Org 2766, every 4 h for 52 h post‐UL. Although infusion was continuous, in the present study the doses are expressed as nmol per 4 h in order to compare the results to a previous study in which animals received a discrete dose of ACTH‐(4–10) at the end of each 4 h period. All animals were compared to saline controls (n = 6). 4 Three symptoms of UL, spontaneous ocular nystagmus, roll head tilt and yaw head tilt, were measured every 4 h for 52 h, beginning at 10 h post‐UL. 5 Rates of infusion of 1, 5 and 10 nmol kg−1 accelerated spontaneous nystagmus compensation; 20 nmol kg−1 produced a significant decrease in the frequency of spontaneous nystagmus, as well as accelerating its compensation; 40 nmol kg−1 had no significant effect on spontaneous nystagmus compensation. 6 In comparison to the effects of Org 2766 on spontaneous nystagmus compensation, Org 2766 had little effect on the compensation of the postural symptoms, yaw head tilt and roll head tilt. Only 5 and 40 nmol kg−1 produced a significant change in postural compensation, and this was a reduction in the rate of roll head tilt compensation. 7 At the optimal infusion rate of 20 nmol kg−1 every 4 h, Org 2766 produced a similar effect on spontaneous nystagmus compensation to that of ACTH‐(4–10). However, Org 2766 was effective in accelerating spontaneous nystagmus compensation at much smaller doses per 4 h period than ACTH‐(4–10). Org 2766 did not have the same effect on postural compensation as it had on the compensation of spontaneous nystagmus.
Pharmacology, Biochemistry and Behavior | 1993
Darrin P.D. Gilchrist; Cynthia L. Darlington; Paul F. Smith
The aim of the present study was to determine if the calcium channel antagonist flunarizine would affect the time course of vestibular compensation for unilateral labyrinthectomy (UL) in guinea pigs. Animals received either a single IP injection of flunarizine 1 h pre-UL or a series of IP injections every 6 h for 24 h post-UL, starting at 6 h post-UL. Flunarizine was dissolved in 50-100% DMSO or suspended in 10% Tween-80 and administered at a dose of 10 mg/kg in the pre-UL condition and 10 or 20 mg/kg in the post-UL condition. All injections were 1 ml/kg in volume. Spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT) were measured using video analysis. When dissolved in DMSO and administered 1 h pre-UL, 10 mg/kg flunarizine had a small but significant effect on the rate of RHT compensation; otherwise, flunarizine had no significant effects on SN, YHT, or RHT when dissolved in DMSO. When suspended in Tween-80, 10 mg/kg flunarizine pre-UL resulted in a significant decrease in SN frequency and YHT relative to the control group, although the magnitude of the differences was small. When 20 mg/kg was given post-UL, both SN and YHT showed a small but significant change in the rate of compensation. No significant differences in RHT were observed. These results demonstrate that IP administration of flunarizine at a dose of 10-20 mg/kg IP has little effect on vestibular compensation compared to the effects obtained with low IM doses (0.8 mg/kg) of verapamil given 1 h pre-UL.
Experimental Neurology | 1996
Mayank B. Dutia; Darrin P.D. Gilchrist; Andrew J. Sansom; Paul F. Smith; Cynthia L. Darlington
The opioid receptor antagonist, naloxone, has been demonstrated to enhance recovery from spinal cord injury and fluid percussion brain injury. The present study investigated, for the first time, the effects of naloxone on behavioral recovery following unilateral peripheral vestibular deafferentation (unilateral labyrinthectomy, UL) in guinea pig. An ip injection of 5 mg/kg naloxone 30 min pre-UL and 5 h post-UL was found to significantly reduce the frequency of spontaneous nystagmus relative to the vehicle control group (P < 0.005). However, a lower dose (2.5 mg/kg) had no effect. At either dose, the effects on the postural symptoms, yaw head tilt and roll head tilt, were small by comparison and in most cases nonsignificant. These results suggest that naloxone can reduce the ocular motor effects of UL in a dose-dependent fashion.
