The hedonic impact and intake of food are increased by midazolam microinjection in the parabrachial nucleus

Benzodiazepines have been reported to induce eating when administered into the brainstem of rats (either the fourth ventricle or the parabrachial nucleus). Benzodiazepines in the brainstem also have been reported to enhance the hedonic impact of taste, as measured by hedonic/aversive taste reactivity patterns, when administered to the fourth ventricle. The present study examined whether the parabrachial nucleus in particular is a brainstem site of the benzodiazepine-produced enhancement of eating and palatability. Food intake (cereal mash) was measured after brainstem microinjections of midazolam or vehicle (0.0, 7.5, and 15.0 microg) into the parabrachial nucleus, the nucleus of the solitary tract, the pedunculopontine tegmental nucleus, or the fourth ventricle (60 microg). We used the taste reactivity paradigm to measure hedonic/aversive affective reactions elicited from rats by oral infusions of a bittersweet solution (7% sucrose-0.01% quinine). Positive hedonic reactions and negative aversive reactions to sucrose-quinine were also measured after microinjections of midazolam (0.0, 7.5, and 15 microg) into the parabrachial nucleus. Midazolam increased food intake and selectively enhanced positive hedonic taste reactivity patterns to the bittersweet solution when microinjections were delivered to the parabrachial nucleus. When administered to the other brainstem sites at the same doses, however, midazolam had no effect. We therefore conclude that the parabrachial nucleus can mediate the benzodiazepine-induced enhancement of the hedonic impact of taste as well as mediating the enhancement of eating behavior.     

Measuring hedonic impact in animals and infants: microstructure of affective taste reactivity patterns

The hedonic impact of taste is reflected in affective facial reactions made by human infants, other primates, and even rats. Originally studied in human infants, affective reactions to taste have also been used by affective neuroscience to identify hedonic brain systems in studies of animals (via application of neural stimulation, pharmacological activation, and neural lesion manipulations). The chief limitation of measuring affective reactions is that it is difficult for experimenters to know how to interpret them, and therefore how to interpret changes produced by brain manipulations. This paper notes guidelines to interpretation. It examines the phylogenetic continuity between humans, other primates, and rats in terms of the microstructure of taste-elicited affective reactions. It reviews evidence that affective taste reactivity patterns truly reflect a 'core hedonic process' of palatability or affect, rather than being an ingestion measure, consummatory behavior measure, or a sensory reflex measure. It reviews affective neuroscience studies of taste reactivity that have identified true hedonic brain substrates, and discriminated them from false hedonic brain substrates. It considers the neural bases of incentive 'wanting' versus 'liking'. Finally, it notes the difference between human subjective affective ratings of pleasure and 'core hedonic processes' reflected by behavioral affective reactions.     

Opioid site in nucleus accumbens shell mediates eating and hedonic ‘liking’ for food: map based on microinjection Fos plumes

Microinjection of opioid agonists, such as morphine, into the nucleus accumbens shell produces increases in eating behavior (i.e. ‘wanting’ for food). This study (1) reports direct evidence that activation of accumbens opioid receptors in rats also augments food ‘liking’, or the hedonic impact of taste, and (2) identified a neural site that definitely contains receptors capable of increasing food intake. Morphine microinjections (0.5 μg) into accumbens shell, which caused rats to increase eating, were found also to cause selective increases in positive hedonic patterns of behavioral affective reaction elicited by oral sucrose, using the ‘taste reactivity’ test of hedonic palatability. This positive shift indicated that morphine microinjections enhanced the hedonic impact of food palatability. The accumbens site mediating morphine-induced increases in food ‘wanting’ and ‘liking’ was identified using a novel method based on local expression of Fos induced directly by drug microinjections. The plume-shaped region of drug-induced increase in Fos immunoreactivity immediately surrounding a morphine microinjection site (Fos plume) was objectively mapped. A point-sampling procedure was used to measure the shape and size of ‘positive’ plumes of Fos expression triggered by microinjections of morphine at locations that caused increases in eating behavior. This revealed a functionally ‘positive’ neural region, containing receptors directly activated by behaviorally-effective drug microinjections. A subtraction mapping procedure was then used to eliminate all surrounding regions containing any ‘negative’ Fos plumes that failed to increase food intake. The subtraction produced a conservative map of the positive site, by eliminating regions that gave mixed effects, and leaving only a positive region that must contain receptors capable of mediating increases in food intake. The resulting mapped ‘opioid eating site’ was contained primarily within the medial caudal subregion of the nucleus accumbens shell, and did not substantially penetrate either into the accumbens core or into other subregions of the shell. Several other structures outside the nucleus accumbens (such as rostral ventral pallidum), immediately medial and adjacent to the shell, also appeared to be included in the functional site. Opioid receptors within this site thus are capable of mediating morphine-induced increases in eating, in part by enhancing the hedonic reward properties of food.     

