Correct utilization and management of peripherally inserted central catheters and midline catheters in the alternate care setting.

Based on patient condition, intravenous therapies, caregiver support, and organizational policy, correct device selection plays an integral part in the overall care and management of the alternate care setting i.v. therapy patient. This paper will identify the various aspects of appropriate device selection for i.v. therapy prescriptions.

Ethanol and cocaine intake by rats selectively bred for oral opioid acceptance.

Lines which accept or reject the potent opioid etonitazene, and a randomly bred control line, were assessed for the specificity of selective breeding. Drug-naive subjects from generation 8 were offered a continuous choice between water and 10% ethanol for 20 days. There was no difference between the accepting and rejecting lines in preference for one fluid, or in amount of ethanol consumed. The same rats were then given a choice between water and increasing concentrations (0.08-0.64 mg/ml) of cocaine, 7 days at each concentration. There were no differences among the lines in preference for the drug, but the rejecting line drank more of the cocaine solution than the accepting line. Finally, these rats were subjected to the regimen used in choosing rats for selective breeding, 4 days of a water-etonitazene choice. In their preference for etonitazene the order of the lines was as expected: accepting > control > rejecting. In addition, the accepting line drank more of the etonitazene solution than the other two lines. These data suggest that selection has been rather specific and not for a generalized tendency to become intoxicated.

Selective breeding for oral opioid acceptance or rejection in rats.

Lines of rats were selectively bred to diverge bidirectionally from a randomly bred control line in the propensity to self-administer an opioid orally. These lines seek or avoid the high-potency opioid etonitazene in a situation in which it is presented continuously as a choice with water. Over seven generations, preferences were measured and selection pressure imposed to develop the accepting and rejecting lines. These animals represent the only contemporary selective breeding program for opioid preference or self-administration, and hold the promise of being a useful resource in the drug-abuse field.

Etonitazene: an opioid selective for the mu receptor types.

Specific radioligand binding protocols were utilized to compare the affinity of morphine and the high-potency opioid etonitazene at mu 1, mu 2, delta, kappa 1 and sigma receptors. Both etonitazene and morphine displayed a mu 1-selective binding profile; however, etonitazene had a 2500-fold higher affinity at this receptor type. The latter result is consistent with the relative potencies or morphine and etonitazene in various behavioral tests.

Augmentation of morphine-induced changes in brain monoamine metabolism after chronic naltrexone treatment.

To investigate the role of opioid mechanisms in the regulation of cerebral monoaminergic neurons, male Wistar rats were continuously infused with naltrexone via an Alzet osmotic minipump, or were sham-implanted, for 14 days. Twenty-four hours after removal of the pumps or sham implants, the rats were given s.c. morphine (3, 10 or 30 mg/kg) or saline and were sacrificed 2 hr postinjection. Eight brain regions were assayed for dopamine, 5-hydroxytryptamine, noradrenaline and their respective metabolites. Chronic naltrexone treatment per se caused only small changes in cerebral monoamines. Morphine elevated dose-dependently the cerebral concentrations of the acidic dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, as well as that of the 5-hydroxytryptamine metabolite, 5-hydroxyindoleacetic acid, and that of the noradrenaline metabolite, free 3-methoxy-4-hydroxyphenylethyleneglycol. In naltrexone-pretreated rats these elevations were significantly larger. Furthermore, in the naltrexone-pretreated rats 10 mg/kg of morphine significantly decreased the concentration of the dopamine metabolite 3-methoxytyramine both in the striatum and in the limbic forebrain, whereas in the control rats the 3-methoxytyramine content fell first after the 30-mg/kg dose and only in the striatum. Thus, both the stimulatory and the inhibitory effects of morphine on cerebral monoaminergic neurons seem to be potentiated by chronic naltrexone treatment. These data suggest that the activity of cerebral monoaminergic systems is to some degree regulated by an endogenous opioid input. When that input is chronically blocked, the basal metabolism of monoamines is not much altered but the systems' responsiveness to agonist challenge is increased.

Taste vs. CNS effects in voluntary oral opiate intake: studies with a novel device and technique.

An apparatus is described which negates the influence of rats' position preferences by presenting alternative solutions at the same location. The licks for both solutions were monitored over consecutive short intervals by lick detectors with computer capture of data. Rats given a choice between water and dilute solutions of the high-potency opiates etonitazene (1.0-5.0 micrograms/ml) or fentanyl (10-50 microgram/ml) either licked equally for the two solutions, or gradually developed a preference or aversion regarding the opiate over the course of several days. In contrast, preferential licking for solutions with a definite taste, saccharin or quinine, was established in hours. These data indicate that the taste per se of these opiates is not aversive to rats, and that preferences for or aversions to the opiates have some other base, presumably one or more actions on the central nervous system.

