Amygdala–prefrontal interactions and conditioned bradycardia in the rabbit.

Damage to the amygdala or medial prefrontal cortex (mPFC) produces deficits in learned autonomic adjustments. Whether connections between these 2 structures are necessary for acquiring classically conditioned heart rate (HR) decelerations was studied. Connections between them were interrupted by unilateral lesions of the mPFC and amygdala, but on opposite sides of the brain. One experiment focused on the mPFC and amygdala central nucleus and a second on the mPFC and amygdala basolateral complex. Bilateral lesions of either structure disrupted the HR conditioned response. The response of the 2 crossed lesioned groups also was smaller than that of the sham-operated and unilateral lesioned groups, but significant conditioned stimulus-evoked bradycardia occurred in both, suggesting that although interactions between the amygdala- and mPFC may normally occur during associative emotional responding, these connections are not necessary for the acquisition of conditioned bradycardia. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Lateral septal lesions enhance conditioned bradycardia in the rabbit.

52 New Zealand albino rabbits received sham lesions or complete, medial, lateral, or posterior septal lesions and were subjected to differential conditioning in which tones of different frequencies served as CSs, and paraorbital electric shock was the UCS. EMG, heart rate (HR), blood pressure (BP) CRs, and hippocampal rhythmic slow wave activity (RSA) were recorded. Lateral or complete septal lesions enhanced the bradycardiac HR CR but had no effect on the BP depressor response. Both unconditioned and conditioned EMG responses occurred infrequently and were unaffected by any lesion. Unconditioned HR responses and somatomotor threshold determinations to unsignaled electric shock were also unaffected by the lesions. Complete septal lesions increased locomotor activity relative to sham or other septal lesions. Little hippocampal RSA was detected in Ss with medial lesions, but the HR CR was unimpaired in these Ss. Data implicate the septo-hippocampal circuit in classical conditioning of cardiovascular changes and further suggest that diencephalic forebrain structures may modulate forebrain processing of sensory stimulation, perhaps in terms of assessing its biological significance. (41 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opioid modulation of attention-related responses: delta-receptors modulate habituation and conditioned bradycardia

A rehabilitation program toward restoring upper limb movements based on neuromuscular electrical stimulation (NMES) depends on closed-loop control performance, which has been limited by the development of sensors for practical daily use. This work proposes a system to obtain force feedback. The system is comprised of a Lycra commercial glove with force sensing resistors (FSR's) attached to the distal phalanxes of the thumb, index and long fingers. After amplification and filtering, the signal is digitized through an analog-to-digital (A/D) converter. The polynomial fitting coefficients for the characteristic curves, obtained during the sensor calibration process, were inserted in the software thus enabling the reading of forces exerted during object manipulation. The system was applied to 30 normal subjects in order to verify its feasibility and to acquire knowledge of the normal hand function. Different ways of grasping have been detected according to the Force versus Time curve pattern and to the fingers predominantly used in grasping. Results have also shown the influence of parameters such as gender, age, hand size, and object weight in the normal function. The system did show efficacy. It was able to determine grasp forces during object manipulation for up to 73% of the studied sample. This is significant since a single glove was used in a wide range of subjects. For best results in medical applications, the glove should be tailored to the particular characteristics of an individual user.     

Lateral subthalamic area as mediator of classically conditioned bradycardia in rabbits.

Examined whether a central efferent pathway passing through the lateral zona incerta (LZI) of the subthalamus would selectively mediate the bradycardia conditioned response (CR) in 22 New Zealand albino rabbits. Electrodes were implanted bilaterally in LZI or in control sites just dorsal or ventral to LZI. Two days following surgery, Ss were subjected to Pavlovian conditioning or to pseudoconditioning. Subsequent bilateral electrolytic lesions did not infuence the heart rate (HR) orienting response, unconditioned response (UCR), baseline, or lack of response to pseudoconditioning. Bilateral LZI lesions alone abolished the HR CR. In a follow-up experiment, the corneoretinal potential (CP) CR and HR were recorded in 4 Ss. Bilateral LZI lesions following conditioning to a criterion of 65% CP CRs abolished the HR CR without affecting CP CRs. Findings indicate that LZI is part of an efferent pathway that selectively mediates the HR CR in rabbits. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subicular lesions disrupt but do not abolish classically conditioned bradycardia in rabbits.

