Mediation of diurnal fluctuations in pain sensitivity in the rat by food intake patterns: reversal by naloxone.

Rats maintained on a 12-hour light-dark cycle were tested for pain sensitivity after being deprived of food during either the dark or the light phase of the cycle. Diurnal fluctuations in pain sensitivity were observed. The fluctuations followed food intake patterns rather than a natural circadian rhythm, with food deprivation producing a decrease in pain sensitivity. The analgesic response produced by this mild food deprivation was strongly attenuated by naloxone or feeding, suggesting that endogenous opioid systems may be related to patterns of food intake.

Associative learning in premature hydranencephalic and normal twins.

A hydranencephalic infant lacking cerebral hemispheres and a normal twin were tested for associative learning. After repeated trials in which two stimuli were temporally paired, test trials were given in which the second stimulus was omitted. Cardiac orienting responses to stimulus omission indicated that learning had taken place in both infants.

An analog of enkephalin having prolonged opiate-like effects in vivo.

Intraventricular administration of the enkephalin analog, [D-Ala2]-metenkephalin, induces profound and long-lasting analgesia, as well as other opiate-like behavioral effects in the rat. This analgesia was highly dose dependent, of much greater magnitude, and about 30 times longer lasting than that produced by the naturally occurring peptide, methionine-enkephalin. The behavioral effects of the [D-Ala2] analog could be completely reversed by the opiate antagonist, naloxone, suggesting that these effects were mediated by opiate receptors. Systemic administration of naloxone alone resulted in a significant increase in pain sensitivity. These findings support the view that endogenous opiate systems may play an important role in modulating pain sensitivity.

Vasopressin-induced antinociception: an investigation into its physiological and hormonal basis.

Systemically administered lysine-8-vasopressin (LVP; 16-128 micrograms/kg) was found to induce a potent and dose-dependent antinociceptive effect, as measured by the tail-flick test in the rat. This effect could be seen in the absence of any significant change in general activity, indicating that it was not due to sedation or general motor debilitation. The antinociceptive effect of LVP does not appear to be mediated by endogenous opiates or other pituitary hormones, as evidenced by: 1) the lack of antagonism by the opiate receptor blocker naloxone, 2) the lack of cross-tolerance with morphine, and 3) its persistence after hypophysectomy. Des-glycinamide-LVP, a vasopressin analog with no appreciable pressor or antidiuretic action, showed no antinociceptive activity (128 micrograms/kg), and des-amino-arginine-vasopressin, a vasopressin analog with minimal pressor activity but greatly enhanced antidiuretic activity, was also relatively ineffective (128 micrograms/kg). These results suggest that the antinociceptive activity of vasopressin may be related to receptor types similar to those mediating its pressor effects. Nevertheless, the antinociceptive action of vasopressin does not appear to be secondary to its pressor activity, since phenylephrine failed to induce an antinociceptive effect at a dosage that mimicked the pressor response to vasopressin. These results are in concert with a growing body of evidence suggesting that vasopressin may be one of several nonopiate peptides that play a role in the modulation of pain sensitivity.

Characteristics of abnormal food-intake patterns in children with Prader-Willi syndrome and study of effects of naloxone.

Prader-Willi syndrome (PWS) is characterized by morbid obesity and abnormal appetite. It has been suggested that appetite is reduced by the administration of the opioid antagonist, naloxone. This has led to the hypothesis that appetite disturbance is a consequence of an abnormal hypothalamic response to appetite effects of endogenous opiates and opiate antagonist may be a useful treatment. To characterize the feeding patterns of PWS children and test this hypothesis, we administered an appetite test to 10 PWS children and 9 obese control children. We also examined the effects of naloxone on eating behavior of the children with PWS. While initial rate of eating did not differ, the PWS group showed a much delayed satiety resulting in a longer period of food intake. No difference in food intake was observed with naloxone (1.6 mg im, 30 min before the feeding test) treatment as compared with saline treatment.