Changes in brain monoamine metabolism during withdrawal from chronic oral self-administration of morphine and in response to a morphine challenge in the withdrawn state.

Although p.o. self-administration of morphine is a reliable and convenient means of inducing physical dependence, its effects on brain monoamine metabolism have not been determined. Accordingly, in the present experiment young Wistar rats drank increasing concentrations (0.1-0.5 mg/ml) of morphine in water, or water alone, for 37 days. Half the rats in each group were challenged with morphine (10 mg/kg s.c.) when 27 to 29 hr withdrawn, and half with saline. Rats were sacrificed 2 hr postinjection. Seven brain regions were analyzed for noradrenaline (NA), dopamine (DA), or 5-hydroxytryptamine (5-HT), and their respective metabolites. In all cases in which a comparison could be made with prior work utilizing repeated injections to produce dependence, the p.o. regimen produced the same effects. Thus, the mode of administration does not seem to modify the response of monoaminergic neurons to chronic morphine. In withdrawal, NA turnover increased but DA and 5-HT turnovers decreased. Acute morphine accelerated the turnover of all three monoamines. The NA response was attenuated in some brain regions of withdrawn rats, indicating the development of tolerance to the turnover-enhancing effect of acute morphine in noradrenergic neurons. In contrast, the effect of acute morphine on cerebral 5-HT turnover was not altered, and its effect on cerebral DA turnover was enhanced in withdrawn rats. Our results suggest that there are fundamental differences among the three monoaminergic systems in their capacities for adapting to chronic morphine treatment.

Morphine dependence and protracted abstinence: regional alterations in CNS radioligand binding.

Rats (Fisher F-344) were given free access to a 10% sucrose solution containing 0.5 mg/ml morphine sulfate (controls received the sucrose vehicle only) as their sole source of fluid. Daily morphine intake averaged 119 +/- 21 mg/kg, an amount sufficient to induce physical dependence. After 18 days on this regimen, the control and dependent subjects were sacrificed. A protracted abstinence group was weaned from morphine by reducing its concentration in the vehicle by 20% over the next 5 days, followed by a 5-week drug-free period before sacrifice concurrent with the other groups. These subjects showed no signs of an abstinence syndrome. Binding assays for alpha-2 adrenergic sites (3H-clonidine), beta-1/beta-2 adrenergic sites (3H-dihydroalprenolol), and dopaminergic (D2)/serotonergic (5-HT2) sites (3H-spiroperidol) were performed on tissue from frontal cortex, hippocampus, striatum, and brainstem. No alterations in 3H-clonidine or 3H-dihydroalprenolol binding were observed in dependence or protracted abstinence, suggesting that noradrenergic systems are well-regulated both during dependence and in protracted abstinence. 3H-spiroperidol binding was significantly elevated in the striatum (D2 sites) and hippocampus (5-HT2 sites) during dependence. Hippocampal 3H-spiroperidol binding returned to control levels in protracted abstinence, reflecting a morphine-induced change in 5-HT2 binding sites which had normalized by 5 weeks post-drug. Striatal 3H-spiroperidol binding was significantly decreased below control levels after withdrawal, suggesting that alterations of D2 sites in this structure may play a role in protracted abstinence.

Comparison of regional CNS ligand binding in two inbred rat strains: effects of chronic morphine.

Male rats of the F-344 and BUF inbred strains were given free access to a 10% sucrose solution containing 0.5 mg/ml morphine sulfate (controls received sucrose only) as their sole source of fluids. The daily intake of morphine averaged 101 +/- 13 mg/kg. After 18 days on this regimen, animals were sacrificed and assayed for 3H-clonidine (alpha-2 adrenergic), 3H-dihydroalprenolol (DHA, beta 1 and 2 adrenergic) and 3H-spiperone (SPD, 5-HT2 and D2) binding in several brain regions. In the absence of morphine treatment, BUF rats displayed higher levels of SPD binding in brainstem, as compared with the F-344 strain. In contrast, untreated F-344 rats exhibited higher levels of DHA binding in hypothalamus and SPD binding in striatum than BUF rats. Chronic morphine resulted in an increase in clonidine and DHA binding in the brainstem and hippocampus respectively of BUF, but not F-344 rats, suggesting a greater sensitivity of adrenergic function to opiate treatment in the BUF strain. The two strains differed qualitatively in the effect of morphine on striatal SPD binding, with BUF rats exhibiting a decrease, and F-344 rats an increase. The one consistent change observed in both strains was a quantitatively similar increase in hippocampal SPD binding after chronic morphine. The results demonstrate that despite strain-dependent differences in binding characteristics, chronic morphine elicits a strain-independent alteration in hippocampal 5-HT2 binding. On the basis of these preliminary findings, it may be speculated that this particular neurochemical consequence contributes to morphine-induced behaviors which are observed independent of rat strain.

