The Effect of Parenterally Administered Cyclodextrins on Cholesterol Levels in the Rat

The inclusion complex formation of intravenously administered hydroxypropyl--cyclodextrin and -cyclodextrin with endogenous lipids was studied. We tested the hypothesis that complex formation of endogenous cholesterol with cyclodextrins in the bloodstream leads to extraction of cholesterol from the large lipoprotein particles. The relatively small cholesterol–cyclodextrin complexes then leave the bloodstream via capillary pores, and dissociation of the complex in the extravascular compartment finally causes redistribution of cholesterol from blood to tissue. This hypothesis is supported by the following experimental findings. Intravenous administration of cyclodextrins led to a transient decrease in plasma cholesterol levels in a dose-dependent manner, and in vitro cholesterol-cyclodextrin complexes passed dialysis membranes with a molecular weight cutoff of 6000–8000. Further, cyclodextrins increased protein binding of the steroidal drug spironolactone, probably through removal of cholesterol from plasma protein binding sites. Finally, extravascular redistribution was directly demonstrated in histological studies of the kidneys. Glomerular filtration of the cholesterol–cyclodextrin complex is followed by dissociation of the complex in the ultrafiltrate, resulting in cholesterol accumulation in the proximal tubule cells. The cholesterol--cyclodextrin complex has a limited aqueous solubility. Crystallization of this complex in renal tissue might explain the nephrotoxicity of parenterally administered -cyclodextrin. The absence of such crystallization might explain the lower nephrotoxicity of hydroxypropyl--cyclodextrin after intravenous administration.     

A STUDY OF THE EFFECTS OF STEROIDS ON α-ADRENOCEPTOR-MEDIATED CONTRACTION OF THE RAT VAS DEFERENS

1. Testosterone propionate (0·5 mg/day) administered for 5 weeks to prepubertal rats increased the weight of sex accessory organs but did not alter the rate of gain of body weight. Methandienone, given in a similar dosage regimen, was without effect on these parameters. The synthetic progestagen, norgestrel, administered orally in a dose of 0·5 mg/day increased the weight of the vas deferens but was without effect on seminal vesicle and testis weights and on the growth rate. Given in combination with testosterone, norgestrel caused a marked decrease in testis weight and reversed the effects of testosterone propionate on seminal vesicle weight. Thus, in the dosage regimen used, this progestagen exhibited an endocrine profile comprising androgenic, synandro-genic and anti-androgenic effects. 2. Rats, which were castrated when they weighed 70–80 g, exhibited rates of gain of body weight which were similar to those of control animals. Testosterone propionate in the doses used reversed castration-induced atrophy of the vas deferens and seminal vesicle. 3. The contractility of the vas deferens of intact rats, determined by direct field electrical stimulation, was unaffected by treatment with the steroids used in this study. However, there was a marked impairment of the contractility of the vas deferens following castration, which was not fully restored by testosterone propionate in the dosage regimen used. 4. The efficacies and potencies of the α-adrenoceptor agonists phenylephrine and 1-metaraminol in causing contraction of the vasa deferentia from intact rats were unaffected by the steroid treatments. In contrast, these agonists did not produce sustained, dose-dependent contractions of the vasa deferentia from castrated rats; however testosterone propionate fully restored the efficacy and potency of both agonists. 5. It is concluded from this study that although adequate testosterone levels are necessary for the maintenance of contractility in the rat vas deferens, the integrity of postjunctional adrenoceptors in not modified by a variety of steroid treatments.     

Tolerance development to a disruptive effect of β-phenylethylamine (PEA) on a learned behavior in rats

Several doses (8–64 mg/kg) of -phenylethylamine (PEA), a naturally-occurring sympathomimetic amine structurally related to amphetamine and with similar effects on animal behavior, were administered (IP, daily for ten days) to Fisher 344 rats that were trained to perform a shuttlebox conditioned avoidance response (CAR) at a high, stable rate. PEA 8 mg/kg did not influence avoidance responding after single or multiple injections. Acute administration of PEA 16 mg/kg produced dose-dependent disruptions of the CAR. With repeated administration, complete tolerance to CAR disruption was acquired by the third injection of PEA 16 mg/kg or by the fifth injection of PEA 32 mg/kg and maintained with both doses through ten injections; the use of appropriate controls indicated that tolerance was pharmacological and not behavioral. Over the course of ten injections, tolerance did not develop to shuttlebox disruption caused by 64 mg/kg, and this dose of PEA did not elicit tolerance to stereotyped behavior after 21 injections. These data were interpreted as showing differential tolerance to low vs. high dose effects of PEA: Lower doses produce tolerance to disruption of the CAR, but the highest dose did not because of the presence of incompatible response tendencies (e.g., stereotypy) interfering with the CAR. Our data showing development of tolerance to lower doses of PEA is the first demonstration in the literature that tolerance can develop to a behavioral effect of this compound.     

