Lathrop Taylor

Age-related decline in cholinergic synaptic transmission in hippocampus

Age-dependent changes in central nervous system (CNS) cholinergic synaptic transmission were studied in three age groups of Sprague-Dawley and Fischer 344 rats: 1- to 2-month-old, 8- to 10-month-old, and 18- to 23-month-old. Utilizing intracellular recording techniques and the in vitro hippocampal slice preparation, we report an age-related decline in central cholinergic transmission as a function of age. Slow excitatory postsynaptic potentials (slow EPSPs) were reduced approximately 60% in aged (18- to 23-month-old) compared to younger (1- to 2-month-old) animals. The response of the postsynaptic membrane to the muscarinic agonist, carbachol (0.3 microM), was also reduced with age. These changes were not accompanied by a global decline in muscarinic receptor function since two additional measures of cholinergic function were not changed with age. Both presynaptic inhibition of fast excitatory synaptic transmission and postsynaptic inhibition of the afterhyperpolarization (AHP) following a train of spikes were not changed during aging. Our results suggest that a primary functional decline in central cholinergic mechanisms during aging may be a specific reduction in central cholinergic synaptic transmission.

Sodium valproate decreases synaptic potentiation and epileptiform activity in hippocampus

The actions of sodium valproate (NaVP) were studied in the in vitro hippocampus using extracellular, intracellular and voltage-clamp recording techniques. In the CA1 region, concentrations of 30-200 microM NaVP reduced the amplitude but not the time course of post-tetanic potentiation (PTP) of dendritic field excitatory postsynaptic potentials (EPSPs). Epileptiform discharges were studied intracellularly in CA3 cells after pharmacological blockade of synaptic inhibition and repeated tetanic stimulation. NaVP (100 microM) blocked evoked paroxysmal depolarizing shift (PDS) discharges through a mechanism of increasing the threshold for burst-firing. When the PDS current was studied under voltage-clamp, application of NaVP (100 microM) resulted in a graded reduction of the PDS waveform. All of the actions of NaVP may result from inhibition of excitatory synaptic transmission following repetitive cell firing. A hypothesis is proposed that NaVP may act to decrease excitatory synaptic potentiation necessary for network synchronization.

Effects of acute and chronic ethanol treatment on pre- and postsynaptic responses to baclofen in rat hippocampus

Interactions between the GABAB receptor and acute or chronic ethanol treatment were studied using extracellular and intracellular electrophysiological recording techniques. Bath application of the GABAB receptor agonist, (-)-baclofen (0.1-100 microM) induced concentration-dependent inhibition of extracellularly recorded dendritic excitatory postsynaptic potentials (EPSPs) in the CA1 region of hippocampal slices. Responses to baclofen were unchanged relative to control either by simultaneous application of ethanol (10-60 mM) or by previous chronic ethanol exposure. The membrane potential of CA1 pyramidal neurons was reversibly hyperpolarized an average of 5 mV by pressure ejection of baclofen (1 mM). Bath application of ethanol (30 mM) alone occasionally caused a small depolarization of resting membrane potentials in CA1 neurons but failed to increase hyperpolarizing responses to pressure-ejected baclofen. However, in slices from chronic ethanol-treated animals hyperpolarizing responses to bath-applied baclofen (10 microM) were reduced by approximately 30% relative to controls. These results suggest that GABAB-mediated responses in CA1 hippocampal pyramidal neurons are relatively resistant to the acute effects of ethanol, but that continuous exposure to ethanol sufficient to induce physical dependence may evoke an adaptive reduction in some GABAB receptor mediated responses.

