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Biomedical subjects

B Hoskins

Publications and source records attributed to B Hoskins.

At least 55 records · Page 3Linked to original sources
PubMed1990

Evidence for involvement of cyclic GMP phosphodiesterase in morphine tolerance.

Preliminary evidence had suggested that changes in cyclic GMP (cGMP) hydrolysis via cyclic nucleotide phosphodiesterase(s) occurred during development of tolerance to morphine. To examine this finding further and its possible role in development of tolerance to morphine, rats (150-175 g) were injected with 1 ml of a sustained-release morphine preparation (40 mg/ml). Control rats received 1 ml of the oily vehicle. Antinociception, decreased locomotor activity, respiratory depression and mydriasis were measured at various times from 0.5 through 96 hr of exposure to the drug. Particulate and soluble cGMP hydrolysis were measured for the same time periods from periaqueductal gray (PAG), striatum, medulla and oculomotor nucleus, the brain areas believed to mediate the respective behaviors. Each of the behaviors except mydriasis showed development of complete tolerance (no difference from control behaviors) during the 96 hr of continuous exposure. During development of tolerance, particulate cGMP hydrolysis decreased in PAG and increased in striatum and medulla. Particulate cGMP hydrolysis was not altered in oculomotor nucleus, the brain area mediating mydriasis to which tolerance development was partial or incomplete. Significant changes in soluble cGMP hydrolysis occurred only in PAG before decline in the behavioral effect and did not appear to be involved in tolerance phenomena. Modulation of cyclic nucleotide levels by changes in particulate cGMP hydrolysis may produce or allow for development of complete tolerance to various morphine-induced behaviors.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1989

Comparative studies of muscarinic and dopamine receptors in three strains of rat.

Cholinesterase activities and characteristics of muscarinic and dopamine receptors from 9 week old male Sprague-Dawley (SD), Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) were studied. Plasma cholinesterase activity in WKY was significantly lower (50%) than activity in the other strains. In studies of muscarinic receptors, the number of [3H]QNB binding sites in striata from SD rats was lower (18%) than those from WKY and SHR. However, muscarinic receptor properties (Kd and Bmax) were the same in hypothalami. Studies of dopamine receptors revealed that the densities of both D-1 and D-2 receptors in both striata and hypothalami were significantly higher in SHR than in other strains. However, there were no differences in the affinity constant (Kd). The higher densities in hypothalami from SHR were mainly due to the high population of D-1 and D-2 receptors in the posterior hypothalamus. In the anterior hypothalamus, there was no difference in the population of D-2 receptors. These results provide a substantive basis, i.e. demonstration of alterations in drug metabolizing enzymes and receptor populations, on which to build an understanding of the genetic predisposition to the actions of xenobiotic agents.

Acetylcholinesterase↗
PubMed1989

Differential sensitivity to cocaine in spontaneously hypertensive and Wistar-Kyoto rats.

Physiological, pharmacological and toxicological responses to two regimens of cocaine administration were compared between spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. An initial experiment examined renal excretory and hemodynamic function in response to an acute volume load in anesthetized SHR and WKY following subacute cocaine treatment (20 mg/kg, s.c., twice a day for 9 days). Anticipated renal responses to volume loading were obtained but the responses of cocaine-treated SHR and WKY did not differ from vehicle-treated rats. A second group of experiments compared responses to continuous i.v. infusions of cocaine (1.25 mg/kg.min). In freely moving animals, no differences were noted between SHR and WKY in the increases in mean blood pressure (MBP) and heart rate (HR) produced during cocaine infusion. The elapsed time-to-onset of convulsions (Tc) elicited by cocaine was similar in both strains. However, when rats were subjected to restraint during the infusion period, pressor and tachycardic responses were observed to be significantly less in WKY than in SHR or in freely moving rats of either strain. Restraint also differentially affected rectal temperature (RT) responses to cocaine. Hypothermic responses to cocaine were observed in all WKY. Both hypothermic and hyperthermic responses were observed in SHR. A significant correlation was demonstrated between the Tc and the maximal change in RT produced during cocaine infusion. Division of SHR into two arbitrary groups was made, based on the direction of cocaine-induced change in RT. A significant (p less than 0.01) shortening of the Tc was obvious in SHR (8 of 15) in whom cocaine produced a hyperthermia. These animals were designated SHRH. The mean value for Tc in those SHR which demonstrated a lowering in RT (SHRL; 7 of 15) in response to cocaine was similar to that for WKY. Moreover, the SHRH evidenced significantly greater increases in HR, but not MBP, to cocaine infusion than did SHRL. The results indicate that restraint stress causes expression of a significant heterogeneity in the RT response of SHR to cocaine. The magnitude and direction of the RT responses are negatively correlated with sensitivity to the convulsive effects of cocaine in SHR. Stress may modify toxic responses to cocaine by interactions with body temperature homeostasis.