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is `no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the `taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for `wanting' incentives, but not for `liking' them or for learning new `likes' and `dislikes'.     

Opioid site in nucleus accumbens shell mediates eating and hedonic 'liking' for food: map based on microinjection Fos plumes

Microinjection of opioid agonists, such as morphine, into the nucleus accumbens shell produces increases in eating behavior (i.e. 'wanting' for food). This study (1) reports direct evidence that activation of accumbens opioid receptors in rats also augments food 'liking', or the hedonic impact of taste, and (2) identified a neural site that definitely contains receptors capable of increasing food intake. Morphine microinjections (0.5 microgram) into accumbens shell, which caused rats to increase eating, were found also to cause selective increases in positive hedonic patterns of behavioral affective reaction elicited by oral sucrose, using the 'taste reactivity' test of hedonic palatability. This positive shift indicated that morphine microinjections enhanced the hedonic impact of food palatability. The accumbens site mediating morphine-induced increases in food 'wanting' and 'liking' was identified using a novel method based on local expression of Fos induced directly by drug microinjections. The plume-shaped region of drug-induced increase in Fos immunoreactivity immediately surrounding a morphine microinjection site (Fos plume) was objectively mapped. A point-sampling procedure was used to measure the shape and size of 'positive' plumes of Fos expression triggered by microinjections of morphine at locations that caused increases in eating behavior. This revealed a functionally 'positive' neural region, containing receptors directly activated by behaviorally-effective drug microinjections. A subtraction mapping procedure was then used to eliminate all surrounding regions containing any 'negative' Fos plumes that failed to increase food intake. The subtraction produced a conservative map of the positive site, by eliminating regions that gave mixed effects, and leaving only a positive region that must contain receptors capable of mediating increases in food intake. The resulting mapped 'opioid eating site' was contained primarily within the medial caudal subregion of the nucleus accumbens shell, and did not substantially penetrate either into the accumbens core or into other subregions of the shell. Several other structures outside the nucleus accumbens (such as rostral ventral pallidum), immediately medial and adjacent to the shell, also appeared to be included in the functional site. Opioid receptors within this site thus are capable of mediating morphine-induced increases in eating, in part by enhancing the hedonic reward properties of food.     

Etiological differences between the isolated lateral ventricle and the isolated fourth ventricle

Objective To determine if an etiological difference exists between isolation of the lateral ventricle and isolation of the fourth ventricle after ventricular shunting.Methods Cases of symptomatic isolation of the lateral and fourth ventricles were reviewed retrospectively. The ages at presentation of ventricular isolation, the time course to development of isolation, the number of shunt surgeries leading up to symptomatic isolation, the types of shunt valves utilized, and the background of infection were analyzed.Results Twenty-six patients had lateral ventricle isolation and 11 patients had fourth ventricle isolation. Infection, hemorrhage, Chiari malformation/myelomeningocele, and aqueductal stenosis were factors contributing to hydrocephalus requiring treatment in these patients. Compared to 26.9% of patients with lateral ventricle isolation, 90.9% of patients with fourth ventricle isolation had a previous history of infection.Conclusions Prior meningitis and ventriculitis frequently contributed to fourth ventricle isolation. Lateral ventricle isolation seems to arise from functional obstruction of the foramen of Monro related to prior shunting.     

