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Research report
Opiate receptor avidity is increased in rhesus monkeys following
unilateral optic tract lesion combined with transections of corpus
callosum and hippocampal and anterior commissures
a,b ,
*
c d a ,1Robert M. Cohen
, Richard E. Carson , Richard C. Saunders , Doris J. Doudet
a
Laboratory of Cerebral Metabolism, National Institute of Mental Health, Bethesda, MD 20892-1274, USA b
Geriatric Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892-1274, USA c
PET Department, Clinical Center, National Institute of Health, Bethesda, MD 20892-1274, USA d
Laboratory of Neuropsychology, National Institute of Mental Health, Bethesda, MD 20892-1274, USA
Accepted 23 May 2000
Abstract
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Opiate receptor avidity (Bmax/K ) was measured in four rhesus monkeys following unilateral lesioning of the optic tract combined withD
transection of the corpus callosum and the hippocampal and anterior commissures depriving one hemisphere of visual input (Tract and Split), two animals with transection of commissures only (Split), and nine healthy monkeys with positron emission tomography (PET)
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and 6-deoxy-6-b-[ F]fluoronaltrexone (cyclofoxy, CF), a m- andk-opiate receptor antagonist. Opiate receptor avidity was found to be significantly higher in the Tract and Split animals, only, bilaterally, throughout the lateral cortex and in the cingulate and posterior putamen (41–117%). Ipsilateral changes were consistently greater than those contralateral, but this asymmetry was of statistical significance only in the parietal and occipital cortices. Cyclofoxy avidity was decreased in the medial cortex of both the Tract and Split and Split animals (|25%). The results suggest that opiate pathways undergo extensive alteration in response to changes in brain functional
activities brought about through hemispheric visual deprivation. 2000 Elsevier Science B.V. All rights reserved.
Theme: Neurotransmitters, modulators, transporters, and receptors
Topic: Opioids: anatomy, physiology and behavior
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Keywords: Neurodegeneration; 6-Deoxy-6-b-[ F]fluoronaltrexone; Positron emission tomography; Cortex; Visual system
1. Introduction effects of neurodegeneration or an adaptational response.
To examine the question of functional vs. direct opiate Decreases in opiate receptor avidity as quantified with receptor avidity changes in response to neurodegeneration the positron-emitting opiate antagonist 6-deoxy-6-b- we elected to examine opiate receptor avidity in animals
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[ F]fluoronaltrexone (cyclofoxy, CF) occur in Alzheim- with lesions of the visual system. The visual system has er’s disease [3] and following the 1-methyl-4-phenyl- provided exceptionally useful models with which to study 1,2,3,6-tetrahydropyridine (MPTP) lesioning of rhesus structural and biochemical neuronal plasticity in the con-monkeys [4,5]. While, it is likely that these changes reflect text of development and of altered function [6,14,25]. adaptive responses to alteration in function in the
MPTP-lesioned animals, it is not clear in the Alzheimer’s patients whether the avidity changes reflect primarily the direct
2. Materials and methods
*Corresponding author. Geriatric Psychiatry Branch, NIH, Building 10, 2.1. Subjects Room 3N218, 10 Center Drive, MSC 1274, Bethesda, MD 20892-1274,
USA. Tel.:11-301-402-6985; fax:11-301-480-2847.
Fifteen monkeys (Macaca mulatta), four that had re-E-mail address: [email protected] (R.M. Cohen).
1 ceived unilateral transection of the optic tract combined
Present address: University of British Columbia, Vancouver, BC,
Canada. with transection of the corpus callosum and hippocampal
and anterior commissures (Tract and Split), two that had sion, and metabolite analysis, have been previously de-received transection of the corpus callosum and commis- scribed [1,4,8].
sures only (Split) and nine normal animals were PET (positron emission tomography) scanned using cyclofoxy
2.4. Data analysis as the tracer. The lesioned animals were scanned 3 to 5
years after their surgery.
