D.T. Weldon

Naloxone effects on sucrose-motivated behavior

The opioid system plays an important role in feeding. In general, opioid agonists typically increase feeding and opioid antagonists decrease feeding in nonfood restricted animals. In food restricted animals the effects of these drugs are substantially reduced. Opioid antagonists have shown a marked effectiveness at reducing consumption of sweet foods. Explanations for this robust effect have typically focused on drug induced changes in taste, taste perception, or palatability. The current study relates the effects of the opioid antagonist naloxone on motivation to obtain different sucrose concentrations to the drugs effects on unrestricted sucrose solution consumption. Changes in motivation to respond were assessed under a progressive ratio reinforcement schedule (PR) which required increased response cost for each successive unit of sucrose solution. Motivation, as measured by the PR, increased as sucrose concentration increased and naloxone produced a dose-dependent decrease in motivation to respond for a given sucrose concentration. Thus, the effectiveness of naloxone was indirectly related to strength of the sucrose concentration. Under unrestricted access to sucrose solutions, naloxone reduced consumption greatest under the higher concentrations. The data suggest at least part of naloxones effects on sweet tasting food may be mediated through endogenous opioid reward systems that are reflected in measures of motivation.

Delayed behavioral effects following intrahippocampal injection of aggregated Aβ(1-42)

Beta amyloid protein (A beta) is the major extracellular component of Alzheimers disease (AD) plaques. In the current study, A beta (1-42) was aggregated in vitro using a method which produces A beta aggregates similar to those found in the AD brain. Twelve male Sprague-Dawley rats were trained in two-lever operant chambers under an alternating lever cyclic-ratio (ALCR) schedule. When performance was stable on the ALCR schedule, six subjects were injected (bilaterally into the CA3 area of the dorsal hippocampus) with 5.0 microliters aggregated A beta in suspension, and the remaining six subjects were injected with 5.0 microliters sterile water. Behavioral testing resumed 5 days after surgery and continued for 90 days post-injection. Aggregated A beta injection did not affect the number of lever switching errors made in a daily session but did affect the number of incorrect lever response perseverations. After approximately 30 days post-injection, aggregated A beta injection detrimentally affected ability to track the changing parameters of the schedule, and decreased the efficiency by which subjects obtained reinforcers. From approximately day 50 post-injection onward, A beta-injected subjects demonstrated significantly higher numbers of incorrect lever response perseverations than did sterile water-injected subjects. These effects appeared to be central rather than peripheral, as A beta injection did not decrease running response rates under the ALCR schedule. The delayed onset of behavioral effects seen in this and other behavioral studies may be a result of a cascade of potentially harmful responses induced through glial activation following aggregated A beta injection.

Naloxone administration following operant training of sucrose/water discrimination in the rat

The suppression of food intake observed following naloxone administration has often been ascribed to palatability or taste. Unfortunately, many confounds become apparent when attempts are made to isolate such factors in the investigation of ingestive behaviors. In the present study, rats (two groups) were trained to discriminate either a 10% or 5% sucrose solution from water (0.1 ml). These mildly food deprived subjects (95% of free-feeding weight) were trained to press the appropriate lever in a two-lever operant chamber following sampling of sucrose or water; successful responding was reinforced by delivery of a 45 mg grain food pellet. Following random exposure to reduced sucrose concentrations tested under extinction, a sucrose concentration gradient (1.0, 0.5, 0.1, 0.05, 0.01 and 0.005% sucrose solution) was established for both training groups under IP saline administration. Data collected under IP saline were then compared to those collected following random IP naloxone administration (3.0, 1.0, 0.3 and 0.1 mg/kg). No significant differences were observed between the sucrose concentration gradients obtained under saline and those obtained under naloxone, suggesting that the anorectic effect of naloxone is not primarily determined by discrimination of sweet taste.

