Pharmacological characterization of psychosis-like behavior in the MPTP-lesioned nonhuman primate model of Parkinson's disease.

Investigation of the pathophysiology of psychosis in Parkinson's disease (PD), as well as the assessment of potential novel therapeutics, has been limited by the lack of a well-validated animal model. MPTP-lesioned primates exhibit abnormal behaviors that are distinct from dyskinesia and parkinsonism and may represent behavioral correlates of neural processes related to psychosis in PD. Here we assess four types of behavior--agitation, hallucinatory-like responses to nonapparent stimuli, obsessive grooming, and stereotypies that are termed "psychosis-like"--and define their pharmacology using a psychosis-like behavior rating scale. By assessing the actions of drugs known to enhance or attenuate psychosis in PD patients, we find that the pharmacology of these behaviors recapitulates, in several respects, the pharmacology of psychosis in PD. Thus, levodopa and apomorphine elicited psychosis-like behaviors. Amantadine significantly decreased levodopa-induced dyskinesia but exacerbated psychosis-like behaviors. Haloperidol reduced psychosis-like behaviors but at the expense of increased parkinsonian disability while the atypical neuroleptics clozapine and quetiapine reduced psychosis-like behaviors without significant effect on parkinsonian disability. The response of different components of the psychotomimetic behavior suggested the involvement of both dopaminergic and nondopaminergic mechanisms in their expression.     

Neurobiology of early life stress: nonhuman primate models

Numerous studies have shown that early life stress in nonhuman primates produces profound and long-lasting changes in behavior and biological function. We review several aspects of the neurobiology of early life stress, focusing on nonhuman primate experimental paradigms. There is experimental evidence that even prenatal stress can produce profound alterations in biological factors such as regulation of the hypothalamic-pituitary-adrenal (HPA) axis, biogenic amines, and immune function, as well as in behavioral measures of attention and sociability. An ongoing struggle in research studies is defining the relative contributions of nature and nurture in mediating the long-term effects of stress. Studies of social support contend that this has the capacity to buffer the deleterious effects of stressful early rearing environments, whereas social deprivations appear to have negative behavioral and medical outcomes, most notably deficits in immune function. From studies involving variable foraging demand (VFD)-reared nonhuman primates and other models, we suggest that many of the behavioral and biochemical changes produced resemble those seen in humans who suffer from depressive and anxiety conditions. Finally, there appears to be remarkable consistency of key neurobiological findings across species.     

Effects of interferon-alpha on rhesus monkeys: a nonhuman primate model of cytokine-induced depression.

BACKGROUND: Interferon (IFN)-alpha is an innate immune cytokine that causes high rates of depression in humans and therefore has been used to study the impact of cytokines on the brain and behavior. To establish a nonhuman primate model of cytokine-induced depression, we examined the effects of IFN-alpha on rhesus monkeys. METHODS: Eight rhesus monkeys were administered recombinant human (rHu)-IFN-alpha (20 MIU/m(2)) or saline for 4 weeks in counterbalanced fashion, and videotaped behavior, as well as plasma and cerebrospinal fluid (CSF), were obtained at regular intervals to assess behavioral, neuroendocrine, immune, and neurotransmitter parameters. Additionally, expression and activity of IFN-alpha/beta receptors in monkey peripheral blood mononuclear cells (PBMCs) were assessed. RESULTS: Compared with saline treatment, IFN-alpha administration was associated with persistent increases in anxiety-like behaviors and decreases in environmental exploration. In addition, IFN-alpha induced significant increases in plasma concentrations of corticotropin (ACTH), cortisol, and interleukin-6 that tended to diminish after chronic administration, especially in dominant animals. Interestingly, in three animals, depressive-like, huddling behavior was observed. Monkeys that displayed huddling behavior exhibited significantly higher plasma concentrations of ACTH and lower CSF concentrations of the dopamine metabolite homovanillic acid. Rhesus monkey PBMCs were found to express mRNA and protein for the IFN-alpha/beta receptor. Moreover, treatment of PBMCs with rHu-IFN-alpha led to induction of STAT1, one of the primary IFN-alpha-induced signaling molecules. CONCLUSIONS: IFN-alpha evoked behavioral, neuroendocrine, and immune responses in rhesus monkeys that are similar to humans. Moreover, alterations in hypothalamic-pituitary-adrenal axis responses and dopamine metabolism may contribute to IFN-alpha-induced depressive-like huddling behavior.     