Pixel by pixel V (volume of distribution) images wereT generated by a non-linear parameter estimation algorithm 2.2. Surgical procedures
[1]. The algorithm is used to generate estimates of three parameters based on a one-compartment model and the All animals were initially sedated with ketamine
measured plasma CF input curve: K (ml plasma / min / ml (ketamine HCl, 10 mg / kg) and surgical level of anesthesia 1
tissue) the CF influx constant from plasma to tissue, k
achieved with isoflurane gas. All neurosurgical procedures 2
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were carried out under aseptic conditions with the aid of an (min ) the CF efflux constant from tissue to plasma, and operating microscope. Intravenous fluids were provided V the plasma volume (ml plasma / ml tissue). From thesep throughout the surgical procedure. The animal was wrap- estimated parameters, the total volume of distribution (V )T ped in a heating blanket and its vital signs (heart and was calculated from the ratio of K to k . Based on the1 2 respiration) monitored continually. The head was secured assumptions of the model, this value is equal to the in a head holder and commissurotomy performed by a concentration ratio at equilibrium between tissue and dorsal approach. The cerebral midline was exposed plasma and includes tracer in the tissue that is free, through a unilateral bone flap and reflection of a dural flap. non-specifically bound, and specifically bound to receptor. The corpus callosum was exposed with gentle retraction of Another interpretation of V is the volume of plasma whichT the medial wall of one hemisphere. Using a small glass contains an equivalent amount of tracer as 1 ml of tissue, pipette together with suction, the corpus callosum through- thus the units of ml plasma / ml tissue.
out its rostral–caudal extent was transected. At a level To estimate the binding potential or avidity of opiate immediately caudal to the descending columns of the receptors (the specific volume of distribution, V , roughlyS fornix the anterior commissure was visualized through the equivalent to the estimate of Unoccupied Receptor
Den-9 third ventricle and transected. Upon completion of the sity / the Dissociation Constant of the Receptor, i.e., Bmax/ commissurotomy the dura was replaced over the brain and K ), also referred to as CF avidity, an estimate ofD the bone flap sewn in position using nylon sutures. nonspecific binding (V ) is required (VNS S5VT 2V ). InNS The optic tract was visualized through an orbitofrontal practice, this is obtained from the volume of distribution of approach. A small craniotomy was made over the prefron- a region with little or no specific opiate receptor binding tal cortex, the dura reflected and the frontal lobe gently which in the monkey is the cerebellum and in humans is retracted to view the ventral medial portion of the brain. the primary occipital cortex. The general use in PET tracer Using a glass pipette the optic tract was transected studies of the avidity measure, V , instead of receptorS immediately behind the optic chiasm. The wound was density (Bmax), is the result of not being able to accurately closed in anatomical layers using absorbable suture. estimate receptor density based on a single injection of Prophylactic doses of antibiotics were administered and tracer. The single injection PET study is roughly equiva-continued for 2 weeks postoperative. In general the lent to an in vitro study in which the binding of only a monkeys recovered without incident. single low (relative to the K ) concentration of radioac-D tively labeled ligand to tissue is measured. The use of a 2.3. PET scan procedure region without specific binding in the PET study for determination of VNS is roughly equivalent to the in vitro On the day of scan, each monkey was intubated and had binding of labeled ligand to tissue in the presence of a high venous and arterial lines inserted under barbiturate anes- concentration of unlabeled ligand. Tissues that bind more thesia. During the scan each animal was maintained under labeled ligand in vitro after subtracting nonspecific binding light anesthesia with isoflurane and positioned prone in a have a higher binding potential either as a result of stereotaxic frame. 62.5% of the tracer dose (2–5 mCi, increased receptor density, decreased K or a combinationD specific activity53.0961.74 Ci / mmole) of CF was ad- of both. In the in vivo instance, differences in V can alsos ministered as a bolus while the rest of the dose was arise as a result of changes in endogenous ligand con-administered as a continuous infusion to achieve constant centrations leading to more or less competition with the radioactivity levels in all brain regions between 60 and 90 labeled tracer for the receptor.
[4,5,8] and by comparison with each animal’s MRI scan attempt to determine the likelihood that any significant and an atlas of the rhesus monkey brain in coronal planes. changes observed in the Tract and Split animals were All the ROIs were placed by a single investigator ex- likely to be the result of the transection of the commissural perienced in nonhuman primate neuroanatomy and the use fibers, only, rather than the combination of optic tract of the template. lesion and transection of commissural fibers.
2.5. Statistical analysis
3. Results
Where homologous left and right hemispheric regions
could be evaluated, the effect of the Tract and Split on 3.1. Tract and Split opiate receptor avidity was determined using two-way
ANOVARs (repeated measures) with GROUP (normal, As previously reported [4] and illustrated in Fig. 1, the lesion) as the between-subject factor and SIDE (ipsilateral, in vivo pattern of CF binding in monkey brain closely contralateral) as the within-subject factor. In the presence resembles that reported for the pattern of in vitro naloxone of a significant statistical interaction effect (GROUP3 binding [26]. Aside from the medial frontal cortex, in-SIDE), the effect of lesion was assessed separately for the creases in opiate receptor avidity were seen in all the ipsilateral and contralateral sides by independent t-test. cortical regions (occipital, parietal, temporal, frontal, cen-Because there were only two split animals, a separate tral) of the Tract and Split animals examined compared to ROI statistical analysis using the independent t-test for healthy controls (Table 1). The largest effects were comparison to normal controls was used in an exploratory observed in the occipital and parietal cortices where there
Table 1
a Table of distribution volumes for the opiate receptor-dependent tracer cyclofoxy in normal (n59) and Tract and Split (n54) monkeys
Specific distribution volumes (V )S % Differences in Vs Effect of lesion Normals Optic Tract and Split
Right Left Ipsi Contra (T and S-Normal) F1,11 (P-value)
Mean (s.d.) Mean (s.d.) Mean (s.d.) Mean (s.d.) Ipsi Contra
Medial Medial Medial
Mean (s.d.) Mean (s.d.)