Effect of housing on open-field test behavior of gestating gilts

Abstract Open-field test behaviors of 36 gestating gilts maintained in either tethers, crates, loose stalls or dirt-lot ( N = 9 per treatment) were recorded. The gestation crates (C) were 0.6 m wide by 1.7 m long and enclosed by bars on all 4 sides. Tethered (T) gilts were anchored to the concrete floor by 50.8-cm chains attached to neck collars. The 0.6 × 1.7-m loose stalls (LS) opened into a slatted concrete dunging area (0.7 × 1.7 m) containing a nipple waterer which was shared by 3 loose stalls. The dirt-lot (DL) was 15.2 × 30.5 m with a 2-sided shed at one end which contained 3 feeding stalls (each 0.6 × 1.7 m) and a den area (2.9 × 1.9 m). The gilts were tested for 5 min 3 days after being bred and placed in their respective treatments, and weekly thereafter for 8 weeks. The field tests were conducted in a 3 × 12-m enclosure on pasture. Data collected included numbers of bouts and time spent chewing, grazing, snout employment (rooting, nudging and sniffing), vocalizations, standing, walking, trotting, running/bucking and distance traveled. Across all test days, the T and C gilts performed more bouts of standing and walking than did DL gilts. Crated gilts ran/bucked more than T gilts, who ran/bucked more than LS gilts, and LS gilts ran/bucked more than DL gilts. These findings suggest that an increased specific-action potential for specific innate motor patterns results from maintaining gilts in housing with minimal amounts of maneuvering and interaction room.

Dose range finding study for the efficacy of meloxicam administered prior to sodium urate-induced synovitis in cats.

OBJECTIVE To determine the lowest efficacious dose of oral meloxicam for relieving pain in cats with a sodium urate (SU)-induced acute inflammatory synovitis. STUDY DESIGN Randomized, blinded, controlled, and four-way crossover study. ANIMALS Eight surgically neutered cats (four males, four females) paired according to sex. METHODS Each pair of cats was treated with 0 (placebo), 0.025, 0.05, or 0.075 mg kg(-1) oral meloxicam once daily for 4 days prior to injection, into alternating stifles, of 1 mL of 20 mg mL(-1) SU crystals, beginning with the right stifle. Each cat received each of the four treatments, separated by at least 21 days. Analgesic efficacy was evaluated based on objective (e.g., pressure mat data total force, contact pressure, and contact area) and subjective (e.g., scores for Analgesia Scale [AS], Lameness Scale [LS], and Visual Analog Scale [VAS]) outcome measures for pain assessment. All outcome measures were recorded before and during 30 hours after SU injection. The pre-defined primary outcome measure was the area under the response-time curve (AUC(0-30) hours) of the total force of the injected limb. Data were analyzed by analysis of variance. A sequential test procedure was applied and the test sequence stopped in case of a nonsignificant result. RESULTS Meloxicam at doses of 0.05 and 0.075 mg kg(-1) day(-1) PO was significantly different from placebo for the pre-defined primary outcome measure (i.e., AUC(0-30) hours of total force). All tested meloxicam doses were lower than placebo for the subjective outcome measures (i.e., AUC(0-30) hours of AS, LS, and VAS). CONCLUSIONS AND CLINICAL RELEVANCE The lowest efficacious dose of meloxicam for relieving pain in cats with an SU-induced synovitis was 0.05 mg kg(-1) day(-1) PO according to the pre-defined primary outcome measure. However, lower doses may also be effective as seen in the subjective outcome measures.

Effect of housing on in situ postures of gestating gilts

Abstract Twelve cross-bred gilts were blocked by breeding dates and randomly assigned to one of four treatments, tethers (T), crates (C), loose stalls (LS) or dirtlot (DL), for each of three replications ( N = 36). Behavior was time-lapse video-recorded for 48-h observation periods commencing on Days 0, 7 and 63. Lying was the most frequent activity for all treatments over all observation periods (ranging from 65 to 90% of the observation periods). Gilts were up (includes standing and locomotion) for 10–33% of the observation periods, and spent 2% or less of the time sitting. Over all observation periods, the T and C gilts were up less, lay down more, lay for longer periods and changed their lying position more frequently. These findings may reflect the relative difficulty of getting up and lying down in these facilities. Time trends occurred from Day 0 to Day 65 which generally reflected fewer changes of position for all treatments. This reduction in position changes may be indicative of adjustment to their respective housing treatments and/or advancing pregnancies.