Response properties of high-threshold cutaneous cold receptors in the primate

Cutaneous high-threshold cold receptors (HCRs) in the monkey were identified as sensitive only to cold temperatures below 27°C and not responsive to mechanical or heat noxious stimulation. Some HCRs had axons conducting in the low A-δ range while others had C fibers. The response properties of HCRs were contrasted with those of mechanothermal nociceptors, the latter believed to contribute to the sense of cold pain. HCRs with Aδ fibers may contribute to the sense of innocuous cold below temperatures to which low-threshold cold receptors are maximally responsive.     

Persistence of primate hand preference despite initial training to the contrary

Forty-six stumptail monkeys were tested for hand preference on a simple reaching task. Initial repeated reaches with the hand chosen for the first reach went unrewarded. All reaches following and including the earliest reach with the opposite hand were rewarded and were used to calculate overall hand preference for the task. A significant majority of the animals continued to prefer the hand initially used in unrewarded trials rather than the hand first receiving a reward. These results suggest that monkeys are predisposed to choose the hand preferred for a new task.     

The morphological correlates of primate cerebrospinal fluid absorption

Arachnoid villi from cynomolgus monkeys subjected to various states of cerebrospinal fluid (CSF) absorption have been examined with scanning (SEM) and transmission (TEM) electron microscopy. Pressures within the superior sagittal sinus and the subarachnoid space were rigidly controlled, both prior to and during perfusion fixation and, as such, we created and studied conditions of normal, absent and increased cerebrospinal fluid absorption. Under normal conditions, the most prominent feature of the CSF/blood interface was the presence of endothelial intracytoplasmic vacuoles. The presence of these vacuoles was suggested with SEM and readily confirmed with TEM. Occassionally, these vacuoles coalesced with both the CSF and sagittal sinus fronts, thereby creating transcellular channels as identified by TEM or surface pores as seen with SEM. Villi perfused during conditions of no CSF flow exhibited none of the previously described vacuoles, channels, or pores, whereas increased CSF flows were associated with increased numbers of these structures. The significance of these findings was discussed in relation to CSF absorption and to previously reported ultrastructural studies.     

The impact of treatment with selective serotonin reuptake inhibitors on primate cardiovascular disease,behavior, and neuroanatomy

Selective serotonin reuptake inhibitor (SSRI) use is ubiquitous because they are widely prescribed for a number of disorders in addition to depression. Depression increases the risk of coronary heart disease (CHD). Hence, treating depression with SSRIs could reduce CHD risk. However, the effects of long term antidepressant treatment on CHD risk, as well as other aspects of health, remain poorly understood. Thus, we undertook an investigation of multisystem effects of SSRI treatment with a physiologically relevant dose in middle-aged adult female cynomolgus monkeys, a primate species shown to be a useful model of both depression and coronary and carotid artery atherosclerosis. Sertraline had no effect on depressive behavior, reduced anxious behavior, increased affiliation, reduced aggression, changed serotonin neurotransmission and volumes of neural areas critical to mood disorders, and exacerbated coronary and carotid atherosclerosis. These data suggest that a conservative approach to prescribing SSRIs for cardiovascular or other disorders for long periods may be warranted, and that further study is critical given the widespread use of these medications.     

Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate

Mutations in the glucocerebrosidase 1 (GBA1) gene are related to both Parkinson disease (PD) and Gaucher disease (GD). In both cases, the condition is associated with deficiency of glucocerebrosidase (GCase), the enzyme encoded by GBA1. Ambroxol is a small molecule chaperone that has been shown in mice to cross the blood‐brain barrier, increase GCase activity and reduce alpha‐synuclein protein levels. In this study, we analyze the effect of ambroxol treatment on GCase activity in healthy nonhuman primates. We show that daily administration of ambroxol results in increased brain GCase activity. Our work further indicates that ambroxol should be investigated as a novel therapy for both PD and neuronopathic GD in humans.     

Activity of primate precentral neurons during voluntary movements triggered by visual signals

Awake, intact monkeys were trained to perform discrete flexion or extension movements of the hand about the wrist in response to visual signals. The object of the movement was to align a cursor, coupled to a manipulandum, on a target line. Cursor and target lines were displayed on a video monitor placed in front of the monkey. The target line was stepped to the right or left, randomly with regard to direction and timing, with each step implying an instruction for the monkey to make a voluntary movement for alignment. Single unit recording was made in the forelimb area of contralateral precentral cortex. Neurons were classified by their responses to passive sensory stimulation and the effects of local intracortical microstimulation into two populations: wrist flexion-extension (F-E) neurons, and all other forelimb neurons (non-wrist (F-E)). A significantly higher proportion of wrist (F-E) neurons as compared to non-wrist (F-E) neurons were task-related. Moreover the wrist (F-E) neurons exhibited exclusively reciprocal responses to the oppositely directed visual signals, whereas the non-wrist (F-E) neurons showed both reciprocal and bidirectional responses. No significant differences in mean latencies of responses, either in respect to the visual signals or to movement onset, were observed between the two populations of neurons. However the range of latencies in both instances was greater in the non-wrist (F-E) populations. The wrist (F-E) population showed significantly less response variability than the non-wrist (F-E) population with regard to response latencies to visual signals and movement onsets, and the degree of correlation between duration of response and reaction time.     

Synaptic terminal coverage of primate triceps surae motoneurons

This study examined the synaptic terminal coverage of primate triceps surae (TS) motoneurons at the electron microscopic level. In three male pigtail macaques, motoneurons were labeled by retrograde transport of cholera toxin-horseradish peroxidase that was injected into TS muscles bilaterally and visualized with tetramethylbenzidine stabilized with diamino-benzidine. Somatic, proximal dendritic, and distal dendritic synaptic terminals were classified by standard criteria and measured. Overall and type-specific synaptic terminal coverages and frequencies were determined. Labeled cells were located in caudal L5 to rostral S1 ventral horn and ranged from 40 to 74 μm in diameter (average, 54 μm). The range and unimodal distribution of diameters, the label used, and the presence of C terminals on almost all cells indicated that the 15 cell bodies and associated proximal dendrites analyzed here probably belonged to α-motoneurons. Synaptic terminals covered 39% of the cell body membrane, 60% of the proximal dendritic membrane, and 40% of the distal dendritic membrane. At each of these three sites, F terminals (flattened or pleomorphic vesicles, usually symmetric active zones, average contact length 1.6 μm) were most common, averaging 52%, 56%, and 58% of total coverage and 56%, 57%, and 58% of total number on cell bodies, proximal dendrites, and distal dendrites respectively. S terminals (round vesicles, usually asymmetric active zones, average contact length 1.3 μm) averaged 24%, 29%, and 33% of coverage and 33%, 35%, and 36% of number at these three sites, respectively. Thus, S terminals were slightly more prominent relative to F terminals on distal dendrites, than on cell bodies. C terminals (spherical vesicles, subsynaptic cisterns associated with rough endoplasmic reticulum, average contact length 3.5 μm) constituted 24% and 11% of total terminal coverage on cell bodies and proximal dendrites, respectively, and averaged 11% and 6% of terminal number at these two locations. M terminals (spherical vesicles, postsynaptic Taxi bodies, some with presynaptic terminals, average contact length 2.7 μm) were absent on cell bodies and averaged 3% and 7% of total coverage and 2% and 5% of terminals on proximal and distal dendrites, respectively. Except for M terminals, which tended to be smaller distally, terminal contact length was not correlated with location. Total and type-specific coverages and frequencies were not correlated with cell body diameter. Primate TS motoneurons are similar to cat TS motoneurons in synaptic terminal morphology, frequency, and distribution. However, primate terminals appear to be smaller, so that the fraction of menitrane covered by them is lower. © 1994 Wiley-Liss, Inc.     