Short-term infusion of pancreatic polypeptide: effect on children with Prader-Willi syndrome.

Ten children with Prader-Willi syndrome (PWS) were given two 90-min infusions of pancreatic polypeptide (PP) (100 pmol.kg-1.h-1) counterbalanced with two saline infusions. Thirty minutes into each infusion, a 60-min appetite test was given. Tests were done after an overnight fast and 1 h after a 275-kcal breakfast meal. Serum assays for biochemistry, glucose, insulin, C peptide, glucagon, cortisol, and PP were performed at the beginning and end of the infusion. Although infusion of PP increased PP concentrations 10-fold, it did not cause physical signs or symptoms, changes in vital signs, or changes in serum biochemistry. Although the test design was sufficiently sensitive to reveal an effect of the pretest meal on subsequent food intake, there was no difference in eating behavior with the saline and PP infusions. This suggests that a short-term normalization of blood PP concentrations does not correct the excessive food intake.

Cardiac psychophysiology and autonomic space in humans: empirical perspectives and conceptual implications.

Contemporary findings reveal that autonomic control of dually innervated visceral organs does not lie along a single continuum extending from parasympathetic to sympathetic dominance. Rather, a bivariate autonomic space bounded by sympathetic and parasympathetic axes is the minimal representation necessary to capture the modes of autonomic control. We here empirically instantiate a quantitative bivariate model for the chronotropic control of the heart in humans. This model provides a more comprehensive characterization of psychophysiological response than simple measures of end-organ state and permits a differentiation of behavioral states and processes that would otherwise remain obscure. The model also illuminates and subsumes general principles such as the law of initial values and reveals a fundamental physiological rationale for the selection of heart period over heart rate as a metric for cardiac chronotropy. The present article also considers strategies for psychophysiological investigations within the autonomic space model, the limitations of these methods, and analytical tools for assessing their validity.

Multilevel integrative analyses of human behavior: social neuroscience and the complementing nature of social and biological approaches.

Social and biological explanations traditionally have been cast as incompatible, but advances in recent years have revealed a new view synthesized from these 2 very different levels of analysis. The authors review evidence underscoring the complementing nature of social and biological levels of analysis and how the 2 together can foster understanding of the mechanisms underlying complex behavior and the mind. Specifically, they review the utility of considering social influences on biological processes that are often viewed as outside the social domain including genetic constitution, gene expression, disease, and autonomic, neuroendocrine, and immune activity. This research underscores the unity of psychology and the importance of retaining multilevel integrative research that spans molar and molecular levels of analysis. Especially needed in the coming years is more research on the mechanisms linking social and biological events and processes.

Autonomic determinism: the modes of autonomic control, the doctrine of autonomic space, and the laws of autonomic constraint.

Contemporary findings reveal that the multiple modes of autonomic control do not lie along a single continuum extending from parasympathetic to sympathetic dominance but rather distribute within a 2-dimensional space. The physiological origins and empirical documentation for the multiple modes of autonomic control are considered. Then a formal 2-dimensional conception of autonomic space is proposed, and a quantitative model for its translation into a functional output surface is derived. It is shown that this model (a) accounts for much of the error variance that has traditionally plagued psychophysiological studies, (b) subsumes psychophysiological principles such as the law of initial values, (c) gives rise to formal laws of autonomic constraint, and (d) has fundamental implications for the direction and interpretation of a wide array of psychophysiological studies.

Cholinergic inputs to the rat medial prefrontal cortex mediate potentiation of the cardiovascular defensive response by the anxiogenic benzodiazephine receptor partial inverse agonist FG 7142.