Cortical structures
*Medial frontal 14.39 (2.24) 10.65 (1.93) 226.0% 8.3 (0.015)
*Orbital 12.04 (1.69) 11.16 (2.07) 17.03 (5.16) 16.76 (5.28) 41.4% 50.2% 8.0 (0.016) *Frontal 10.96 (1.70) 10.78 (1.55) 16.50 (4.38) 16.38 (4.11) 50.5% 51.9% 12.9 (0.0043) *Central 6.59 (1.29) 6.52 (1.29) 11.10 (3.06) 10.85 (3.01) 68.4% 66.4% 15.4 (0.0024) *Temporal 11.77 (1.74) 10.92 (2.21) 18.63 (3.94) 16.60 (2.44) 58.3% 52.0% 20.5 (0.00086) [*Parietal 7.37 (1.82) 7.52 (1.32) 13.08 (1.89) 11.38 (2.16) 77.5% 51.3% 22.4 (0.0006) [*Occipital 3.81 (1.42) 3.75 (1.26) 8.25 (1.40) 6.25 (1.26) 116.5% 66.7% 20.4 (0.00087) Limbic and paralimbic
*Cingulate 12.21 (1.60) 15.79 (3.05) 29.1% 8.1 (0.016)
Hippocampus 9.87 (2.31) 10.38 (2.67) 13.48 (2.11) 12.63 (2.13) 36.6% 21.7% 4.38 (0.06) Amygdala 23.91 (2.77) 24.09 (3.44) 25.58 (5.75) 26.08 (5.08) 7.0% 8.3% 0.6 (NS) Basal ganglia
Caudate 29.61 (4.19) 29.12 (4.03) 31.30 (7.73) 31.55 (7.42) 5.7% 8.3% 0.4 (NS) Ant. putamen 23.75 (2.83) 23.26 (2.29) 25.70 (9.94) 24.65 (10.95) 8.2% 6.0% 0.2 (NS) *Post. putamen 14.32 (2.35) 14.51 (2.19) 20.53 (3.93) 20.90 (3.71) 43.4% 44.0% 15.0 (0.0026) Globus pallidus 17.63 (2.70) 16.81 (4.67) 21.95 (6.67) 20.63 (5.59) 24.5% 22.7% 2.4 (NS) Subcortex
Medial thalamus 29.65 (3.95) 27.30 (4.82) 27.9% 0.86 (NS)
Thalamus 25.67 (3.45) 24.24 (3.19) 25.45 (5.64) 23.90 (5.15) 20.9% 21.4% 0.01 (NS)
Hypothalamus 29.07 (3.91) 25.6 (7.46) 211.9% 1.27 (NS)
a
Means and standard deviations for the specific distribution volumes (ml plasma / ml tissue) of the regions of interest (ROIs) and the total distribution volumes for the cerebellum (non-specific CF avidity) and muscle (background) for the normal controls and Tract and Split (unilateral optic tract lesion combined with transection of callosal fibers) monkeys are tabulated with standard deviations in parentheses. Where there were homologous left and right ROIs, the effect of lesion was determined as the F [1,11] value and its corresponding P-value for the main effect of the two-way repeated measures analysis of variance (ANOVAR) with GROUP, i.e. lesion or normal as the grouping factor and SIDE, (ipsilateral vs. contralateral) as the within-group factor. When the interaction, i.e. GROUP3SIDE was significant, paired comparisons between the ipsilateral sides of the normal and lesioned animals, and between the contralateral sides of the normal and lesioned animals were made by the least significant difference method (LSD). Where statistical analyses were not determined for homologous left and right ROIs, e.g. the hypothalamus, means and standard deviations are tabulated as ‘Medial’. In these instances the F-values and corresponding P-values are based on one-way ANOVAs. Statistical significance, observed either by ANOVA or ANOVAR for the effect of GROUP, i.e. lesion, is indicated by a ‘*’ and a significant interaction by a ‘[’ placed next to the name of the ROI.