Rabbits and rats received horseradish peroxidase injections in the medial prefrontal cortex. and retrograde labeling was examined in the hippocampus (HC) and subicular complex (SC). Labeled cells were observed in HC and SC in the rat, but only in the SC of the rabbit. In a second experiment, separate groups of rabbits with sham, SC, or cortical control lesions were subjected to differential classical heart rate conditioning, in which 4-s, 75-db tones served as conditioned stimuli and a 3-mA paraorbital shock was the unconditioned stimulus. Although conditioned bradycardia was obtained in animals with SC lesions, it was slower to develop and was much shorter in duration than in the cortical and sham control groups. In the animals with SC lesions, the bradycardiac response was quickly replaced with tachycardia, suggesting a sympathetic bias in these animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Modulation of the acquisition of the rabbit eyeblink conditioned response by conditioned contextual stimuli.

Three experiments were conducted to ask if conditioned emotional responses (CERs) controlled by contextual cues modulate the acquisition of eyelid conditioned responses (CRs) to discrete conditioned stimuli (CSs). Experiment 1 showed that 30-s auditory stimuli that were paired with aversive shocks to one paraorbital region or the other controlled discriminated CERs, as measured by potentiation of a startle response. In Experiments 2 and 3, similarly trained 30-s stimuli served as contexts in which 1,050-ms CSs were paired with a paraorbital unconditioned stimulus (US). Reinforced contexts both impaired (Experiments 2A and 2B) and facilitated (Experiment 3B) acquisition of the eyeblink CR, depending on the locus of the USs involved. The data are consistent with the interpretation that CERs controlled by contextual cues facilitate CR acquisition, but do so in the face of blocking effects of CR tendencies also conditioned to the contextual cues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired learning of classically conditioned bradycardia in rats following fourth ventricle administration of D-ala2-methionine-enkephalinamide.

Prior to differential classical conditioning on two successive days, three groups of rats received an infusion (10 μg) of either the opioid peptide D-alanine2-methionine-enkephalinamide (DALA), DALA plus naltrexone (5 μg), or saline into the rostral region of the fourth ventricle. A fourth group, which served as a control to help localize DALA's site of action, received an infusion of DALA (10 μg) into the brain stem area on the floor of the ventricle. The group given DALA alone in the ventricle showed no evidence of a heart rate conditioned response (CR) either during conditioning or during a nondrug test session given 2 days after conditioning. Interference with the CR by DALA was reversed by the concomitant infusion of naltrexone. The control group given DALA in the brain stem developed a normal CR. It was suggested that DALA-induced opioid-receptor activity in the region of the periaqueductal/periventricular gray or locus coeruleus region of the ventricle may have prevented the learning of a CR. This could have occurred through a blunting of the emotional aftereffects of the unconditioned stimulus or through interference with projection pathways to other areas. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Bilateral nature of the conditioned eyeblink response in the rabbit: Behavioral characteristics and potential mechanisms.

In Pavlovian eyeblink conditioning, the conditioned response (CR) is highly lateralized to the eye to which the unconditioned stimulus (US) has been directed. However, the initial conditioning of one eye can facilitate subsequent conditioning of the other eye, a phenomenon known as the intereye transfer (IET) effect. Because a conditioned emotional response (CER), as well as the eyeblink CR, is acquired during eyeblink conditioning and influences the development of the CR, the CER acquired in initial training can plausibly account for the IET effect. To evaluate this possibility, the present study utilized previously determined eyeblink conditioning procedures that effectively decouple the degree of CER and CR development to investigate the IET effect. In each of 3 experiments rabbits were initially trained with comparison procedures that differentially favored the development of the eyeblink CR or the CER, prior to a shift of the US to the alternate eye. The observed differences in the IET suggest that the effect depends largely on the specific development of eyeblink CRs rather than the CER. The neurobiological implications of this apparent bilaterality of the eyeblink CR are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparative dopamine-acetylcholine interactions in the ventral and dorsal striatum of rabbit and rat brain