Animals↗
PubMed1989

Effects of diisopropylfluorophosphate on brain acetylcholinesterase, butyrylcholinesterase, and neurotoxic esterase in rats.

The inhibition and the recovery of brain AChE, BuChE, and NTE activities after acute and subacute administration of DFP were studied in the rat. DFP displayed different specificities in inhibiting these enzymes; inhibition was greatest for BuChE followed by AChE and NTE. Recovery was most rapid for BuChE followed by NTE and AChE. The recovery rates of AChE and BuChE following acute and subacute treatment were similar. However, the recovery rate of NTE in subacutely treated rats was significantly faster than that in acutely treated rats. The results suggest that DFP inhibits these three enzymes and the rates of regeneration of these enzymes are significantly different.

Acetylcholinesterase↗
PubMed1989

Changes in drinking activity, urine volume and urinary electrolyte excretion after intracerebroventricular administration of diisopropylfluorophosphate.

The effects of i.c.v. administration of diisopropylfluorophosphate on drinking activity, urine volume and urinary electrolyte excretion were examined in the conscious, unrestrained rat. An i.c.v. dose of 5 micrograms of diisopropylfluorophosphate was found to inhibit acetylcholinesterase activity in five nuclei in the anterior, dorsal portion of the hypothalamus. This dose of diisopropylfluorophosphate also resulted in a dipsogenic episode, a diuresis and a biphasic effect on urinary sodium and potassium excretion. Each response was independent of the other two responses. The responses were mediated by muscarinic cholinergic receptors other than nicotinic receptors as they were blocked by both atropine and pirenzepine but not mecamylamine. The results suggest that the muscarinic receptors responsible are probably of muscarinic receptor M1 class.

Animals↗
PubMed1988

Cocaine-induced changes in 3H-naloxone binding in brain membranes isolated from spontaneously hypertensive and Wistar-Kyoto rats.

Effects of sub-acute cocaine treatment on 3H-naloxone binding to 6 brain regions were examined in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Cocaine hydrochloride (3 mg/kg, i.v.) was given by bolus injection daily for five days. Rats were decapitated 24 hr following the final injection and crude membrane fractions prepared from the cortex (CT), hippocampus (HI), striatum (ST), hypothalamus (HY), midbrain (MB) and medulla/pons (MD). Binding of 3H-naloxone was consistent with a single site model in CT, HI, HY, MB and MD from vehicle-treated SHR and WKY. Cocaine treatment of SHR significantly decreased the maximal binding capacity (Bmax) of 3H-naloxone in the HI, ST and HY and the binding affinity was increased in HI. In contrast, a significant increase in Bmax was noted in CT and HI membranes isolated from cocaine-treated WKY. The binding affinity of 3H-naloxone to MB membranes of WKY was significantly decreased by cocaine treatment. The binding characteristics of 3H-naloxone in MD membranes were not different following cocaine treatment or between strains. Scatchard analysis indicated biphasic binding of 3H-naloxone binding to ST membranes from both SHR and WKY. Our results indicate that cocaine produces complex and differential changes in opiate receptors and, presumably, opioid peptide neuronal function in SHR and WKY.

Animals↗
PubMed1988

Effects of subacute treatment with cocaine on activities of N-demethylase, UDP-glucuronyltransferase and sulfotransferase in WKY and SHR rat liver--sex and strain differences.

The effects of subacute treatment with cocaine on activities of cocaine N-demethylase, UDP-glucuronyltransferase (GT) toward 4-nitrophenol and phenolphthalein and sulfotransferase (ST) toward androsterone and 4-nitrophenol in livers from Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were investigated. Hepatic metabolism of cocaine was different between the sexes (with males having higher N-demethylase activity) and the strains (with WKY rats having higher activity). The effects of subacute cocaine administration on the activity of cocaine N-demethylase were also sex- and strain-related. Whereas cocaine administration increased activity of hepatic N-demethylase in both female strains, it decreased activity in male WKY and had no effect on activity in male SHR. Sex and strain-related as well as cocaine-induced differences were also found in activities of hepatic GT toward 4-nitrophenol and phenolphthalein as well as in activity of hepatic ST towards andersterone and 4-nitrophenol. These results suggest that some of the individual variation in the effects of cocaine may be due to sex and genetic differences in the hepatic metabolism of cocaine and/or in sexually and/or/genetically-determined differences in how cocaine affects hepatic metabolism of other xenobiotics.

