The combined effects of pyridostigmine and chronic stress on brain cortical and blood acetylcholinesterase, corticosterone, prolactin and alternation performance in rats.

Thousands of soldiers who served in the Gulf War have symptoms that have been collectively termed Gulf War Illness (GWI). It has been suggested that a combination of operational stress and pyridostigmine, a drug given as a pretreatment to protect soldiers against the effects of exposure to nerve agents, might have had unexpected adverse health effects causing these symptoms. Our laboratory has previously modeled operational stress in rats using a paradigm of around-the-clock intermittent signalled footshock. In the present studies, this model was used to investigate the potential synergistic effects of chronic stress and pyridostigmine on physiology and behavior. Seventy-two rats were trained to perform an alternation lever pressing task to earn their entire daily food intake. The rats were then implanted with osmotic minipumps containing vehicle, pyridostigmine (25 mg/ml pyridostigmine bromide) or physostigmine (20 mg/ml eserine hemisulfate). The pumps delivered 1 microl/h, which resulted in a cumulative dosing of approximately 1.5 mg/kg/day of pyridostigmine or 1.2 mg/kg/day of physostigmine, equimolar doses of the two drugs. The rats were then returned to their home cages where performance continued to be measured 24 h/day. After 4 days, 24 of the 72 rats were trained to escape signalled footshock (avoidance-escape group) and 24 other rats (yoked-stressed group) were each paired to a rat in the avoidance-escape group. The remaining 24 rats were not subjected to footshock (unstressed group). Shock trials were intermittently presented in the home cage 24 h/day for 3 days, while alternation performance continued to be measured. Since only 12 test cages were available, each condition was repeated to achieve a final n of six rats per group. Pyridostigmine and physostigmine each decreased blood acetylcholinesterase levels by approximately 50%. Physostigmine also decreased brain cortical acetylcholinesterase levels by approximately 50%, while pyridostigmine had no effect on cortical acetylcholinesterase activity. Alternation performance was impaired on the first day of stress and then recovered. Neither pyridostigmine nor physostigmine affected performance in the absence of stress or increased the effects of stress alone. Corticosterone was significantly increased in the yoked stress group compared to unstressed controls. These data suggest that pyridostigmine does not exacerbate the effects of stress on performance or levels of stress hormones. Furthermore, these data do not suggest that stress enables pyridostigmine to cross the blood brain barrier.

The reality of picture archiving and communication systems (PACS): a survey.

Toward the end of 1997 vendors were succeeding in installing picture, archiving and communication systems (PACS) in larger numbers. It was hard to separate fact from fiction at times. This survey was undertaken by 2 members of the academic community to confirm what was operational, how well the installed systems worked, and what they were doing. Fax questionnaires were sent to nearly 1,000 facilities worldwide to identify PACS of any size in clinical operation on a date certain, February 1, 1998. A total of 177 PACS were identified. Facilities furnished responses during the first survey period from May 1 to November 1, 1998. A second survey, done in February and March of 2000, sought long-term follow-up data. Many systems operated 5 or more types of modalities. Computed tomography (CT) was the most common modality type at 83%, but the distribution of the rest held surprises. There also was an unexpectedly large use of soft copy reading and filmless operation in 1998. Clear trends toward increased use of computed radiography and digital radiography and a significant expansion on the percentage of all of a facility's examinations on the PACS were seen over the 2 years. Satisfaction with original PACS vendors was relatively high. Eighty-nine percent remained with their original vendor. Only 10 sites reported they changed vendors, and 4 facilities said they abandoned their system. The users reported their expectations of the PACS had been met in 81% of cases. Some (65%) declared their systems were cost effective. The most striking response was that 97% of the users would recommend PACS to others.

Secondary hypoxemia exacerbates the reduction of visual discrimination accuracy and neuronal cell density in the dorsal lateral geniculate nucleus resulting from fluid percussion injury.