Quisqualate- and NMDA-sensitive [3H]glutamate binding in primate brain

Excitatory amino acids (EAA) such as glutamate and aspartate are probably the neurotransmitters of a majority of mammalian neurons. Only a few previous studies have been concerned with the distribution of the subtypes of EAA receptor binding in the primate brain. We examined NMDA- and quisqualate-sensitive [3H]glutamate binding using quantitative autoradiography in monkey brain (Macaca fascicularis). The two types of binding were differentially distributed. NMDA-sensitive binding was most dense in dentate gyrus of hippocampus, stratum pyramidale of hippocampus, and outer layers of cerebral cortex. Quisqualate-sensitive binding was most dense in dentate gyrus of hippocampus, inner and outer layers of cerebral cortex, and molecular layer of cerebellum. In caudate nucleus and putamen, quisqualate- and NMDA-sensitive binding sites were nearly equal in density. However, in globus pallidus, substantia nigra, and subthalamic nucleus, quisqualate-sensitive binding was several-fold greater than NMDA-sensitive binding. In thalamus, [3H]glutamate binding was generally low for both subtypes of binding except for the anterior ventral, lateral dorsal, and pulvinar nuclei. In the brainstem, low levels of binding were found, and strikingly the red nucleus and pons, which are thought to receive glutamatergic projections, had approximately 1/20 the binding observed in cerebral cortex. These results demonstrate that NMDA- and quisqualate-sensitive [3H]glutamate binding are observed in all regions of primate brain, but that in some regions one subtype predominates over the other. In addition, certain areas thought to receive glutamatergic projections have low levels of both types of binding.     

A remotely operated pump for intracerebral micro-injection in the primate

A method is described for making small (2-6 microliters) localized intracerebral drug injections in the conscious monkey. A base plate and guide cannula are initially secured to the skull under general anaesthesia. A mechanical pump containing the drug solution and fitted with an injection needle is located on the base plate assembly. In the conscious animal the pump is triggered magnetically to deliver a predetermined volume into the target brain region.     

Reverse cellular distribution of calmodulin to S-100 protein in primate brain

Both calmodulin and S-100 protein are Ca2+-binding proteins of the EF-hand family. Immunocytochemical study revealed that calmodulin existed mainly in the neurons, whereas S-100 protein was localized primarily in the glial cells of the cerebral and cerebellar cortices of man and monkey. The observed reverse cellular distribution of calmodulin to S-100 protein in primate brain suggests that calmodulin might be replaced in its role as a Ca2+-binding protein by S-100 protein in the glial cells.     

A Golgi analysis of the primate globus pallidus. III. Spatial organization of the striato-pallidal complex

An atlas of transverse sections of the globus pallidus and striatum was established in macaque with reference to ventricular coordinates. The three-dimensional geometry of the striato-pallidal complex was investigated by means of sagittal and horizontal reconstructions. Both a personal case studied with autoradiography and data from literature were used to analyze the distribution of cortical axons into the striatum. One may distinguish two striatal territories: one, somatotopically arranged, sensorimotor territory extending over the major part of the putamen; and the other, an associative territory, comprising the caudate nucleus and antero-medial and postero-inferior parts of the putamen. The striato-pallido-nigral bundle was studied using Golgi, Perls, and Fink-Heimer techniques. The bundle is described in four parts: prepallidal (subdivided into caudato-pallidal and putamino-pallidal subparts), transpallidal, pallido-nigral, and nigral. The tracing of the limit between the caudate (associative) and putaminal (essentially sensorimotor) territories shows that the two components are of roughly the same size in the pallidum. The data were compared with geometry and orientation of the dendritic arborizations of large pallidal neurons analyzed in Yelnik et al. ('84). Each pallidal dendritic disc is able to receive axons from a wide region of the striatum. This leads to a convergence on pallidal neurons of striatal axons from different striatal somatotopic strips and from the sensorimotor and associative territories. This is an indication that the globus pallidus may have an integrative role.     