经小脑延髓裂入路行第四脑室手术的显微解剖研究

目的 探讨经小脑延髓裂入路到达第四脑室的解剖研究，及在不切开下蚓部的情况下如何分离此裂隙以获得最佳的手术视野。方法 应用显微外科解剖技术，对经甲醛固定、颈内动脉系统彩色乳胶灌注的10具成人尸头标本，在手术显做镜下解剖分离小脑延髓裂，观察第四脑室顶部、底部及外侧隐窝等，切开脉络膜等暴露第四脑室各区域。结果 小脑延髓裂充分暴露后，可以不切开下蚓部，即可获得第四脑室各壁的良好术野。开放小脑延髓裂可依据第四脑室壁的位置及需要暴露的程度分为3种方式：广泛型(导水管型)、外侧壁型及外侧隐窝型。结论 经小脑延髓裂入路可通过正常的解剖间隙到达第四脑室以及脑干，且术野充分，可减少手术的损伤及术后并发症。因广泛型可以最大程度显露第四脑室底部及各区域，因此可以作为该入路的标准方式。     

Dopamine D2 receptors in the posterior region of the nucleus tractus solitarius mediate the central pressor action of quinpirole (LY171555)

Our previous studies demonstrated that intravenous (IV) administration of the selective dopamine (DA) D2 receptor agonist quinpirole (LY171555) induces a pressor response in conscious Sprague-Dawley (S-D) rats through a central mechanism. The present study was designed to identify the neurons which medicate this pressor response. Injection of quinpirole (1-150 micrograms/kg) into the 4th ventricle produced a greater pressor response of a more rapid onset than similar injections into the lateral ventricle in conscious, freely moving S-D rats, suggesting a site of action in brainstem. Further, microinjections (5-10 micrograms/kg in 200 nl) of quinpirole into major hypothalamic nuclei of conscious, freely moving rats elicited no pressor response. Uni- or bilateral microinjections of quinpirole (5 micrograms/200 nl) into the posterior region of nucleus tractus solitarius (P-NTS) caused a consistent increase in mean arterial pressure (MAP) (Max = 12.4 +/- 1.1 mmHg, n = 12) with a rapid onset (less than 30 sec) in unanesthetized decerebrate S-D rats, while microinjections into the anterior region of NTS, area postrema, C1/A1 regions, raphe obscurus nucleus, locus coeruleus or regions 0.5 mm lateral, superior or inferior to P-NTS produced little or no response. The pressor response induced by bilateral microinjections of quinpirole into P-NTS was not different from that of unilateral microinjection. The pressor response to microinjection of quinpirole into P-NTS was abolished by pretreatment with metoclopramide (5 mg/kg, IV or 25 micrograms/200 nl, P-NTS injection; 5 min before), a selective DA D2 antagonist that crosses the blood-brain barrier.(ABSTRACT TRUNCATED AT 250 WORDS)     

Motor neuron disease-like syndrome secondary to trapped fourth ventricle and obstruction of cerebrospinal fluid pathway

The trapped fourth ventricle is caused by occlusion of outlets of fourth ventricle, including cerebral aqueduct and foramina of Luschka and Magendie. It is an uncommon entity that mainly occurs in children with hydrocephalus after successful shunting of lateral ventricles. The most common etiologies of obstruction to outflow of the fourth ventricle are infection and hemorrhage. Typical manifestation of trapped fourth ventricle is posterior fossa syndrome. Here, we report a 22-year-old man with hydrocephalus developed after successful removal of traumatic subdural hemorrhage. After shunting of lateral ventricles, hydrocephalus resolved initially. However, trapped fourth ventricle occurred 9 months later. Unlike previous reports of trapped fourth ventricle, his presentation was motor neuron disease-like syndrome, including hand muscle weakness and atrophy, generalized brisk deep tendon reflexes, and absence of sensory deficits. Imaging study showed isolated dilatation of fourth ventricle and edema of cervical cord from obex to C7 level. After surgical decompression and lysis of adhesion of posterior fossa, neurological deficits well recovered. The pathogenesis of hand muscle atrophy is secondary to cervical cord edema caused by trapped fourth ventricle and obstruction of cerebrospinal fluid (CSF) pathway. Furthermore, the anterior horn cells and lateral corticospinal tract are located in the highly vulnerable region of spinal cord, either possibly due to venous engorgement or arterial insufficiency.     