The purpose of this study was to determine the impact of secondary hypoxemia on visual discrimination accuracy after parasagittal fluid percussion injury (FPI). Rats lived singly in test cages, where they were trained to repeatedly execute a flicker-frequency visual discrimination for food. After learning was complete, all rats were surgically prepared and then retested over the following 4-5 days to ensure recovery to presurgery levels of performance. Rats were then assigned to one of three groups [FPI + Hypoxia (IH), FPI + Normoxia (IN), or Sham Injury + Hypoxia (SH)] and were anesthetized with halothane delivered by compressed air. Immediately after injury or sham injury, rats in groups IH and SH were switched to a 13% O2 source to continue halothane anesthesia for 30 min before being returned to their test cages. Anesthesia for rats in group IN was maintained using compressed air for 30 min after injury. FPI significantly reduced visual discrimination accuracy and food intake, and increased incorrect choices. Thirty minutes of immediate posttraumatic hypoxemia significantly (1) exacerbated the FPI-induced reductions of visual discrimination accuracy and food intake, (2) further increased numbers of incorrect choices, and (3) delayed the progressive recovery of visual discrimination accuracy. Thionine stains of midbrain coronal sections revealed that, in addition to the loss of neurons seen in several thalamic nuclei following FPI, cell loss in the ipsilateral dorsal lateral geniculate nucleus (dLG) was significantly greater after FPI and hypoxemia than after FPI alone. In contrast, neuropathological changes were not evident following hypoxemia alone. These results show that, although hypoxemia alone was without effect, posttraumatic hypoxemia exacerbates FPI-induced reductions in visual discrimination accuracy and secondary hypoxemia interferes with control of the rat's choices by flicker frequency, perhaps in part as a result of neuronal loss and fiber degeneration in the dLG. These results additionally confirm the utility of this visual discrimination procedure as a sensitive, noninvasive means of assessing behavioral function after experimental traumatic brain injury.

Behavioral effects Of 8-OH-DPAT in chronically stressed male and female rats.

The present study tested the hypothesis that chronic stress desensitizes serotonergic 5-HT(1A) receptors and alters behavioral changes following 5-HT(1A) agonist administration. Eating, acoustic startle response (ASR), and locomotor activity were measured in stressed and nonstressed male and female rats after 8-OH-DPAT administration. Stressed rats were paired and stressed by around-the-clock intermittent foot shock. Controllable stress (CS) rats could avoid/terminate shock for themselves and their yoked partners by pulling a ceiling chain, whereas their partners, the uncontrollable stress (UCS) rats, could not. Rats earned their entire daily ration of food by pressing a lever. In previous experiments, this paradigm was stressful, but not debilitating and rats continued to eat, groom, sleep, and avoid/escape greater than 99% of shock trials. Locomotor activity and ASR were measured in the present study after saline and 8-OH-DPAT administration (0.25 mg/kg, IP) before, 24 h, and 72 h after shock onset. 8-OH-DPAT only decreased food intake significantly in male and female rats after the first administration. Stress decreased food intake in both the CS and UCS rats, with UCS rats eating the least. However, the effects of stress and 8-OH-DPAT were not additive. 8-OH-DPAT significantly increased peak startle amplitude at 100 and 120 dB, and decreased latency to peak startle amplitude at 100 dB in male and female rats. In contrast, 8-OH-DPAT did not alter percent prepulse inhibition (%PPI) at 100 dB, but significantly decreased %PPI in males but not females at 120 dB. Stress did not have a consistent effect on ASR, but reduced %PPI in males, but not females. Neither stress nor 8-OH-DPAT significantly altered locomotor activity. Although the results do not show an increased sensitivity to 8-OH-DPAT in stressed rats, the unexpectedly weak effects of 8-OH-DPAT alone on the behavioral measures chosen limits the conclusions that can be drawn.

Arteether-induced brain injury in Macaca mulatta. I. The precerebellar nuclei: the lateral reticular nuclei, paramedian reticular nuclei, and perihypoglossal nuclei.