A methotrexate-bisphosphonate conjugate containing a peptide bond has been found to possess over five times greater antineoplastic activity against osteosarcoma in experimental animal models compared with methotrexate alone. METHODS: The conjugate was labeled with 99mTc in the presence of stannous ions to determine biologic distribution, with special reference to osseous tissue. Biodistribution studies were carried out in mice after intravenous administration of the labeled conjugate. Radionuclide imaging of rabbits was also performed. RESULTS: The labeled conjugate behaved like a bone-seeking agent. CONCLUSION: The present study indicates that the concept of treating osteosarcoma or metastatic tumors of bone with this class of agents has a firm basis.     

Changes in electrical activity of rabbit olfactory bulb and cortex to conditioned odor stimulation.

Rabbits with chronically implanted electrodes in olfactory bulb and cortex were classically conditioned to give an increase in relative frequency of sniffing to odor stimuli (CS+) reinforced with mild electric shock. Electroencephalographic high-frequency (35–85 Hz) bursts were recorded from an ensemble of nine bulbar depth electrodes and a second ensemble of 50 cortical surface electrodes. The olfactory cortex responded to the CS+ with sustained elevation of burst amplitude even though the olfactory bulb, from which it receives its primary centripetal input, underwent a marked decline in burst amplitude during the same time period. The amplitude reduction was not spatially uniform: The burst of the bulbar region that declined most in amplitude had the greatest phase lag with respect to the bulbar ensemble average burst. These effects were learning related because they did not occur for CS+ trials at the beginning of conditioning or for unreinforced control trials at any time. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of the naltrexone implant on rodent social interactions and cocaine-induced conditioned place preference

It is well known that excessive thyroid hormone in the body is associated with bone loss. However, the mechanism by which thyroid hormone affects bone turnover remains unclear. It has been shown that it stimulates osteoclastic bone resorption indirectly via unknown mediators secreted by osteoblasts. To determine if interleukin-6 (IL-6) or interleukin-11 (IL-11) could be the mediator(s) of thyroid hormone-induced bone loss, we studied the effects of 3,5,3'-tri-iodothyronine (T3) on basal and interleukin-1 (IL-1)-stimulated IL-6/IL-11 production in primary cultured human bone marrow stromal cells. T3 at 10(-12)-10(-8) M concentration significantly increased basal IL-6 production in a dose-dependent manner. It also had an additive effect on IL-1-stimulated IL-6 production, but failed to elicit a detectable effect on basal or IL-1-stimulated IL-11 production. Treatment with 17beta-estradiol (10(-8) M) did not affect the action of T3 on IL-6/IL-11 production. These results suggest that thyroid hormone may stimulate bone resorption by increasing basal and IL-1-induced IL-6 production from osteoblast-lineage cells, and these effects are independent of estrogen status.     

Chaotic components in the high-frequency EEG of rabbit cortex during formation of a conditioned defensive reflex

The chaotic component of the high-frequency EEG of the rabbit cortex was studied during the development of a conditioned defensive reflex to nonrhythmic light stimulation with electric reinforcement applied to the animal's paw. Regular changes in the dynamic parameters of the chaotic component of the high-frequency EEG were demonstrated. Characteristic changes in the asymptotic evaluations of the correlational dimensionality of the attractor of the chaotic component (DCC) of the high-frequency EEG were detected in the cortical regions studied both during the action of the conditioned stimulus and in background conditions before presentation of combinations. These changes affected both the afferent and efferent cortical regions of the conditioned reflex arc, as well as regions not directly addressed by the conditioned or unconditioned stimuli. These results allow the dynamics of changes in the morphofunctional structures of the conditioned reflex to be seen at the cortical level during learning. Significant differences in the early and late stages of conditioned reflex formation were detected.     