Interaction of barbiturates with benzodiazepine receptors in the central nervous system

The interaction of barbiturates with benzodiazepine receptors was studied in extensively washed membrane preparations from rat brain. Sedative/hypnotic and anesthetic barbiturates such as pentobarbital, and convulsant barbiturates such as DMBB, enhanced [3H]diazepam binding in a stereospecific fashion. Freeze-thawing of membranes resulted in a decrease in the potency of barbiturates to enhance [3H]diazepam binding, while the maximum response to barbiturates remained unchanged. Significant differences in both the potency and maximum enhancement of [3H]diazepam binding by pentobarbital was observed among brain regions. The rank order potency of pentobarbital in different brain regions was: cerebellum greater than cortex greater than hippocampus, while the rank order efficacy of pentobarbital in these brain regions was reversed. The effects of a combination of anesthetic and/or convulsant barbiturates on [3H]diazepam binding suggested that these compounds function as partial agonists while a combination of anesthetic or convulsant barbiturates with phenobarbital suggested that latter compound antagonized the actions of both anesthetic and convulsant barbiturates. The convulsant benzodiazepine Ro-5-3663 and inosine were more potent as inhibitors of pentobarbital-enhanced than basal (non-pentobarbital enhanced) [3H]diazepam binding. Solubilization of benzodiazepine receptors with Lubrol-PX resulted in a complete loss of barbiturate enhanced [3H]diazepam binding, and greater than a 75% loss in efficacy in the remaining (insoluble receptor) tissue. These data, coupled with recent observations from this and other laboratories, suggests that the site(s) at which barbiturates act to enhance [3H]diazepam binding to benzodiazepine receptors is distinct from the site at which GABA acts to enhance [3H]diazepam binding. The phenomenon of enhanced benzodiazepine binding by barbiturates may be related to the depressant actions of the barbiturates, that is, their direct effects to increase chloride conductance. Although it is premature to assign a pharmacologic correlate to this neurochemical phenomenon, it appears that this action may be related to the anesthetic effects of the barbiturates. However, the definitive assignment of either the electrophysiologic or pharmacologic sequelae to this neurochemical action will require further investigation.     

Clinical evaluation of an isolated fourth ventricle

Since the introduction of the CT scan in 1976, we have experienced 6 cases of the isolated fourth ventricle among 244 hydrocephalic patients (2.5%). Age at diagnosis of the isolated fourth ventricle ranged from 1 year 8 months to 13 years (mean age, 8 years, 6 months). The time interval between the first shunting procedure and the diagnosis of the isolated fourth ventricle varied from 1 year 5 months to 7 years 4 months (mean interval, 4 years 1 months). The prior hydrocephalus were due to intraventricular hemorrhage in two patients, meningomyelocele in a patient and brain tumor in three patients. Two patients had history of cerebrospinal fluid (CSF) infection and five cases underwent multiple shunt revisions. Posterior fossa signs were evident in all cases. It was quite easy to make a diagnosis of the isolated fourth ventricle with CT scan, which demonstrated a large rounded or pear-shaped midline cyst in the posterior fossa. Slit-like lateral ventricles were noted in three cases, while the remaining three had enlarged lateral ventricles. Ventriculography confirmed the isolation of the fourth ventricle in 5 cases. Metrizamide which had been injected into the fourth ventricle was diluted when CT scan was performed 48 hours later, and contrast medium disappeared since then. Magnetic resonance imaging (MRI) well showed the characteristic findings of the isolated fourth ventricle: cystic dilatation of the fourth ventricle, compression and distortion of the brain stem, upward tentorial herniation, occlusion of the aqueduct, downward displacement of the occipital lobe, septum formation of the fourth ventricle and accompanied anomalies such as, Chiari malformation or syringomyelia.(ABSTRACT TRUNCATED AT 250 WORDS)     

In vivo infusions of exogenous growth factors into the fourth ventricle of the adult mouse brain increase the proliferation of neural progenitors around the fourth ventricle and the central canal of the spinal cord