Malaria poses a threat across several continents: Eurasia (Asia and parts of Eastern Europe), Africa, Central and South America. Bradley (1991) estimates human exposure at 2,073,000,000 with infection rates at 270,000,000, illnesses at 110,000,000, and deaths at 1,000,000. Significant mortality rates are attributed to infection by the parasite Plasmodium falciparum, with an estimated 90% among African children. A worldwide effort is ongoing to chemically and pharmacologically characterize a class of artemisinin compounds that might be promising antimalarial drugs. The U.S. Army is studying the efficacy and toxicity of several artemisinin semi-synthetic compounds: arteether, artemether, artelinic acid, and artesunate. The World Health Organization and the U.S. Army selected arteether for drug development and possible use in the emergency therapy of acute, severe malaria. Male Rhesus monkeys (Macaca mulatta) were administered different daily doses of arteether, or the vehicle alone (sesame oil), for a period of either 14 days, or 7 days. Neuropathological lesions were found in 14-day arteether treated monkeys in the precerebellar nuclei of the medulla oblongata, namely: (1) the lateral reticular nuclei (subnuclei magnocellularis, parvicellularis, and subtrigeminalis), (2) the paramedian reticular nuclei (subnuclei accessorius, dorsalis, and ventralis), and the perihypoglossal nuclei (n. intercalatus of Staderini, n. of Roller, n. prepositus hypoglossi). The data demonstrate that the simina meduallry precerebellar nuclei have a high degree of vulnerability when arteether is given for 14 days at dose levels between 8mg/kg per day and 24 mg/kg per day. The neurological consequences of this treatment regimen could profoundly impair posture, gait, and autonomic regulation, while eye movement disorders might also be anticipated.

Chronic sustained stress increases levels of anterior pituitary prolactin mRNA.

Our laboratory is investigating the effects of chronic stress on physiological, endocrine and behavioral measures, in order to elucidate the neuronal substrates for the pathophysiological consequences of stress in humans. In these studies, we have employed a rodent model of sustained stress in which rats are exposed to around-the-clock intermittent footshock that can be avoided or escaped by rats in the controllable stress group, but not by rats in the uncontrollable stress group. Each rat in the uncontrollable stress group is paired (yoked) to a rat in the controllable stress group such that the controllable stress group rat avoids or escapes shock for both rats. A third group of rats receives no shock (controls). We have previously reported that in male rats, plasma prolactin levels were elevated after 3 days of stress in both stress groups. In the present experiments we determined whether the increases in plasma prolactin were correlated with increases in anterior pituitary prolactin mRNA. In addition, we measured hormones and mRNA at three time points and we examined these responses in female as well as male rats. Adult male and female Sprague-Dawley rats were exposed to chronic stress for 1, 3 or 14 days. In unstressed control rats, levels of anterior pituitary prolactin mRNA were fivefold higher in female as compared to male rats. However, stress increased levels of anterior pituitary prolactin mRNA over baseline in both genders. After 1 day of stress, anterior pituitary prolactin mRNA levels increased in male and female rats belonging to both stress groups, with no significant difference seen between the uncontrollable vs. controllable stress groups. After 3 days of stress, anterior pituitary prolactin mRNA levels were even more elevated, and rats in the uncontrollable stress group had higher anterior pituitary prolactin mRNA levels than those in the controllable stress group. After 14 days of stress, there were no significant differences in control and stressed groups with respect to anterior pituitary prolactin mRNA. These data suggest that chronic sustained stress increases the synthesis of anterior pituitary prolactin mRNA during the first days of stress, and that levels return to prestress values sometime between 3 and 14 days of stress.

Sustained stress disrupts the performance and acquisition of delayed alternation in rats.