were significant interactions between LESION and SIDE regions of the cerebellum (VT510.661.8 for the normal (Occipital: F1,11517.0, P,0.002; Parietal: F1,11517.9, controls and 8.561.3 for the Tract and Split animals, P,0.002). Independent t-tests, confirmed the presence of P5NS) and of an area of neck and shoulder muscle higher CF avidity on both the ipsilateral and contralateral (VT56.861.3 for the normal controls and 6.361.1 for the sides of the Tract and Split animals (parietal: ipsilateral, Tract and Split animals, P5NS). Thus, the differences in t55.16, P,0.0004; contralateral, t54.04, P,0.002; oc- specific CF distribution volumes (V ) in the opiate re-S cipital: ipsilateral, t55.24, P,0.0003; contralateral, t5 ceptor-rich brain areas are unlikely to be the result of 3.3, P,0.008). Thus, the significant interactions were the changes in the nonspecific uptake of CF.
result of larger increases on the ipsilateral compared to the
contralateral sides. For example, compared to the healthy 3.2. Split controls the increase in the ipsilateral occipital cortex of
statistically significant difference with the Split animals bolic and blood flow studies in normal as well as lesioned having a lower V (10.6S 60.07, t52.28, P,0.05) which animals that have established that the areas of the brain was almost identical to that of the Tract and Split animals contributing to and essential for many visual system (see Table 1). Although statistical power was limited, this functions are extensive [6,12–14,28]. Areas of the brain was not the likely explanation for failing to find regional thought to contribute to visual function include frontal, CF avidity differences of the magnitude of those observed temporal and parietal cortex, and cingulate as well as some in the Tract and Split animals as the CF avidity was lower areas of the subcortex including the posteroventral than that of the normal controls of most regions with only putamen, all areas showing increases in CF avidity in a few ROIs slightly higher, but never approaching those response to the optic lesion.
observed in the Tract and Split animals.
4.2. Specificity of opiate responses
4. Discussion The likelihood that the CF avidity changes are
non-specific in nature is made less likely by prior findings in 4.1. Possible causes of opiate responses to lesions unilaterally- [5] and bilaterally-lesioned [4] MPTP ani-mals. In response to these lesions of the dopamine system, The likely causes of a reduction in CF avidity in a the CF avidity of the amygdala, thalamus, caudate and region, as was observed in the medial frontal cortex in the anterior putamen were decreased compared to the healthy Tract and Split animals, are axonal (Wallerian) degenera- controls. These same brain areas were found to be unaf-tion and transneuronal degeneraunaf-tion. The locaunaf-tion of the fected in the current study. Thus, despite the extensiveness medial region together with the observation of similar and the size and bilateral nature of the CF avidity increases changes in the Split animals are consistent with either of observed in the Tract and Split monkeys, they are likely to the above mechanisms. Thus, the lowering of CF avidity in be specific responses to hemispherically selective visual the medial frontal cortex was likely to have been the result deprivation.
of the transection of the callosal fibers. In those brain Consistent with this working hypothesis are studies in regions, however, in which higher opiate receptor avidity the rat following unilateral orbital enucleation where was found in the Tract and Split animals, and not in the selective neurotransmitter receptor density changes, on the Split animals, another mechanism must be at work. In order of 20%, have been noted to occur at synapses both these areas, if cutting the callosal fibers had any effect primary and secondary to the lesion and with different time these were likely to have been the result of an interaction dependencies [2]. For example, while GABA and 5-HTA 1 with the unilateral optic tract lesion, i.e., through eliminat- (serotonin) receptors were reduced in the visually deprived ing many of the pathways that might distribute visual cortex, 5-HT2 and cholinergic receptors were not. The information from the ‘seeing’ cortex to the visually reductions in GABA and 5-HT receptors were associatedA 1 deprived cortex. A similar conclusion was drawn by other with the reductions in cerebral metabolic activities in the investigators with respect to the effect of callosal transec- visual cortex. Analogous adaptations may occur in the tion on the hypometabolic regional pattern observed in primate [10,11], as reorganization of pathways and adap-their Tract and Split animals prepared by a nearly identical tive changes in input from other brain areas would be method [13]. expected to be involved in the adjustment of the brain to
If opiate pathways were responsive to changes in various forms of deprivation. regional functional activities, an explanation would be
apparent not only for the widespread, and bilateral nature 4.3. Nature of opiate response measured of the increases in CF avidity observed in the Tract and
Split animals, but also for the nonhypothesized changes in While the current study demonstrates a response in the opiate avidity found in five patients with Huntington’s opiate system it does not address the specific nature of the Disease (decreases in thalamus and anterior cingulate and response. Because CF binds to both m- and k-opiate
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