Consistent with its putative anxiogenic actions, administration of the benzodiazepine receptor partial inverse agonist FG 7142 has been shown to potentiate defensive-like cardiovascular reactivity to an acoustic stimulus in the rat, an effect that appears to be mediated by the basal forebrain cholinergic system. The present studies tested the hypothesis that the basal forebrain cholinergic projections to the medial prefrontal cortex, an area that has been implicated in both anxiety and autonomic control, may be a relevant pathway underlying this response potentiation. Infusions of the muscarinic receptor agonist carbachol into the medial prefrontal cortex, but not into the lateral prefrontal cortex or the basolateral amygdala, mimicked the effects of systemically administered FG 7142 on the cardioacceleratory response. Infusions of the muscarinic antagonist atropine blocked this effect, as well as the response-potentiating actions of FG 7142. The effects of FG 7142 were also blocked by lesions of the cholinergic inputs to the medial prefrontal cortex produced by local infusions of the immunotoxin 192 immunoglobulin G-saporin into this area. These findings indicate that cholinergic activation of the medial prefrontal cortex is sufficient to enhance the cardioacceleratory defensive response, and that cholinergic inputs to the medial prefrontal cortex are necessary for the response-potentiating effects of FG 7142. These results are consistent with a recent neurobiological model of anxiety and autonomic control that attributes the enhanced processing of anxiety-related stimuli and contexts to increases in activity in cortical cholinergic inputs.

Blockade of epinephrine priming of the cerebral auditory evoked response by cortical cholinergic deafferentation.

The present study tested hypotheses derived from a neurobehavioral model of anxiety that posits an important role of the basal forebrain cholinergic system in the cortical processing of anxiety-associated stimuli and contexts. We hypothesized that visceral afferent activity induced by systemic administration of epinephrine would enhance the processing of auditory stimuli as evidenced by the cerebral auditory evoked response. We further predicted that selective lesions of the basal forebrain cortical cholinergic projection system would disrupt this processing, and would further block the effects of epinephrine. Results confirmed these hypotheses. Epinephrine was found to enhance the amplitude of the P70 component of the auditory evoked response in rats. Selective lesions of the basal forebrain corticopetal cholinergic projection, by intrabasalis infusions of 192 IgG saporin, delayed and reduced the amplitude of the P70 component, and blocked the potentiating effects of epinephrine on the auditory evoked response. The present results are consistent with the view that visceral afferent input may modulate cortical processing of sensory signals via the basal forebrain cholinergic system. These considerations emphasize the potential importance of ascending, bottom-up modulation of processing by telencephalic circuits that may impact on a wide range of behavioral functions.

Cardiac startle and orienting responses in the great apes.

Cardiac patterns of startle and orienting in response to auditory and vibrotactile stimuli were investigated in the infant chimpanzee and gorilla. Results revealed a notable cardiac acceleration in response to the initial presentations of stimuli of either modality. This acceleratory response appeared to reflect the cardiac correlate of startle and was closely associated with the elicitation of somatic startle responses. This initial cardiac acceleration was subject to rapid habituation and was replaced on subsequent trials by cardiac deceleration, which appeared to reflect the orienting response. Results from the chimpanzees and the gorilla were similar, although a slower rate of habituation was apparent in the gorilla. Taken together, these results are highly consistent with those obtained from humans and monkeys, and they provide the first characterization of cardiac patterns associated with startle and orienting responses in the great apes.

Specificity of the cardiac response to conspecific vocalization in chimpanzees.

Heart rate measures were used to examine the functional response of young chimpanzees and orangutans to acoustic stimuli, including white noise and chimpanzee vocalizations (threat, stress, and alarm). The initial response of the animals to all stimuli was characterized by a prominent cardiac deceleration and an increase in heart period variability. The deceleratory responses persisted with repeated presentations of the noise, stress, and alarm stimuli. In contrast, the response of chimpanzees to the conspecific threat stimulus reverted over trials to a notable cardiac acceleration. This acceleratory response was not attributable to potential patterns of evoked somatic responses. The features of the cardiac response, together with the results of frequency-domain analyses of heart period variability, suggest that this acceleratory response was consistent with the evocation of an aversive or a defensive reaction characterized by sympathetic activation. This pattern of cardiac response appeared early in ontogeny (within 48 hr postnatally) and was not manifest in orangutans. Taken together, the results suggest the existence of specialized perceptual processing mechanisms for vocal stimuli in the chimpanzee. Further examination of these mechanisms may contribute to our understanding of central perceptual processes and the evolution of vocal communication.