Animals↗
PubMed1988

Toxicity study of continuous administration of physostigmine salicylate.

The present study demonstrates that continuous administration with physostigmine salicylate (0.12 or 0.24 mg/kg/hr via mini-osmotic pumps) induces toxicities (e.g., body weight loss, decreased water consumption, tremors, decreased body temperatures, mortality) in guinea pigs. Both blood and brain cholinesterase activity is inhibited dose-dependently by physostigmine salicylate. The signs of toxicity in the guinea pigs which received the low dose appeared within 2 or 3 days and then the animals recovered, while toxic signs in the guinea pigs treated with the high dose of the drug persisted throughout the experiments. The study further shows that continuous administration of physostigmine salicylate also caused down-regulation of muscarinic receptors in the striata of the guinea pigs.

Acetylcholinesterase↗
PubMed1988

Prevention of soman toxicity after the continuous administration of physostigmine.

Protective effects of continuous administration of physostigmine alone, or in addition to scopolamine, against soman-induced toxicity were studied in guinea pigs. The results clearly demonstrated that treatment with physostigmine continuously via implanted mini-osmotic pumps for 4 or 7 days prior to soman exposure significantly protected from soman-induced mortality. In vehicle-infused guinea pigs, tremors, convulsions and loss of righting reflex occurred prior to their deaths induced by soman. Although all of the guinea pigs which received physostigmine pretreatment for 4 days prior to soman administration also displayed soman-induced tremors and convulsions, the onsets of these symptoms were significantly delayed. When animals continuously treated with physostigmine received injections of scopolamine 10 min prior to soman injections, there was a decreased incidence of all three toxicity symptoms as well as an increase in the latency to onset of tremors. Scopolamine was also able to reverse toxicity symptoms when soman was administered earlier. In animals which had been continuously treated with physostigmine via mini-osmotic pumps, the protective action against soman-induced toxicity was still apparent. On the contrary, acute physostigmine administration failed to protect against soman lethality. The present results suggest that the prophylactic uses of physostigmine via mini-osmotic pumps might be more useful than the acute bolus administration of physostigmine.

Acetylcholinesterase↗
PubMed1988

Effects of acute and subacute administration of bicuculline on dopamine and muscarinic receptors in rat brain.

The changes of characteristics of dopamine (D1 and D2) and muscarinic receptors after acute and subacute administration of bicuculline were examined in rat brain. The results demonstrated that in striatal region, the Bmax of D2 receptor was significantly increased with no change of affinity after subacute administration of bicuculline. However, neither Bmax nor Kd or the D2 receptor was changed after single administration. The characteristics of D1 receptor were not changed by either acute or subacute administration. The Bmax of muscarinic receptor in striatal area was significantly increased without changes of affinity after both a single and repeated administration of bicuculline. However, in hippocampus, the Bmax of muscarinic receptor was significantly decreased after subacute administration of bicuculline. The results suggest that the interactions among GABAergic, dopaminergic and cholinergic neuron exist in central nerve system.

Animals↗
PubMed1988

Cerebellar GABAA and benzodiazepine receptor characteristics in young and aged mice.

Age-related differences in GABAA and benzodiazepine receptors were investigated in cerebella of young (1-month-old), mature adult (3 months old), older (8 months old) and aged (20 months old) mice. In cerebellar membranes of aged mice, [3H]muscimol binding was significantly higher as compared to those from all three younger age groups. Binding was the same in these younger age groups. Scatchard analysis of binding isotherms in cerebellum of young and aged mice showed the presence of two components (with different affinities and binding capacities). In aged mice, a significantly lower KD of low affinity sites and a significantly higher Bmax of high affinity sites were noted as compared to those in young mice. However, [3H]flunitrazepam binding to benzodiazepine receptors in cerebellar membranes was the same in both age groups. These results suggested that GABAA receptor binding was increased during senescence in cerebella without altering benzodiazepine binding.