Effects of a histamine synthesis inhibitor and antihistamines on the sexual behavior of female rats

Intraventricular administration of -hydrazinohistidine, a histamine synthesis inhibitor, at different doses and times before testing produced a significant decrease of lordotic responses and sexual receptivity in ovariectomized estrogen plus progesterone-primed female rats. The H₁-antihistamines pyrilamine and chlorfeniramine and the H₂-antihistamine metiamide, injected in the lateral ventricle, significantly decreased the lordosis quotient but did not modify receptivity; antihistamine-injected rats showed no soliciting behavior. Exploratory activity was decreased by both -hydrazinohistidine and metiamide but not by the H₁-antihistamines. It is concluded that treatments which either deplete histamine or block their receptors can alter female copulatory responsiveness. The mechanism of this antihistamine effect appears to be unrelated to that of other side effects, such as motor impairment, sedation, or local anesthesia.     

Effect of Testosterone Suppression on the Pharmacokinetics of a Potent GnRH Receptor Antagonist

Purpose. The expression of cytochrome P450 enzymes (CYPs) in animals and humans is under complex hormonal regulation. Chronic treatment with drugs that alter sex hormone levels such as GnRH receptor agonists or antagonists may affect the expression of hormone-dependent CYPs, and as a result the pharmacokinetics of drugs metabolized by them. Methods. Enzyme kinetic parameters were obtained by incubating AG-045572 (0.1-30 M) with human or rat liver microsomes, or expressed CYP3A4 and CYP3A5. The pharmacokinetics of AG-045572 (10 mg/kg i.v. or 20 mg/kg p.o.) were studied in intact male, female, castrated male and male rats pretreated with AG-045572 for 4 days. Results. AG-045572 is metabolized by CYP3A in both rats and humans. The K_m values were similar in male and female human, female rat liver microsomes, and expressed CYP3A4 and CYP3A5 (0.39, 0.27, 0.28, 0.25, and 0.26 M, respectively). The K_m in male rat liver microsomes was 1.5 M, suggesting that in male and female rats AG-045572 is metabolized by different CYP3A isozymes. The oral bioavailability of AG-045572 in intact male rats was 8%, while in female or castrated male rats it was 24%. Pretreatment of intact male rats with AG-045572 i.m. for 4 days resulted in suppression of testosterone to castrate levels, accompanied by an increase in oral bioavailability of AG-045572 to 27%. In the same experiment, the male-specific pulsatile pattern of growth hormone remained unchanged with slightly elevated baseline levels. Conclusions. The potent GnRH receptor antagonist AG-045572 is metabolized by hormone-dependent CYP3A. As a result, suppression of testosterone by pretreatment with AG-045572 feminized its own pharmacokinetics.     

Radioimmunoassay of β-endorphin basal and stimulated levels in extracted rat plasma

Summary A sensitive radioimmunoassay for -endorphin is described. Antibodies against human -endorphin which exhibit a high avidity for the C-terminal of the peptide were raised in rabbits following the injection of thyroglobulin-coupled human -endorphin (h-E) as immunogen. Methionineenkephalin, - -endorphin, as well as ACTH peptides did not cause interference in the radioimmunoassay. -Lipotropin, however, showed a 50% cross-reactivity. The sensitivity of the assay is 25 pg/0.5 ml tube volume for -endorphin. -Endorphin was extracted with a high recovery from the rat plasma using silicic acid and -endorphin levels as low as 100 pg/ml could be measured.Basal levels of -endorphin-like immunoreactivity in plasma of rats were about 400 pg/ml. -Endorphin levels in adrenalectomized rats and in animals chronically treated with the cortisol synthesis blocker metyrapone were found to be markedly increased (about 7-fold). Exposure of the rats to electrically induced foot-shocks caused a similar increase of immunoreactive -endorphin in plasma. A significant increase was also seen after insulin injection.     

The Pharmacokinetics of β-Cyclodextrin and Hydroxypropyl-β-cyclodextrin in the Rat

Hydroxypropyl--cyclodextrin was analyzed by HPLC using postcolumn complexation with phenolphthalein and negative colorimetric detection, with a detection limit of 20 µg/ml. The pharmacokinetics of -cyclodextrin and of hydroxypropyl--cyclodextrin were studied after intravenous administration to permanently cannulated rats. The pharmacokinetic behavior of both cyclodextrins was similar to that of inulin, showing rapid distribution over extracellular fluids. Elimination occurred through glomerular filtration. When a dose of 200 mg/kg -cyclodextrin was administered the elimination rate was decreased, probably as a result of nephrotoxicity of -cyclodextrin. Within 24 hr after administration most of the cyclodextrin dose was recovered unchanged in urine. After oral administration, only insignificant amounts of intact -cyclodextrin were absorbed from the gastrointestinal tract.     