Autonomic origins of cardiac responses to nonsignal stimuli in the rat.

Heart rate (HR) and blood pressure responses to nonsignal auditory stimuli were measured in rats after saline or pharmacological blockade of the sympathetic or vagal innervation of the heart. HR responses to the low-intensity stimulus were predominantly deceleratory, whereas responses to the high-intensity stimulus were more notably acceleratory. Both stimuli elicited a biphasic pressor-depressor response, although potential baroreflex influences accounted for only a small proportion of the HR response variance. Deceleratory responses to the low-intensity stimulus were eliminated by scopolamine and thus appeared to be predominantly of vagal origin. Acceleratory response to the high-intensity stimulus appeared to be mediated primarily by sympathetic activation because it was substantially attenuated by the beta 1 antagonist atenolol. Furthermore, HR responses to the low-intensity stimulus appeared to reflect coactivation of both sympathetic and vagal systems.

Antinociceptive effects of central and systemic administrations of nicotine in the rat.

Nicotine (0.16--0.50 mg/kg, SC) was found to exert a potent antinociceptive action on thermal stimuli as measured by the tail-flick test. This antinociceptive action of nicotine could be blocked by centrally active nicotinic or muscarinic blockers implicating both classes of cholinergic receptors in this effect. Quaternary blockers, however, failed to prevent nicotine-induced antinociception. This finding, together with the ability of small doses of nicotine (25 micrograms) to induce potent antinociceptive effects when administered centrally, suggests a central site of action for the antinociceptive action of nicotine. The present results also support the suggestion that nicotine may selectively reduce sensitivity to certain classes of pain stimuli, perhaps through a central releasing action on acetylcholine.

Psychotogenic properties of benzodiazepine receptor inverse agonists.

The neurochemical, behavioral, and cognitive effects of the benzodiazepine receptor partial inverse agonist beta-carboline FG 7142 (FG), a drug traditionally described as exhibiting 'anxiogenic' effects, are proposed to model core components of present theories of the neuronal mechanisms of schizophrenia. FG activates the mesolimbic dopaminergic system and, via increases in dopaminergic activity in the nucleus accumbens, disinhibits corticopetal cholinergic projections. The latter effect of FG is hypothesized to mediate the hyperattentional impairments that contribute to the development of psychotic cognition. Furthermore, the FG-induced abnormal overprocessing of conditioned stimuli and contexts provides an explanation of the 'anxiogenic' effects of FG. The FG-induced increases in the activity of cortical cholinergic inputs and the FG-induced cognitive impairments in rats and monkeys were demonstrated to be attenuated by the administration of typical and atypical antipsychotic drugs. Compared to the classic psychotogenic drugs amphetamine and phencyclidine, the effects of FG serve as an alternative psychotogenic manipulation in research focusing on the cortical and cognitive aspects of current theories of schizophrenia.

Attenuation of the bidirectional effects of chlordiazepoxide and FG 7142 on conditioned response suppression and associated cardiovascular reactivity by loss of cortical cholinergic inputs.