Rapid determination of dopamine uptake in synaptosomal preparations.

A rapid method for assay of dopamine uptake in synaptosomal preparations involving reisolation of radiolabeled synaptosomes by rapid centrifugation is described. Utilizing this technique it was found that dopaminergic synaptosomes are relatively short lived, thus emphasizing the importance of rapid assay following tissue preparation. The effects of d-amphetamine, nomifensine and amfonelic acid were tested using the new procedure. The results of these experiments show a relative potency of uptake inhibition by these compounds which is comparable to previously published data.

Interaction of opiates with dopamine receptors: receptor binding and behavioral assays.

We examined the hypothesis that opiates act as dopamine (DA) receptor-blocking agents thereby inducing a compensatory increase in DA receptor density during chronic administration, and that increased receptor density could account for the behavioral hypersensitivity to DA agonists seen after treatment with opiates. Morphine and methadone did not inhibit the specific binding of 3H-spiroperidol to DA receptors in vitro, nor did they decrease affinity or apparent receptor density in the striatum when administered acutely in vivo in behaviorally effective doses. In contrast, neuroleptics had the expected inhibitory effect in both these experiments. Stereotypy and locomotion in response to apomorphine were measured before and after a 3-week treatment with saline or methadone. About half the methadone-treated rats showed significant increases over predrug baselines in stereotypy or locomotion, as did a few saline-treated animals. However, in those animals showing enhanced stereotypy or locomotion, DA receptor density was not elevated in striatum or mesolimbic areas respectively. These results indicate that opiates do not act as antagonists at DA receptor sites, and that changes in DA receptor density cannot account for opiate-induced behavioral hypersensitivity.

Pentobarbital induces a naloxone-reversible decrease in mesolimbic self-stimulation threshold.

The effects of sodium pentobarbital and naloxone were tested on intracranial self-stimulation (ICSS) in rats implanted with electrodes in the ventral tegmental area. Threshold for ICSS was determined using a rate-independent current titration paradigm. A low dose of pentobarbital (5 mg/kg) did not have a significant effect on ICSS thresholds, while a high dose (20 mg/kg) rendered the subjects too ataxic to respond reliably in the operant task. An intermediate dose (10 mg/kg) induced a highly significant lowering of threshold (17% below saline baseline levels) without apparent deterioration in response capability. The concurrent administration of naloxone (2 mg/kg) significantly reversed the pentobarbital-induced threshold decrease, while naloxone treatment alone had no effect on the ICSS threshold.

Time course of dopaminergic hypersensitivity following chronic narcotic treatment.

Guinea pigs were injected SC for 3 weeks with 3 different dosage schedules of morphine or methadone, or with saline. For 8 weeks thereafter they were challenged weekly with the dopamine agonist apomorphine. Hypersensitivity was manifested in more intense stereotypies, as compared to the saline group, by all morphine and methadone groups. Hypersensitivity persisted longer after the termination of methadone treatment (maximum of 8 weeks) than after morphine administration (maximum of 3 weeks). The degree of hypersensitivity, and its duration after treatment, was positively related to methadone dosage. In some groups a period of hyposensitivity was seen following hypersensitivity. These data are interpreted with reference to the hypothesized mechanism underlying the development of hypersensitivity, the different durations of action of morphine and methadone, and the retention of methadone in brain following treatment.

Behavioral supersensitivity to apomorphine following chronic narcotic treatment in the guinea pig.

Male albino guinea pigs were treated for 3 weeks with methadone, morphine, haloperidol, or saline. One week and 5 weeks following termination of treatment they were challenged with the directly acting dopaminergic agonist apomorphine. At the week 1 test the haloperidol and saline groups did not differ, but behavioral supersensitivity was apparent in significantly elevated mean stereotypy scores of the methadone and morphine groups relative to the saline group. The source of differences in mean scores was a higher peak score rather than increased duration of action. At the week 5 test the scores of the methadone group were even higher, the morphine group's scores were equivalent to the saline group's, and the haloperidol group's scores were significant depressed. This study indicates that a 3-week treatment period with methadone or morphine is sufficient to induce dopaminergic supersensitivity and suggests that there may be different time courses for the retention or expression of supersensitivity following these narcotics.

Sensitivity to apomorphine in the guinea pig as a function of age and body weight.

Male albino guinea pigs aged 4--10 weeks were challenged with 0.1, 0.2, and 0.4 mg/kg apomorphine. Mean stereotypy scores rose signfiicantly as a function of age. Stereotypy scores were better correlated with age than with body weight, suggesting that CNS maturation, rather than weight-related factors, were responsible. Although age and body weight were correlated, there was enough variability to make bvody weight an unreliable indicator of age.