The effects of sustained stress on acquisition and performance of a delayed alternation task were studied in male rats. Rats lived 24 h per day in operant cages where they earned all of their food via lever pressing. During the stress portion of each experiment, one group of rats was able to avoid or escape signaled intermittent footshock (Avoidance/Escape group), a second group (Yoked) did not have control over shock termination, a third group never received shock (Control). Shock trials were presented around-the-clock at approximately 5-min intervals and the stress portion of each study lasted 1 week. We have previously reported that rats tolerate this paradigm well and avoid/escape 99% of the shock trials. Three experiments were conducted. In Experiment 1, rats learned the delayed alternation task prior to stress onset; in Experiment 2, rats were exposed to stress and the alternation task concurrently; in Experiment 3, rats were stressed for 14 days prior to being required to perform the delayed alternation task. In the first experiment, stress decreased both food intake and the accuracy of responding during the first days of stress. In the second experiment (acquisition), stressed rats required more days to reach asymptotic performance on the alternation task. In Experiment 3, rats stressed for 14 days prior to acquisition of the delayed alternation task performed similarly to controls.

Visual system degeneration induced by blast overpressure.

The effect of blast overpressure on visual system pathology was studied in 14 male Sprague-Dawley rats weighing 360-432 g. Blast overpressure was simulated using a compressed-air driven shock tube, with the aim of studying a range of overpressures causing sublethal injury. Neither control (unexposed) rats nor rats exposed to 83 kiloPascals (kPa) overpressure showed evidence of visual system pathology. Neurological injury to brain visual pathways was observed in male rats surviving blast overpressure exposures of 104-110 kPa and 129-173 kPa. Optic nerve fiber degeneration was ipsilateral to the blast pressure wave. The optic chiasm contained small numbers of degenerated fibers. Optic tract fiber degeneration was present bilaterally, but was predominantly ipsilateral. Optic tract fiber degeneration was followed to nuclear groups at the level of the midbrain, midbrain-diencephalic junction, and the thalamus where degenerated fibers arborized among the neurons of: (i) the superior colliculus, (ii) pretectal region, and (iii) the lateral geniculate body. The superior colliculus contained fiber degeneration localized principally to two superficial layers (i) the stratum opticum (layer III) and (ii) stratum cinereum (layer II). The pretectal area contained degenerated fibers which were widespread in (i) the nucleus of the optic tract, (ii) olivary pretectal nucleus, (iii) anterior pretectal nucleus, and (iv) the posterior pretectal nucleus. Degenerated fibers in the lateral geniculate body were not universally distributed. They appeared to arborize among neurons of the dorsal and ventral nuclei: the ventral lateral geniculate nucleus (parvocellular and magnocellular parts); and the dorsal lateral geniculate nucleus. The axonopathy observed in the central visual pathways and nuclei of the rat brain are consistent with the presence of blast overpressure induced injury to the retina. The orbital cavities of the human skull contain frontally-directed eyeballs for binocular vision. Humans looking directly into an oncoming blast wave place both eyes at risk. With bilateral visual system injury, neurological deficits may include loss or impairments of ocular movements, and of the pupillary and accommodation reflexes, retinal hemorrhages, scotomas, and general blindness. These findings suggest that the retina should be investigated for the presence of traumatic or ischemic cellular injury, hemorrhages, scotomas, and retinal detachment.

Exposure to sublethal blast overpressure reduces the food intake and exercise performance of rats.