Stem cells isolated from the fourth ventricle and spinal cord form neurospheres in vitro in response to basic fibroblast growth factor (FGF2)+heparin (H) or epidermal growth factor (EGF)+FGF2 together. To determine whether these growth factor conditions are sufficient to induce stem cells within the fourth ventricle and spinal cord to proliferate and expand their progeny in vivo, we infused EGF and FGF2, alone or together, with or without H, into the fourth ventricle for 6 days via osmotic minipumps. Animals were injected with bromodeoxyuridine (BrdU) on days 4, 5 and 6 of infusion in order to label cells proliferating in response to the growth factors. Infusions of EGF+FGF2+H into the fourth ventricle resulted in the largest proliferative effect, a 10.8-fold increase in the number of BrdU+ cells around the fourth ventricle, and a 33.5-fold increase in the number of BrdU+ cells around the central canal of the spinal cord, as compared to vehicle infused controls. The majority of the cells were nestin+ after 6 days of infusion. Seven weeks post-infusion, 22 and 30% of the number of BrdU+ cells induced to proliferate after 6 days of EGF+FGF2+H infusions were still detected around the fourth ventricle and central canal of the spinal cord, respectively. Analysis of the fates of the remaining cells showed that a small percentage of BrdU+ cells around the fourth ventricle and in the white matter of the spinal cord differentiated into astrocytes and oligodendrocytes. BrdU+ neurons were not found in the brainstem or in the grey matter of the cervical spinal cord 7 weeks post-infusion. These results show that endogenous stem cells and progenitors around the fourth ventricle and central canal of the spinal cord proliferate in response to exogenously applied growth factors, but unlike in the lateral ventricle where they generate some new neurons, they only produce new astrocytes and oligodendrocytes at 7 weeks post-infusion.     

Primary large B-cell lymphoma of the fourth ventricle

We present a patient with an isolated primary central nervous system lymphoma (PCNSL) of the fourth ventricle. A 77-year-old man had a 1 week history of intermittent vertigo, nausea, vomiting, and progressively unsteady gait. CT scans of the brain showed a fourth ventricle tumor. MRI revealed a 2.5 cm dumbbell-shaped avidly-enhancing tumor in the fourth ventricle. Metastasis or high-grade glioma was suspected. The neuropathological findings were compatible with a diffuse large B-cell lymphoma. A slit lamp examination, bone marrow biopsy, and imaging studies for extracranial lesions were unremarkable. We suggest that PCNSL be listed in the differential diagnosis of fourth ventricle tumors with well-circumscribed margins and homogenous contrast enhancement.     

Aging, diazepam exposure and benzodiazepine receptors in rat cortex

Densities of two benzodiazepine receptor subtypes (BDZ₁ and BDZ₂) in the frontal cortex of 10- and 27-month-old male Fischer-344 rats were nearly identical. Acute diazepam pretreatment produced a 73% increase in receptor density in the aged rats, mainly in the BDZ₂ sites, whereas with the normal adult rat the density increased 42%, primarily due to stimulation of BDZ₁ sites. Chronic exposure elicited similar increases of 28–29% in both normal and aged rats but there were subtle differences in the distribution of specific receptors. This study demonstrates a definite effect of age on the response of benzodiazepine receptors to diazepam pretreatment.     

Characterization of pharmacoresistance to benzodiazepines in the rat Li-pilocarpine model of status epilepticus

Status epilepticus is usually initially treated with a benzodiazepine such as diazepam. During prolonged seizures, however, patients often lose their sensitivity to benzodiazepines, thus developing pharmacoresistant seizures. In rats, administration of LiCl followed 20–24 h later by pilocarpine induces a continuous, self-sustained, and reproducible form of status epilepticus that can be terminated with diazepam when it is administered soon after the pilocarpine injection. However, when administered after a 45 min delay, diazepam is less effective. Previous findings have suggested that the development of pharmacoresistance is related to the stage of status epilepticus. In the present study, we characterized the seizure stage-dependence of diazepam pharmacoresistance. Following administration of different doses of diazepam at varying time intervals after specific behaviorally- and electrographically-defined seizure stages, stage-, time-, and dose-dependent pharmacoresistance to diazepam developed. We also studied two other antiepileptic drugs commonly used in the treatment of status epilepticus, phenobarbital and phenytoin. Consistent with previous studies, our results indicated a similar relationship between stage, time and dose for phenobarbital, but not for phenytoin. Our data are consistent with rapid modulation of GABA_A receptors during status epilepticus that may result in pharmacoresistance to antiepileptic drugs that enhance GABA_A receptor-mediated inhibition.     