Experimental Brain Research | 1993
Andrew J. Sansom; Cynthia L. Darlington; Paul F. Smith; Darrin P.D. Gilchrist; Ciandra J. Keenan; Robert Kenyon
The effects of three injections (0.5–4.5 h postoperation) of 1-[bis-(p-chlorophenyl)methyl]-3-[2,4-dichloro-beta-(2, 4-dichlorobenzyloxy)phenethyl]-imidazolium chloride (calmidazolium chloride, R24571), into the ipsilateral medial vestibular nucleus or fourth ventricle, on vestibular compensation for unilateral labyrinthectomy was studied in guinea pigs. R24571, a calmodulin antagonist and inhibitor of several Ca2+-dependent enzymes, caused a significant reduction in the average frequency of spontaneous ocular nystagmus (spontaneous nystagmus) during the first 53 h following unilateral labyrinthectomy (n= 5), compared with vehicle-injected animals (n=5). Although a statistical analysis was not performed on the yaw head tilt and roll head tilt data because of the large variability between animals over the 53-h period of compensation, most R24571 treated animals had less yaw head tilt (4/4 animals) and roll head tilt (4/5 animals) at 9–11 h post-labyrinthectomy than the average values for the vehicle groups at that time. The decrease in the frequency of spontaneous nystagmus following R24571 treatment was not associated with general ataxia or sedation. These results are consistent with recent biochemical studies in suggesting that intracellular pathways associated with Ca2+ may be involved in the neuronal mechanisms of vestibular compensation following unilateral labyrinthectomy.
Neuroscience Letters | 1992
Cynthia L. Darlington; Paul F. Smith; Darrin P.D. Gilchrist
The effects of adrenocorticotrophic hormone fragment 4-10 (ACTH-(4-10)) on single medial vestibular nucleus (MVN) neurons, in brainstem slices from guinea pigs which had undergone vestibular compensation for a previous ipsilateral surgical unilateral labyrinthectomy, were compared with those on MVN neurons in slices from labyrinthine-intact guinea pigs observed in a previous study. Although the average resting discharge of MVN neurons in slices from compensated animals was significantly higher than that for MVN neurons from labyrinthine-intact animals, the responses of the two groups of MVN neurons to ACTH-(4-10) were very similar. These results suggest that ACTH-(4-10) treatment is unlikely to accelerate behavioral recovery following unilateral labyrinthectomy (vestibular compensation) by acting on a receptor within the MVN for which sensitivity to ACTH-(4-10) changes during the compensation process.
European Journal of Pharmacology | 1994
Darrin P.D. Gilchrist; Cynthia L. Darlington; Paul F. Smith
The adrenocorticotrophic hormone fragment 4-9 (ACTH-(4-9)) analog, Org 2766 has been shown to accelerate vestibular compensation. However, N-methyl-D-aspartate (NMDA) receptor antagonists disrupt the recovery process. When Org 2766 was administered at a dose of 20 nmol/kg every 4 h for 52 h, it prevented the disruption of compensation usually produced by a single 5 mg/kg i.p. injection of the NMDA receptor antagonist 3-([+]-2-carboxy-piperazin-4yl)-propyl-1-phosphonic acid (CPP). NMDA receptor antagonists and ACTH-like peptides may produce their effects on compensation by acting directly or indirectly at the same receptor complex.
Restorative Neurology and Neuroscience | 1992
Darrin P.D. Gilchrist; Cynthia L. Darlington; Paul F. Smith
Following unilateral labyrinthectomy (UL), spontaneous nystagmus (SN) was measured in guinea pigs which received i.m. injections of 100 or 400 µg/kg ACTH(4-10) or 800 µg/kg [D-Phe7]ACTH(4-10), every 4 h for 48 h post-UL. The results were compared to those from a previous study, conducted under identical conditions, in which guinea pigs received similar injections of 200 µg/kg ACTH(4-10) or 0.1 ml/kg saline. ACTH(4-10) significantly accelerated the rate of compensation of SN at 100, 200, and 400 µg/kg doses, although the average effects were larger for the 200 µg/kg condition. [D-Phe7]ACTH(4-10) significantly increased the frequency of SN following UL compared to saline-treated animals; however, it also accelerated the rate of SN compensation. These results indicate that the acceleration of SN compensation in guinea pig by ACTH(4-10) follows an inverted U-shaped dose-response curve and that [D-Phe7]ACTH(4-10) increases the frequency of SN.
Peptides | 1996
Darrin P.D. Gilchrist; Cynthia L. Darlington; Paul F. Smith
Vestibular compensation is a process of CNS plasticity that is correlated to a return of resting activity in medial vestibular nucleus (MVN) neurons ipsilateral to a peripheral vestibular deafferentation. Systemic administration of melanocortin peptides accelerates the compensation process; the ACTH/MSH(4-9) analogue, Org 2766, accelerates this process at smaller doses than ACTH/MSH(4-10). The present study investigated the effect of Org 2766 on MVN neurons in vitro using extracellular single-cell recording. Org 2766 was less potent at the neuronal level than ACTH/MSH(4-10). When Org 2766 and ACTH/MSH (4-10) were tested consecutively on the same neuron, the response was often different. Org 2766 and ACTH/MSH (4-10) may have a different mode and/or site of action.
Brain Research Reviews | 1996
Cynthia L. Darlington; Darrin P.D. Gilchrist; Paul F. Smith