Aging↗
PubMed1988

Bicuculline up-regulation of GABAA receptors in rat brain.

Effects of acute and subacute administration of bicuculline on [3H]muscimol, [3H]flunitrazepam, and t-[35S]butylbicyclophosphorothionate ([35S]TBPS) binding to various brain regions were studied in Sprague-Dawley rats. Acute administration of bicuculline affected neither the KD nor the Bmax of the three receptor sites. In rats treated subacutely with bicuculline (2 mg/kg, i.p., daily for 10 days), [3H]muscimol binding was increased in the frontal cortex, cerebellum, striatum, and substantia nigra. Scatchard analysis revealed that subacute treatment of rats with bicuculline resulted in a significantly lower KD of high-affinity sites in the striatum and in a significantly lower KD of high- and low-affinity sites in the frontal cortex. In the cerebellum, two binding sites were apparent in controls and acutely treated animals; however, only the high-affinity site was defined in subacutely treated animals, with an increase in the Bmax value. Triton X-100 treatment of frontal cortical membranes eliminated the difference in [3H]muscimol binding between control and subacute bicuculline treatments. On the other hand, [3H]muscimol binding was significantly increased in the cerebellum from bicuculline-treated animals even after Triton X-100 treatment. The apparent Ki of bicuculline for the GABAA receptor was also decreased in the frontal cortex and the striatum following the treatment. However, subacute administration of bicuculline affected neither the KD nor the Bmax of [3H]flunitrazepam and [35S]TBPS binding in the frontal cortex and the cerebellum. These results suggest that GABAA receptors are up-regulated after subacute administration of bicuculline, with no change in benzodiazepine and picrotoxin binding sites.

Animals↗
PubMed1988

Evidence that alterations in gamma-aminobutyric acid and acetylcholine in rat striata and cerebella are not related to soman-induced convulsions.

Many reports have suggested that gamma-aminobutyric acid (GABA) may play a role in organophosphate-induced convulsions. The balance between GABA and acetylcholine (ACh) in the brain also has been suggested by some investigators to be related to brain excitability. We examined these questions by studying the levels of GABA and ACh and the ratios of GABA to ACh in rat striata and cerebella (two major motor control areas in the CNS) after the administration of soman, an organophosphate acetylcholinesterase inhibitor also known as nerve gas. Male Sprague-Dawley rats weighing 250-300 g were injected subcutaneously with three different doses of soman: a subconvulsive dose of 40 micrograms/kg (approximately 30% of the ED50 for convulsions in rats), a convulsive dose of 120 micrograms/kg (approximately one ED50 for convulsions), and a higher convulsive dose of 150 micrograms/kg (approximately 120% of the ED50 for convulsions). The incidence and severity of convulsions were monitored in individual rats until they were sacrificed by focused microwave irradiation of the head at the following time points after soman administration: 4 min, a time prior to the onset of convulsions; 10 min, the time of onset of convulsions; 1 h, the time of peak convulsive activity; and 6 h, a time at which rats were recovering from convulsions. Results showed that in rat striata and cerebella, neither changes in levels of GABA and ACh nor changes in ratios of GABA to ACh were related to soman-induced convulsions, i.e., none of the changes in either levels or ratios of these two neurotransmitters were related to the initiation of, maintenance of, or recovery from soman-induced convulsions.

Acetylcholine↗
PubMed1988

Evidence that changes in levels of cyclic nucleotides in the CNS are not related to soman-induced convulsions.

Others have suggested that organophosphate-induced convulsions are related to changes in levels of cyclic nucleotides, especially in cerebella. We have examined this question by subcutaneously injecting male Sprague-Dawley rats (approx 250-300 gm) with three different doses of soman: a subconvulsive dose of 40 micrograms/kg, a convulsive dose of 120 micrograms/kg (which is approx 90% of the ED50 for convulsions) and a higher convulsive dose of 150 micrograms/kg. The incidence and severity of convulsions were monitored until the rats were sacrificed by focused microwave irradiation of the head at the following times after injections: 4 min, 10 min, 1 hr and 6 hr, which represent times prior to onset of convulsions, at onset of convulsions, at peak convulsive activity and during recovery from convulsions, respectively. Results showed that in rat striata, cerebella and thoracic spinal cord, neither changes in levels of cyclic AMP and cyclic GMP nor changes in ratios of cyclic AMP to cyclic GMP were correlated with soman-induced convulsions, i.e., none of the changes in cyclic AMP and cyclic GMP and/or in the ratios of cyclic AMP to cyclic GMP were related to the initiation of, maintenance of, or recovery from soman-induced convulsions.