An endoscopic,cadaveric analysis of the roof of the fourth ventricle

We performed endoscopic dissections of the roof of the fourth ventricle in eight fresh human cadaveric heads to characterize the endoscopic anatomy of the roof of the fourth ventricle and the anatomical configuration of the structures forming its roof. We also made three-dimensional (3D) silicone casts of the fourth ventricle in seven formalin-fixed specimens to evaluate the 3D configuration of the structures that create the roof of the fourth ventricle. The roof of the fourth ventricle can be divided into three zones. The upper zone is formed by the superior cerebellar peduncle and superior medullary velum and is associated with the lingula. The middle zone is formed by the inferior cerebellar peduncles and inferior medullary velum and is associated with the nodule in the midline and with the peduncle of the flocculus. The lower zone is formed by the tela choroidea and is associated with the tonsils. The 3D shape of the roof the fourth ventricle resembles that of a rhomboid-based pyramid; the edges of the base represent the borders of the ventricle, and the apex is the cerebellar fastigium. The lateral recess is shaped like a triangular-based pyramid, with its base connected to the cavity of the fourth ventricle and its tip opening into the lateral cerebellomedullary cistern through the foramen of Luschka. Our results may help in the endoscopic exploration of and microsurgical approaches to the fourth ventricle through its roof.     

Cardiovascular effects of microinjections of adenosine analogs into the fourth ventricle of rats

Rats were implanted with chronic indwelling cannulae into the posterior region of the fourth ventricle. After recovery from surgery, acute experiments on blood pressure were conducted under urethane anesthesia. The blood pressure and heart rate responses following administration of two adenosine analogs, NECA and L-PIA were examined. Microinjections of both analogs produced dose-dependent reductions in blood pressure and heart rate. NECA was approximately 20-fold more potent than L-PIA in reducing blood pressure and depressing heart rate. The cardiovascular effects of both analogs were antagonized by parenteral injections of caffeine. These findings show that microinjections of analogs of adenosine into the fourth ventricle can influence areas of the central nervous system involved in cardiovascular control.     

The lateral,third, and fourth ventricle choroid plexus of the dog: A structural and ultrastructural study

The morphology of the choroid plexuses of the lateral, third, and fourth ventricles in dogs was studied by histological and ultrastructural techniques after in situ fixation. Most portions of the plexus in the lateral ventricle showed a parallel arrangement of capillaries, producing a fine corrugation of the overlying layer of epithelial cells. Relatively large amounts of connective tissue separated the capillaries from the epithelium. The fourth ventricle choroid plexus showed short capillary loops projecting into the ventricle and more intimately covered by epithelium. Smaller amounts of connective tissue separated the capillaries from the epithelium. The choroid plexus of the third ventricle showed characteristics seen in the plexuses of both the lateral and fourth ventricles. The total surface of the choroid plexuses in the dog averaged 10.7 cm², of which 55% was fourth ventricle choroid plexus.     

Stimulus-sensitive myoclonus of the baboon Papio papio: pharmacological studies reveal interactions between benzodiazepines and the central cholinergic system

The baboon Papio papio develops a nonepileptic myoclonus 20 to 30 min after i.m. benzodiazepine injection. It is characterized by bilateral jerks involving mainly the neck and the trunk, by the absence of any correlative EEG paroxysmal discharge, and by its facilitation during movement or agitation. This myoclonus resembles the intention myoclonus of human patients as seen, for example, after anoxia. We found in experiments on 10 adolescent baboons that atropine alone induced the myoclonus for several hours, that physostigmine completely antagonized the benzodiazepine-induced as well as the atropine-induced myoclonus, and that the peripherally acting cholinergic antagonist, methyl-QNB, and agonist prostigmine had no action on the myoclonus, suggesting that the benzodiazepine-induced myoclonus in this species depends on a strong depression of the central cholinergic system by benzodiazepine. The benzodiazepine-induced myoclonus was mediated by benzodiazepine receptors as it was blocked by the specific benzodiazepine receptor antagonist, Ro 15-1788, which did not block atropine-induced myoclonus; latency to myoclonus after benzodiazepine was longer than after atropine. These facts suggest that benzodiazepines, by an as yet unknown mechanism, induce a depression of the cholinergic system which in turn leads to the development of myoclonus. Finally, the benzodiazepine-induced myoclonus of the baboon can be considered as a good model for testing drugs that act on the muscarinic cholinergic system and also for testing benzodiazepine-acetylcholine interactions.