Effect of haloperidol on reflex activation of rat α-motoneurones

Summary Effects of haloperidol on rat flexor and extensor -motoneurones were studied in ventral roots of laminectomized rats under halothane anesthesia. The -motoneurones were activated by tetanic stimulation of low-threshold afferents (group I and II), either of the ipsilateral peroneal nerve (flexor -motoneurones) or gastrocnemius-soleus nerve (extensor -motoneurones).Haloperidol, given in the doses of 0.075, 0.15 and 0.30 mg/kg i.p. inhibited the reflex activation of flexor -motoneurones; higher doses seemed to be more effective than lower ones. Apomorphine (2 mg/kg s.c.) partially antagonized the inhibitory action of haloperidol with some latency. Higher doses of haloperidol (0.15–0.60 mg/kg i.p.) also inhibited the reflex activation of extensor -motoneurones; this inhibitory effect was, at least for a short time, antagonized by apomorphine (2 mg/kg s.c.).The threshold for reflex activation both of flexor and extensor -motoneurones was raised by haloperidol and lowered by a subsequent administration of apomorphine.Our results suggest that akinesia and catalepsy, induced in rats by haloperidol might be, at least in part, due to a decrease in sensitivity of -motoneurones to proprioceptive stimuli.     

Cardiostimulatory effects of cyclic 3′,5′-adenosine monophosphate and its acylated derivatives

Summary The effects of cyclic 3,5-AMP and of two acylated derivatives, dibutyryl (DBA) and dihexanoyl-3,5-AMP (DHA) were investigated in isolated perfused hearts of guinea pigs, rats and rabbits.In guinea pig hearts, DBA (Ca- and Na-salt) and DHA-Na in high doses (10 moles) produced strong and long lasting increases in the rate and amplitude of contractions, coronary flow, and moderate increases in phosphorylase activity in the majority of experiments. The positive ino- and chronotropic effects occured 3–5 min after injection of the drug, mostly in a fluctuating manner with several maxima. Theophylline augmented the effects of DBA-Na and revealed positive inotropic actions of non substituted 3,5-AMP.In rat hearts, similar, but more pronounced and dose-dependent effects were observed after 1, 5 and 10 moles DBA-Na. Propranolol (50 g) did not block the action of 10 moles DBA-Na. Non substituted 3,5-AMP, 5-AMP and ATP in doses of 10 moles had no significant positive inotropic effects.In rabbit hearts, DBA-Na (50 moles) produced moderate, non fluctuating rises in the amplitude of contraction.The results provide evidence that under certain conditions cyclic 3, 5-AMP itself, like its acylated derivatives DBA and DHA, may produce strong and direct positive inotropic and chronotropic effects in the heart. These findings support the view that cyclic 3,5-AMP is the cellular mediator of the cardiostimulant actions of substances that increase its rate of production in the myocardial cell.The excellent technical help of Mrs. Vera Bauer is gratefully acknowledged by the authors.     

Lack of involvement ofδ-opioid receptors in mediating the rewarding effects of cocaine

The non-selective opioid antagonist naltrexone and the partial agonist buprenorphine have been reported to reduce cocaine self-administration (SA) and relapse in both humans and rhesus monkeys. Data suggesting an involvement of-opioid receptors in modulating the conditioned rewarding effects of cocaine were also recently presented. In view of such findings, the present SA and place conditioning studies were conducted to examine the influence of the selective-opioid receptor antagonist naltrindole upon the rewarding effects of cocaine. Sprague-Dawley rats were trained to self-administer cocaine (1.0 mg/kg per infusion) on an FR2 schedule of reinforcement. Dose-response and antagonist testing commenced once stable rates of cocaine SA were achieved. For antagonist testing, rats received naltrindole (0.03–10.0 mg/kg, IP) 30 min prior to the start of 2-h SA sessions. SA behavior in response to cocaine delivery (0.25 and 1.0 mg/kg per infusion) was then determined. Naltrindole in doses of 0.03–3.0 mg/kg did not alter the number of cocaine infusions taken by the rats. A higher dose of naltrindole (10.0 mg/kg), which markedly depressed locomotor activity, resulted in a 16% reduction of cocaine (0.25 mg/kg per infusion) SA behavior. When SA sessions were terminated and naltrindole (1.0 mg/kg) was administered repeatedly for 3 days, no alterations in the re-acquisition of cocaine SA were seen. Place conditioning studies also failed to find an effect of naltrindole (0.1–3.0 mg/kg) on cocaine (10 mg/kg) — induced conditioned place preferences. Naltrindole, by itself, did not induce significant place conditioning. These data fail to indicate a role of-opioid receptors in modulating either the positive reinforcing or conditioned rewarding effects of cocaine. Furthermore, they suggest that the therapeutic actions of naloxone, naltrexone and buprenorphine on cocaine SA behavior may not result from the specific blockade of-opioid receptors.     