Exposure to blast overpressure can typically inflict generalized damage on major organ systems, especially gas-containing organs such as the lungs and the gastrointestinal tract. The purpose of the present study was to use rat's food intake and exercise wheel running as behavioral correlates of the perhaps more subtle damage to these organ systems induced by sublethal blast overpressure. Toward this end, all rats were exposed to a 12-h light/dark cycle and food was available only in the dark period. Prior to exposure, rats in the (E)xercise group were required to execute five rotations of an activity wheel for a food pellet; wheel turns that occurred at times other than when a rat was feeding were recorded separately and labeled exercise running. In the (S)edentary and (A)nesthesia groups, wheel running was not possible and rats were required to execute five leverpresses for a single pellet. A compressed air-driven shock tube was used to expose rats to a supra-atmospheric wave of air pressure. The tube was separated into two sections by a polyester membrane, the thickness of which determined peak and duration of overpressure. All rats were anesthetized with 50 mg/kg of phenobarbital. After reaching a deep plane of anesthesia, they were individually tied in a stockinet across one end of the shock tube. In preliminary tests, the membrane thickness was 1000 (A)ngstroms and rats in Group L(ethality) were exposed to a 129 kPa (peak amplitude) wave of overpressure. Three of six rats survived exposure to this peak pressure; pathology was evident in the lungs and gastrointestinal tract of all non-survivors. Rats in Groups E and S were tested with a 500 A membrane, which resulted in an 83 kPa peak amplitude. All rats survived exposure to this lower peak pressure. On the day of exposure to blast, the relative reduction of intake during the first 3 h of the dark period was significantly greater for Group E than for Groups S and A; the intake of Groups E and S remained reduced for four additional recovery days. Bodyweight was not significantly affected. Exercise wheel running also was reduced significantly on the day of exposure and during subsequent recovery days. These preliminary findings suggest that exposure to sublethal blast overpressure can reduce food consumption and exercise performance, perhaps as a consequence of damage to the gastrointestinal tract and lungs.

Arteether: risks of two-week administration in Macaca mulatta.

Male rhesus monkeys (Macaca mulatta) were administered daily doses of the antimalarial drug arteether. The 14-day treated group received either 24 mg/kg/day, 16 mg/kg/day, or 8 mg/kg/day. The seven-day treatment group received either 24 mg/kg/day or 8 mg/kg/day. All control cases in each group received the sesame oil vehicle alone. Neurologic signs were absent for animals in the seven and 14-day treatment groups except for one monkey which showed diffuse piloerection on day 14, and another monkey receiving 24 mg/kg/day for seven days showed mild lethargy after the fourth day. Mild, sporadic anorexia was noted in all animals by day 14, and a single animal showed diffuse piloerection on day 14. Surgical anesthesia preceded killing by exsanguination and was accompanied by perfusion fixation of the central nervous system. Brain sections were cut and then stained for study by light microscopy. Evidence of neuronal pathology, both descriptive and numerical, was collected. The neuroanatomic and neuropathologic findings demonstrated that arteether produced extensive brainstem injury when administered for 14 days. The magnitude of brainstem neurotoxicity was dose-dependent, where injury was greatest at the 24 mg/kg/day dose level, less at the 16 mg/kg/day dose level, and least at the 8 mg/kg/day dose level. Arteether induced multiple systems injury to brainstem nuclei of 1) the reticular formation (cranial and caudal pontine nuclei, and medullary gigantocellular and paragigantocellular nuclei); 2) the vestibular system (medial, descending, superior, and lateral nuclei); and 3) the auditory system (superior olivary nuclear complex and trapezoid nuclear complex). The vestibular nuclei and the reticular formation were most severely injured, with the auditory system affected less. The cranial nerve nuclei (somatic and splanchnic) appeared to escape damage, with the exception of the abducens nerve nucleus. The same brainstem nuclear groups of seven-day treated monkeys appeared normal. The statistical data are concordant with the descriptive data in demonstrating neurotoxic effects. In summary, no neurologic deficits were detected in any of the vehicle control monkeys (14-day and seven-day cases). Monkeys in the 14-day treatment group were free of clinical neurologic signs throughout the first week. At day 14, fine horizontal nystagmus was seen in one monkey, and another monkey exhibited diffuse piloerection. Monkeys in the seven-day treatment group were free of clinical neurologic signs except for one case. This monkey was treated with 24/mg/kg/day of arteether and exhibited lethargy after the fourth day. These indications of dysfunction arose too late to be practical indicators of neurotoxicity.

Sustained stress and fixed interval performance.