Evidence of plasticity in the pontocerebellar conditioned stimulus pathway during classical conditioning of the eyeblink response in the rabbit

Electrical stimulation thresholds required to elicit eyeblinks with either pontine or cerebellar interpositus stimulation were measured before and after classical eyeblink conditioning with paired pontine stimulation (conditioned stimulus, CS) and corneal airpuff (unconditioned stimulus, US). Pontine stimulation thresholds dropped dramatically after training and returned to baseline levels following extinction, whereas interpositus thresholds and input-output functions remained stable across training sessions. Learning rate, magnitude of threshold change, and electrode placements were correlated. Pontine projection patterns to the cerebellum were confirmed with retrograde labeling techniques. These results add to the body of literature suggesting that the pons relays CS information to the cerebellum and provide further evidence of synaptic plasticity in the cerebellar network.     

Time and stimulus specificity in extinction of the conditioned nictitating membrane response in the rabbit (Oryctolagus cuniculus).

The present experiments demonstrated that, in the rabbit nictitating membrane preparation, a conditioned response (CR) can be selectively eliminated in one portion of a conditioned stimulus (CS) while it is still paired with the unconditioned stimulus (US). Rabbits were initially trained with two stimuli (tone, light). Each was paired with the US by using a mixture of two CS-US interstimulus intervals (ISIs): 200 ms and 1,200 ms in Experiment 1; 150 ms and 500 ms in Experiment 2. The CRs showed double peaks, one for each ISI. Subsequently, one CS (A) was trained with only the longer ISI, whereas the other CS (B) continued to be trained with both ISIs. Consequently, the CR peak based on the shorter ISI disappeared for CSA but not for CSB. The later CR peaks during both CSA and CSB were maintained. These results support time-based models of conditioning. Implications for proposed mechanisms of extinction are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Microinjections of anisomycin into the intermediate cerebellum during learning affect the acquisition of classically conditioned responses in the rabbit

Galactosylhydroxylysine (GHL) is released during bone resorption and has been shown to be elevated in subjects with metabolic bone loss. GHL is relatively specific for bone, it is not recycled or significantly metabolized during collagen turnover, and the levels are not influenced by diet. Previous measurements of GHL levels in urine have been performed using reverse-phase high performance liquid chromatography following pre-column derivatization. We produced polyclonal antibodies to GHL using GHL purified from sea sponges and developed an immunoassay that can recognize GHL in urine. The antibodies have minimal cross-reactivity with a physiological mixture of amino acids (< 1%), galactose (< 0.2%), lactose (< 0.3%), and glucosylgalactosylhydroxylysine (< 1%). This competitive immunoassay requires no dilution or pretreatment of the samples and provides a rapid and easy method for the evaluation of GHL in urine. Analysis of clinical samples from normal individuals, post-menopausal women, osteoporotic patients and individuals with Paget's disease show that the assay can discriminate between groups with differing levels of bone resorption as well as deoxypyridinoline (Dpd).     

Glucagon therapy in the treatment of symptomatic bradycardia

Symptomatic bradycardia is commonly seen in the emergency department. Effective drug therapy for this clinical scenario is limited. Although glucagon has been used in no clinical trial in this setting, its cardiac activity may prove useful, particularly in the setting of beta-adrenergic blockade. We report a case series comprising three patients taking maintenance beta-blocker therapy who presented to the ED with symptomatic bradycardia and hypotension and in whom glucagon therapy obviated the need for further treatment. Further study is warranted to evaluate and define the role of glucagon in the treatment of symptomatic bradycardia.     

Theophylline for chronic symptomatic bradycardia in the elderly

The treatment of choice for chronic, symptomatic bradycardia is the placement of a cardiac pacemaker. Individuals who refuse or cannot tolerate pacemaker insertion usually require pharmacologic therapy. Hydralazine, prazosin, anticholinergics, and sympathomimetic agents have been administered for this indication, but adverse effects and limited data hinder routine, long-term use. Theophylline has emerged as a reasonable alternative strategy. For the medical management of bradycardia in the elderly, the literature supports theophylline dosages between 400 and 600 mg/d (approximately 8 mg/kg/d) administered in divided doses. This dosage range should result in a steady-state serum concentration between 5 and 15 mg/L. While some investigators recommend potentially higher initial doses (up to 12 mg/kg/d), lower dosages are more appropriate in the elderly due to decreased theophylline clearance. Initial dosage titration may be indicated and prolonged therapy is expected on the basis of the common etiologies of bradycardia in this patient group. Patient specifics such as altered theophylline metabolism (e.g., smoking), drug interactions (e.g., ciprofloxacin), and concomitant disease states (e.g., hepatic disease, heart failure) should always be considered in theophylline dosage recommendations. Clinicians should adjust the theophylline dose on the basis of patient response, including heart rate and clinical symptomatology, as well as measurement of occasional theophylline concentrations, if deemed appropriate. Theophylline should be avoided in the bradycardia-tachycardia manifestations of sick sinus syndrome or when ventricular ectopy is frequent. Additional investigation will further define the role of theophylline in elderly patients with chronic, symptomatic bradycardia.     