The primate amygdala and the neurobiology of social behavior: implications for understanding social anxiety.

The amygdala has long been implicated in the mediation of emotional and social behaviors. Because there are very few human subjects with selective bilateral damage of the amygdala, much of the evidence for these functional associations has come from studies employing animal subjects. Macaque monkeys live in complex, highly organized social groups that are characterized by stable and hierarchical relationships among individuals who engage in complex forms of social communication, such as facial expressions. Understanding the role of the amygdala in animals that display a level of social sophistication approaching that of humans will help in understanding the amygdala's role in human social behavior and in psychopathology such as social anxiety. Selective bilateral lesions of the amygdala in mature macaque monkeys result in a lack of fear responses to inanimate objects and a "socially uninhibited" pattern of behavior. These results imply that the amygdala functions as a protective "brake" on engagement of objects or organisms while an evaluation of potential threat is carried out. They also suggest that social anxiety may be a dysregulation or hyperactivity of the amygdala's evaluative process. Finally, recent data from developmental studies raise the possibility that, at least at some developmental stages, fear in social contexts may be subserved by different brain regions than fear of inanimate objects.     

Androgen receptor systems in the brain stem of the primate

The nuclear uptake and retention of [³H]dihydrotestosterone ([³H]DHT) or one of its metabolites was studied in the cerebellum and brain stem of the rhesus monkey. Three days before the injection of the tritiated hormone, we removed both ovaries and the right adrenal gland of 3 female rhesus monkeys under ketamine and halothane or fluothane anesthesia with aseptic surgical procedures. Two days later, we removed the left adrenal gland under similar conditions. Shortly after the second operation, each animal received 100 mg prednisolone sodium succinate. On the day of autopsy, we injected into a femoral vein of each animal 1 μg of 5α-dihydro[1,2,4,5,6,7-³H]- testosterone (107 Ci/mmol). One of these animals also received an i.v. injection of 100 μg/kg body weight of unlabeled DHT to serve as a control. One hour after injection, we rapidly exsanguinated each animal through a femoral venous catheter and perfused the vascular system with approximately 3 1 of Ringer's solution through a femoral arterial catheter. The cerebella and brain stems were removed and processed for autoradiography. Unlike in the rat, nuclear uptake and retention of [³H]DHT was found in both motor and sensory systems of these monkeys and in other areas less well defined. These data indicate that there are major species differences in the nuclear uptake and retention of androgen by the cerebellum and brain stem of rats and primates.     

Immunocytochemical and electron microscope observations on astroglial interlaminar processes in the primate neocortex

At variance with the rat, previous observations disclosed the presence of long interlaminar astroglial processes in the cerebral cortex of adult nonhuman primates. To examine its presence in human cerebral cortex, samples of frontal and temporal cerebral cortices were obtained during programmed brain surgery from a young patient with an intraventricular astrocytoma, and from one young and two adult patients with frontal and temporal lobe focal epilepsy, respectively. Samples of the visual cortex were also obtained at an autopsy of an 84-year-old woman without any known neurological disease. Brain tissues were processed for GFAP-IR immunocytochemistry. Long, interlaminar, GFAP-IR astroglial processes of usually 300–500 μm, but occasionally reaching almost 1,000 μm, were observed. These processes resembled those previously described in the cerebral cortex of adult New World monkeys. Available data suggest that they may represent a predominant characteristic in postnatal primate cerebral cortex. EM analysis of club-like endings disclosed a multilamellar organization of GFAP-IR intermediate filaments, and the presence of mitochondria and amorphous, electron dense material. Their possible function is yet to be determined. J. Neurosci. Res. 48:352–357, 1997. © 1997 Wiley-Liss, Inc.