RATIONALE: Basal forebrain cortical cholinergic projections have been hypothesized to mediate the enhanced cardiovascular defensive response initiated by the putative anxiogenic benzodiazepine receptor (BZR) partial inverse agonist FG 7142 (FG). The present study was designed to test the broader hypothesis that the integrity of this cholinergic projection is required for the mediation of the bidirectional modulatory effects of BZR agonists and inverse agonists on anxiety and associated cardiovascular reactivity. OBJECTIVES: The interactions between the effects of 192 IgG-saporin-induced lesions of basal forebrain corticopetal cholinergic neurons and of the BZR agonist chlordiazepoxide (CDP) and FG on the performance of rats tested in a conditioned suppression paradigm and on associated cardiovascular reactivity were assessed. METHODS: Lesioned and control animals were equipped with a telemetric device to record heart rate, trained in an operant lever task, and then tested for suppression of responding during presentation of a conditioned stimulus (CS) and a general contextual cue that was previously associated with shock. FG, CDP (8 mg/kg) and vehicle were administered IP in separate extinction sessions. RESULTS: In control animals, operant responding was suppressed during presentation of the CS and contextual cue. Administration of FG enhanced this suppression, while CDP attenuated it. Lesions attenuated overall response suppression as well as the modulatory effects of BZR ligands on responding during presentation of the contextual stimulus. Likewise, lesions attenuated the cardioacceleratory response to the contextual stimulus and the ability of the BZR ligands to modulate this response. CONCLUSIONS: The behavioral and autonomic responses to anxiety-related stimuli, as well as the modulatory effects of BZR ligands, are mediated in part via cortical cholinergic inputs.

Neurobehavioral organization and the cardinal principle of evaluative bivalence.

The principle of evaluative bivalence asserts that behavioral processes often organize along the evaluative dimension, due to a fundamental pattern of bivalent neurobehavioral organization extending throughout the neuraxis. This principle offers a powerful approach to the explication of complex behavioral relationships and the integration of diverse literatures. It also offers a guiding conceptual framework for the study of neurobehavioral relationships which holds the promise of integrating rather than diversifying the study of neural mechanisms for disparate behavioral phenomena.

Autonomic, neuroendocrine, and immune responses to psychological stress: the reactivity hypothesis.

We examined the effects of brief psychological stressors on cardiovascular, neuroendocrine, and cellular immune response in 22 older women to investigate the common effects of stress across systems. Results revealed that psychological stressors heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected the cellular immune response (ps < 0.05). In a replication and extension, 27 women caring for a spouse with a progressive dementia (high chronic stress) and 37 controls category matched for age and family income (low chronic stress) performed the 12-min laboratory stressor. Measures were taken before (low acute stress) and immediately following (high acute stress) exposure to the laboratory stressors as well as 30 min after termination of the stressor (recovery period). Acute stress again heightened cardiac sympathetic activation, elevated plasma catecholamine concentrations, and affected cellular immune responses (ps < 0.05), whereas chronic stress was associated with higher reports of negative affect, enhanced cardiac sympathetic activation, elevated blood pressure and plasma levels of ACTH, and diminished production of interleukin-1 beta (ps < 0.05). Correlational analyses in both studies further suggested that individuals who showed the greatest stress-related changes in HPA activation also exhibited the greatest diminution in cellular immune response.

Pancreatic polypeptide infusions reduce food intake in Prader-Willi syndrome.

Prader-Willi syndrome is characterized by dramatic hyperphagia and morbid obesity, and is associated with a deficiency in basal and meal-stimulated serum pancreatic polypeptide (PP) levels. Intravenous infusions of pancreatic polypeptide (90 min, 50 pmol/kg/h) restored normal serum PP levels, and a regimen of morning and afternoon PP infusions was found to significantly reduce food intake in Prader-Willi subjects. Food intake was evaluated in a 60-min free-feeding test that shows high reliability and validity. Basal food intake during saline infusions was striking (approximately 60 chicken sandwich quarters), and this intake was reduced overall by approximately 12% during PP infusions. This reduction was apparent only for female subjects, and may have reflected enhanced satiation rather than an overall suppression of food intake. No differences were apparent across subjects, in either basal food intake or the PP-related decrease in food intake, in the presence or absence of the widely recognized chromosomal marker for this syndrome [deletion of 15(q11-q13)]. More specific gene defects as recently reported in these subjects, however, suggest that the Prader-Willi syndrome may represent an important model for the study of food intake regulation.