Temporally specific extinction of conditioned responses in the rabbit (Oryctolagus cuniculus) nictitating membrane preparation.

Extinguishing a conditioned response (CR) has entailed separating the conditioned stimulus (CS) from the unconditioned stimulus (US). This research reveals that elimination of the rabbit (Oryctolagus cuniculus) nictitating membrane response occurred during continuous CS-US pairings. Initial training contained a mixture of 2 CS-US interstimulus intervals (ISIs): 200 ms and 1,200 ms. The CRs showed double peaks, one for each ISI. When 1 ISI was removed, its CR peak showed the hallmarks of extinction: a decline across sessions, spontaneous recovery between sessions, and rapid reacquisition when the absent ISI was reintroduced. These results support real-time models of conditioning that segment the CS into microstimuli while challenging theories that rely on contextual control, US representations, CS processing, and response inhibition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Relative bradycardia and lymphopenia in patients with babesiosis

The medical records of 17 patients with babesiosis were reviewed. Nine of 17 patients (52.9%) presented with fever (temperature, > 101 degrees F), and 8 of the 9 patients (88.9%) had relative bradycardia. Four of the nine patients (44.4%) had morning temperature spikes during initial hospitalization. As revealed by laboratory analysis, 13 of 17 patients (76.5%) with babesiosis had lymphopenia, and 5 of 17 patients (29.4%) had rouleaux formation in their peripheral blood smears. These newly described clinical and laboratory findings represent additional clinical and laboratory features that may be used as diagnostic clues in the differential diagnosis of babesiosis.     

Rate adaptive atrial pacing in the bradycardia tachycardia syndrome

In 42 patients (26 men, 16 women; mean age 69 +/- 10 years), who were paced and medicated with antiarrhythmic drugs for the bradycardia tachycardia syndrome, chronotropic response and AV conduction with rapid atrial pacing during exercise were studied. Patients were included if they had no second- or third-degree AV block, no complete bundle branch or bifascicular block, and a PQ interval < or = 240 ms during sinus rhythm at rest. The interval between the atrial spike and the following Q wave (SQ) was measured in the supine position at rest with an AAI pacing rate of 5 beats/min above the sinus rate (SQ-R + 5), and at the end of exercise with 110 beats/min (SQ-E110). Bicycle ergometry was performed using the Chronotropic Assessment Exercise Protocol with the pacemakers being programmed to AAI with a fixed rate of 60 beats/min. Chronotropic incompetence was defined as peak exercise heart rate: (1) < 100 beats/min; (2) < 75% of the maximum predicted heart rate; or (3) the heart rate at half the maximum workload < 60 + 2 beats/min per mL O2/kg per minute (calculated O2 consumption). During exercise, one patient developed atrial fibrillation. Chronotropic incompetence was present in 71% (29/41) of the patients according to definition 2, and in 76% (31/41) according to definition 1 or 3. Ten out of 41 patients (24%) exhibited a second-degree AV block with atrial pacing at 110 beats/min at the end of exercise. Only 9 out of the remaining 31 patients (29%) showed a physiological adaptation of the SQ-E110, and 21 patients (68%) exhibited a paradoxical increase of the SQ interval with rapid atrial pacing at the end of exercise as compared to the SQ-R + 5. These observations indicate that the pacing system to be used in most patients paced and medicated for the bradycardia tachycardia syndrome should be dual chamber, and the option of rate adaptation should be considered.