Open-field test behavior of growing swine maintained on a concrete floor and a pasture

Abstract Open-field test behaviors of 5 barrows and 5 gilts from each of two housing treatments ( N = 20) were recorded for 5-min periods. The hogs had been housed in their respective systems (pasture or concrete floor) for 6 weeks and averaged 18 weeks old at the time of the experiment. The 38 × 198-m pasture (P) contained approximately 70% grass of grazeable length and housed 49 pigs. The 3.7 × 7.6-m concrete feeding floor (FF) was located in an open-front building and housed 34 pigs. The open-field tests were conducted in a 3 × 12-m enclosure on pasture. Data collected include time spent chewing, grazing, nudging, sniffing or rooting, number of vocalizations, and time spent lying, standing walking or trotting. FF pigs spent more time grazing and chewing than did P pigs. Standing time was also greater for FF pigs. Only P pigs lay down during the test period. These findings suggest an increased specific-action potential for grazing behaviors resulted from maintaining the hogs in an indoor housing facility.

A pilot study: sodium urate synovitis as an acute model of inflammatory response using objective and subjective criteria to evaluate arthritic pain in cats.

Sodium urate (SU) synovitis was evaluated as a model for feline arthritic pain using a placebo- and positive-controlled (meloxicam) randomized blinded controlled single crossover design. Monosodium urate crystals [20 mg (1 mL) rod-shaped] were injected into alternate stifles of trained anesthetized cats (n = 3) with a 28 day washout. During the first trial phase, two cats received meloxicam (0.1 mg/kg, PO), a nonsteroidal anti-inflammatory drug (NSAID), for three days before and on the day of SU injection; the third cat received placebo. Treatments and stifles were switched for the second trial. Total force, contact pressure and area of the fore and hind limbs were measured using a pressure mat one day and 0.5 h before, and 2, 4, 6, 8, 10, 24, and 30 h post-SU injection. Skin temperature, joint circumference, analgesia, lameness, and visual analogue scale (VAS) pain scores, were measured at the same times. Comparisons were made for each time and for areas under the curve (AUC) using original and change from baseline; P < 0.05 was significant. Significant differences in force mat data and subjective data were found for the hind limb data (total force and total contact pressure at 6, 10, and 30 h; analgesia and VAS for pain at 4 h; lameness at 10, 24, and 30 h) and for AUC(0)-->(24h) and AUC(0)-->(30 h) (total force, total contact pressure, and mean lameness score) and for differences from BL AUC(0)-->(10h) (total contact area) and AUC(0)-->(24h) (total contact area and mean lameness score) and AUC(0)-->(30 h) (total force, total contact area, and mean lameness). No cats required rescue analgesia. Injection of 1 mL of monosodium urate into the stifle of a cat causes moderate transitory pain and was suitable for assessing analgesic efficacy of an NSAID with a pressure mat and subjective criteria.

Acute ethanol dependence or long-term ethanol treatment and abstinence do not reduce hippocampal responses to carbachol.

In the hippocampus of human alcoholics, prolonged ethanol treatment reduces the number of muscarinic ligand binding sites present at autopsy suggesting a decrease in functional muscarinic receptors. Whether these changes are due to alcohol-induced brain damage or ethanol dependence and represent a reduced level of cholinergic function is unknown. The present studies tested the impact of ethanol dependence or long-term ethanol treatment and subsequent withdrawal on the function of pre- and postsynaptic muscarinic receptors in the CA1 region of the rat hippocampus. Field excitatory postsynaptic potentials (EPSPs) were inhibited in a concentration-dependent manner by 0.1-100 microM carbachol. This presynaptic inhibitory action of carbachol involving muscarinic receptors was not significantly reduced either by ethanol treatment (12 days), causing physical dependence, or by long-term ethanol treatment (97-120 days) and abstinence (3-6 months). Postspike after hyperpolarizations (AHPs) were inhibited in a concentration-dependent manner by carbachol (6-2000 nM). This postsynaptic excitatory action of muscarinic receptors also was not significantly reduced either by 12-day ethanol treatment or by long-term ethanol treatment. Taken together, these results suggest that neither pre- nor postsynaptic muscarinic receptor function measured electrophysiologically is reduced by either ethanol dependence or long-term ethanol consumption and abstinence in the rat as suggested by reduced muscarinic ligand binding in the hippocampus of human alcoholics.