Age-related changes in brain proDynorphin gene expression in the rat

Dynorphin has a well-established role in feeding and gustation. Alterations in taste perception and feeding behavior are common with age. We hypothesized that proDynorphin gene expression in brain areas involved in taste and feeding declines with age. Male Sprague-Dawley rats were housed individually with ad libitum access to food and water. Brain punches of the selected regions were dissected out in groups of rats aged 4-6, 12-14 and 18-21 months. ProDynorphin mRNA (measured using a cDNA probe) decreased significantly with age in arcuate nucleus and amygdala; increased significantly with age in hippocampus; and was not significantly affected in nucleus of the solitary tract, cortex, caudate putamen or hypothalamic paraventricular nucleus. These data suggest an age-related decrease in the synthesis of dynorphin in two brain regions strongly associated with feeding behavior, and an increase in dynorphin synthesis in a brain region associated with learning and memory.

Alternating lever cyclic-ratio schedule analysis of the effects of atropine sulfate

Cholinergic dysfunction has been implicated in the behavioral and memory impairment that is the hallmark of conditions such as delirium and Alzheimers Disease. Anticholinergic drugs have been widely used in procedures designed to mimic aspects of the pathology of these conditions in rats. Procedures in use vary widely in sensitivity and behavioral specificity and may be confounded by administration of high drug doses that may not be physiologically relevant. The current study proposes the use of rats responding on an alternating lever cyclic-ratio schedule to study the effects of the anticholinergic compound atropine sulfate. This procedure enables simultaneous measurement of anticipatory ratio tracking (postreinforcement pause durations), perseverations (lever switching errors), and nonspecific peripheral drug effects (running response rates). Results of this study suggest that the schedule is sensitive to low drug doses (0.1-1.0 mg/kg atropine), measures the ability to track changing ratio conditions and to execute lever alternation, and allows for monitoring of peripheral drug effects during behavioral testing. The procedures sensitivity and low effective dose range may make it useful in the study of behaviors related to anticholinergic effects.

Serum anticholinergic activity and behavior following atropine sulfate administration in the rat.

Anticholinergic agents such as atropine and scopolamine have long been suggested to produce delirium-like states in humans and experimental animals. Evidence for an anticholinergic mechanism in the pathogenesis of human delirium has accumulated, leading to studies of the behavioral effects of the anticholinergic drug atropine in animals. The current study addresses the adequacy of animal models of delirium in terms of sensitivity, specificity and pharmacological relevance. A multiple fixed-ratio fixed-interval reinforcement schedule was used to test the effects of relatively low doses of atropine on behavior in rats. Additionally, total serum anticholinergic activity (SAA) was measured under dose and time course conditions identical to those used in the behavioral study. Atropine reduced high and low rates of responding in a dose-dependent manner, and SAA increased in a dose dependent manner. SAA at atropine doses of 0.1 mg/kg to 1.0 mg/kg was similar to that found in delirious humans. These behavioral and serum level data suggest that relatively low doses of atropine, substantially below those used in previous attempts to model delirium using rats, may be more pharmacologically relevant to delirium and may minimize non-specific peripheral effects of this drug.

Neuropsychological Tests for Monitoring Delirium Severity in Elderly Patients

The authors identified neuropsychological tests appropriate for use in monitoring delirium severity in elderly patients. Ten elderly patients were administered a battery of tests while they were delirious and later during their recovery. All of the measures showed significant improvement across the two occasions (P < 0.05). Examination of components of variance suggests that modified versions of the Forward Digit Span, Similarities, or Oral Sentence Spelling tests or a combination of Forward Digit Span and Similarities or Oral Sentence Spelling are likely to be most effective in monitoring delirium severity.

Intrahypothalamic discriminative stimulus effects of neuropeptide Y

Neuropeptide Y (NPY) is one of the most ubiquitous neurotransmitters in the CNS and has been implicated in a variety of psychological and physiological functions. The current study investigated whether intrahypothalamic (I.H.) administrations of NPY were behaviorally discriminable from saline injections. Rats were trained to differentially respond based on whether they received I.H. injections of NPY (0.5 microg/0.5 microl) or saline (0.5 microl 0.9% NaCl). Subjects demonstrated discriminative control (85% correct in 8 out of 10 consecutive sessions) after a mean of 32 sessions. The ability of subjects to discriminate I.H. NPY from saline was dose dependent, with the lowest NPY dose tested (0.03 microg/0.5 microl) generalizing to saline. The opioid antagonist naloxone blocked the discrimination of NPY when administered I.P. (3.0 mg/kg) or I.H. (50 microg/0.5 microl).