The effects of sustained stress on response rate and temporal patterning (quarter-life) of rats performing either a previously learned fixed-interval schedule (FI 60) or learning an FI 60 simultaneously with stress onset were determined. Rats lived 24 h/day in operant cages, where they earned all of their food via lever-pressing. During the stress portion of each experiment, one group of rats was able to avoid or escape signalled intermittent footshock (Avoidance/ Escape Group), a second group (Yoked) did not have control over shock termination, a third group never received shock (Control). Shock trials were presented around the clock at approximately 5-min intervals and the stress portion of each study lasted 1-2 weeks. We have previously reported that rats tolerate this paradigm well and avoid/escape 99% of the shock trials. In rats previously trained on the FI task, both rate of responding and quarter-life values were significantly decreased on the first day of stress for both the Avoidance/Escape and Yoked Groups. Food intakes and quarter-life values were not significantly different from the controls by stress Days 3 and 2, respectively. In the acquisition study, controls learned the F1 task by Day 4 as judged by quarter-life of responding. FI task acquisition was significantly impaired in stressed rats compared to controls, not reaching asymptotic performance until Day 9 of stress. There were no major differences between the 2 stress groups in either study. These data demonstrate that stress may impair both the rate and patterning of behavior, and suggest that this rodent paradigm may usefully model some aspects of the effects of stress in humans.

Hypoxia potentiates traumatic brain injury-induced expression of c-fos in rats.

Halothane-anesthetized male rats were subjected to either moderately severe parasagittal fluid percussion-induced traumatic brain injury (TBI) or sham injury, and for 30 min immediately after injury hypoxia was induced in half the rats from each group by substituting a 13% O2 source to deliver halothane for continued anesthesia. At 60 min post-TBI, Northern blot analysis showed a significant increase in c-fos mRNA levels, by 60-100% above sham control levels in the frontal cortex, cerebellum and hippocampus. Although hypoxia in sham-injured rats did not by itself alter c-fos mRNA levels, it did significantly potentiate the TBI-induced changes in c-fos mRNA in all three brain regions. These findings show that hypoxia is an important factor influencing genomic responses to TBI.

Large picture archiving and communication systems of the world--Part 2.

A survey of 82 institutions worldwide was done in 1995 to identify large picture archiving and communication systems (PACS) in clinical operation. A continuing strong trend toward the creation and operation of large PACS was identified. In the 15 months since the first such survey the number of clinical large PACS went from 13 to 23, almost a doubling in that short interval. New systems were added in Asia, Europe, and North America. A strong move to primary interpretation from soft copy was identified, and filmless radiology has become a reality. Workstations for interpretation reside mainly within radiology, but one-third of reporting PACS have more than 20 workstations outside of radiology. Fiber distributed data interface networks were the most numerous, but a variety of networks was reported to be in use. Replies on various display times showed surprisingly good, albeit diverse, speeds. The planned archive length of many systems was 60 months, with usually more than 1 year of data on-line. The main large archive and off-line storage media for these systems were optical disks and magneto-optical disks. Compression was not used before interpretation in most cases, but many systems used 2.5:1 compression for on-line, interpreted cases and 10:1 compression for longer-term archiving. A move to digital imaging and communication in medicine interface usage was identified.

Large picture archiving and communication systems of the world--Part 1.

This is the report of a worldwide survey of 82 institutions done to identify large scale picture archiving and communication systems (PACS) in clinical operation in 1995. This survey found a continuing strong trend toward the creation and operation of large PACS. In the 15 months since the first such survey, the number of clinical large PACS went from 13 to 23, almost a doubling in that short interval. New systems were added in Asia, Europe, and North America. A strong move to primary interpretation from soft copy was identified, and filmless radiology has become a reality.

Effects of chronic stress on food acquisition, plasma hormones, and the estrous cycle of female rats.