Animals↗
PubMed1987

Evidence for the involvement of presynaptic cholinergic functions in tolerance to diisopropylfluorophosphate.

Rats were treated with diisopropylfluorophosphate (DFP) acutely or daily for 14 days. The involvement of various presynaptic and postsynaptic functions of the cholinergic system in the development of tolerance to DFP was studied. Receptor density and affinity of both muscarinic and nicotinic receptors, high-affinity choline uptake, and [K+]-evoked release of acetylcholine (ACh) by atropine were not changed after acute administration of 2 mg/kg DFP. Both muscarinic and nicotinic receptors were down-regulated to the same extent (40-50%) after subacute administration of DFP (1 mg/kg) without changes in their affinities. Binding sites of muscarinic receptors were maximally decreased after 7 days of DFP administration. Thereafter, they remained constant throughout 14 days of administration. One hour after the last injection of 2 mg/kg DFP to subacutely treated rats, the maximum velocity of high-affinity choline uptake was significantly decreased in the striatum (33%) and hippocampus (53%) without changes in Km values. Twenty-four hours after the last injection of DFP, only a higher dose of DFP (2 mg/kg) significantly inhibited choline uptake. Potassium-evoked release of ACh by slices of striatum was not different between acutely and subacutely treated rats. However, the release of ACh by slices of striatum and hippocampus was significantly increased by atropine in subacutely treated rats. It is suggested that along with the down-regulation of the postsynaptic receptors, subsensitivity of presynaptic functions of the cholinergic synapse also develops during subacute administration of DFP.

Acetylcholine↗
PubMed1987

Changes in ACh levels in the rat brain during subacute administration of diisopropylfluorophosphate.

Rats were treated with diisopropylfluorophosphate (DFP) acutely and daily for 14 days. The total, free, and bound acetylcholine (ACh) levels were monitored in striatum, hippocampus, and frontal cortex after DFP administration. Thirty minutes after daily administration of DFP, the total and free ACh levels were significantly increased and remained constant after each successive dose. The bound ACh levels in striatum and frontal cortex were also significantly increased; however, they were comparable to control levels after the 14th injection of DFP. The total ACh levels 30 min after a challenge dose of 2 mg/kg DFP in saline and DFP subacutely treated rats were significantly increased in hippocampus (34 and 76%) and frontal cortex (49 and 64%) and were not significantly different between the two groups. However, the level of total ACh in striatum was increased less in the tolerant rats (10%) than in the acutely treated rats (36%). The levels of free and bound ACh after acute administration of 2 mg/kg DFP were markedly increased in three brain regions. After subacute administration, the levels of bound ACh were significantly increased in hippocampus (84%) and frontal cortex (40%); however, that in striatum did not change. The increase in the bound ACh level in the subacute treatment group was less than that in acutely treated rats in all three brain regions; however, the duration of the elevation of the free ACh in striatum was shorter in subacutely treated rats. These results suggest that the presynaptic cholinergic storage sites for ACh might be changed during subacute administration of DFP.

Acetylcholine↗
PubMed1987

Quantitative assessment of tolerance development to diisopropylfluorophosphate.

Rats were treated with diisopropylfluorophosphate (DFP) acutely or daily for 14 days. The quantitative assessment of tolerance development after a challenge dose of DFP, 2 mg/kg, was studied. The subacutely-treated rats developed tolerance to DFP-induced tremors. However, the severity of tremors in DFP-tolerant animals was not significantly different from that of the controls after the challenge dose of DFP was administered. Hind-limb abduction was significantly lower in the subacutely-treated group than in the acutely-treated group. The recovery of body weights in subacutely-treated rats (3.5%/day) was significantly higher than that in acutely-treated rats (2.0%/day). The consummatory behaviors (food and water consumption) recovered faster in subacutely-treated rats than in the acutely-treated group. Body temperatures were decreased to the same extent in both groups, but the subacutely-treated group recovered faster. The total mortality was significantly lower in subacutely-treated rats (10%) than in acutely-treated rats (35%). The results further substantiate the finding that tolerance develops to various DFP-induced signs of toxicity.

Animals↗