Our laboratory has previously conducted a number of studies to determine the effects of chronic stress on the physiology and behavior of male rats. The present study was performed to extend these investigations to female rats. Female rats were chronically stressed using a behavioral paradigm of around-the-clock signalled intermittent foot shock in which some rats can pull a chain to avoid/escape shock (stress) while another group of rats is yoked to the first group (yoked-stress) and does not have control over shock termination. Control rats were never shocked but all groups lever pressed for food pellets on an FR1 schedule (one pellet per lever press). Daily vaginal samples were obtained for several weeks prior to stress onset and throughout the chronic stress period. After 14 days of stress, the experiment was terminated and morning blood samples were collected for hormonal assays. Stress transiently decreased lever pressing for food pellets and body weights, but both measures returned to prestress levels by day 14 of stress. Plasma adrenocorticotropic hormone (ACTH) concentrations were significantly elevated in the yoked-stress group compared to the other two groups, but there were no significant effects of 14 days of stress treatment on plasma corticosterone, prolactin, estradiol, or progesterone concentrations. There were no significant differences in estrous cycle length among experimental groups.

The era of health care reform and the information superhighway. Implications for radiology.

Radiology is undergoing dramatic change, along with the rest of the health care system, in its mode of organization, financing, and delivery. Information technology is becoming central to health care delivery and will enable a higher degree of integration of imaging practice with the rest of the health care system. Radiology will need to address the requirements for achieving this integration to continue to be successful in the future.

Reporting and communications.

The future of radiology reporting will be molded by the ever changing health care environment and developments in computer methods. Less reliance on transcription is certain. The challenges of producing faster and more useful reports should be rewarding in a positive sense. The next few years should include many computer approaches to help the radiologist to generate reports directly and to communicate them effectively.

Substitution and caloric regulation in a closed economy.

Three experiments were conducted to study the effect of an imperfect substitute for food on demand for food in a closed economy. In Experiments 1 and 2, rats pressed a lever for their entire daily food ration, and a fixed ratio of presses was required for each food pellet. In both experiments, the fixed ratio was held constant during a daily session but was increased between sessions. The fixed ratio was increased over a series of daily sessions once in the absence of concurrently available sucrose and again when sucrose pellets were freely available. For both series, increases in the fixed ratio reduced food intake, but body weight was reduced only in the no-sucrose condition. In the sucrose condition, body weight and total caloric intake (sucrose plus food) were relatively unaffected by increases in the fixed ratio. At all fixed ratios, food intake was proportionally reduced by the intake of sucrose. In Experiment 3, monkeys obtained food or saccharin by pressing keys; the fixed ratio of presses per food pellet was increased once when tap water was each monkey's only source of fluid, again when each monkey's water was sweetened with saccharin, and a third time when each monkey had concurrent access to the saccharin solution and plain water. Increases in the fixed ratio, but not the intake of the saccharin solution, reduced each monkey's food intake. Because neither rats' sucrose nor monkeys' saccharin intakes affected the slope of the respective demand curves for food, monkeys and rats increased their daily output of presses and thereby defended their daily intake of those complementary elements of food. However, sucrose reduced rats' food intake. The relative constancy of body weight and total caloric intake in the sucrose condition is consistent with the possibility that rats tended to regulate caloric intake.

Time cost of alternation reduced demand for food in a closed economy.

A principal purpose of the present study was to characterize rats' demand for food by increasing the required delay between the alternation of leverpresses. While living in cages that were exposed to a 12:12 light:dark cycle, rats were required to alternate leverpresses for their entire daily food ration. After a press on one lever resulted in the delivery of a food pellet, a red cuelight was illuminated for a fixed duration that equaled the imposed delay between successive leverpresses. After the imposed delay elapsed and the cuelight was turned off, a press on the alternate lever resulted in the delivery of another food pellet. Increases in the imposed delay from 0.01 s to 16 s reduced mean percent correct (alternation) and mean food intake, although both were reduced more rapidly and to a greater extent in the light than in the dark photoperiod. This interaction resulted from a reduction of meal size in the light and a compensatory increase in meal size in the dark as the imposed delay increased. Rats also defended their daily intake in the dark against increasingly larger imposed delays by spending increasingly larger amounts of time alternating and by increasing total (correct + incorrect) presses. These results suggest that photoperiod is a determinant of the motivational value of food as a reinforcer for instrumental behavior in a closed economy.