Influence of phenobarbital pretreatment on thein vitro ring a reduction of Δ4-3-oxo-steroids in rat liver microsomes

Summary The metabolism of 4-androstene-3,17-dione has been studied in rat liver microsomes. Treatment of the animals with repeated doses of phenobarbitalin vivo caused an enhanced rate of formation of 5-androstane-3,17-dione and of polar metabolites from this steroid. On the other hand, no significant increase was found in the 5-reductase activity present in the soluble cytoplasm after phenobarbital administration to the rats. Carbon monoxide and oxidized cytochrome c abolished the formation of polar metabolites from 4-androstene-3,17-dione but did not inhibit the 5-reductase activity. The present findings indicate that the hydroxylation and 5-reduction reactions, although both stimulated by phenobarbital treatment of the animals, do not involve common enzyme components.Supported by grants from the Swedisch Cancer Society, Swedish Medical Research Council (Project no. 13X-2525) and from Caroline Andriette Nobel's foundations for experimental medical research.     

Liver growth and mixed-function oxidase activity: Dose-dependent stimulatory and inhibitory effects of α-hexachlorocyclohexane

Summary -hexachlorocyclohexane (-HCH) elicits liver growth and stimulation of hepatic microsomal mixed-function oxidase. In the present study the extent of these changes was determined in rats 2, 4 and 6 days after treatment with doses of -HCH ranging from 1 to 600 mg/kg. Above the respective threshold doses liver mass, liver DNA, and the rate of aminopyrine demethylation increased in proportion to the log dose. Threshold doses were calculated to be 30 mg/kg for the increase of liver weight and DNA, and 5 mg/kg for the stimulation of aminopyrine demethylation.Liver mass and liver DNA continued to increase up to the highest dose used; in contrast, the rate of aminopyrine demethylation declined at doses exceeding 200 mg/kg. This decline seems to be due to inhibition by -HCH retained in the microsomal fraction: -HCH is a potent, apparently competitive inhibitor of aminopyrine demethylation, and gaschromatographic determinations revealed that the amount of -HCH retained in the microsomes is sufficient to produce considerable inhibition of the enzymatic reaction.Abbreviations -HCH -1,2,3,4,5,6-hexachlorocyclohexane, -benzene hexachloride - EL 241 [,-bis(p-chlorophenyl)-3-pyridinemethanol] - RLW relative liver weight = liver weight in percent of body weight     

The modification of the ethanol withdrawal syndrome in rats by Di-n-propylacetate

Di-n-propylacetate (DPA), a drug known to increase brain -aminobutyric acid (GABA) levels and to inhibit GABA-transaminase (GABA-T) activity, was administered during the ethanol withdrawal period to rats made physically dependent upon ethanol. Under all conditions tested, 400 mg DPA/kg injected i.p. significantly reduced the withdrawal hyperexcitable state induced by acoustic stimulation. The effect was seen as early as 30 min after the administration of DPA and lasted for at least 2 hrs. Readministration of the same dose of DPA 6.5 hrs after its initial injection again mitigated withdrawal symptoms. A 200 mg/kg dose of DPA was significantly effective for only 1 hr after its administration. Neither dose led to mortality or observable tranquilization. The results suggest that DPA may be a useful agent in the control of the hyperexcitable state induced by ethanol withdrawal and that the GABA system may be involved in this state.     

Human studies on the benzodiazepine receptor antagonist β-carboline ZK 93 426: preliminary observations on psychotropic activity

The -carboline ZK 93 426, a benzodiazepine receptor antagonist, was administered intravenously to human volunteers at two different doses (0.01 mg/kg, 0.04 mg/kg) according to a double-blind, placebo controlled design. Vital functions (i.e. blood pressure, heart rate, ECG, EEG), peripheral (finger) skin temperature and performance in psychometric tests for psychotropic and cognitive effects were evaluated. Blood samples were collected in addition and certain pharmacokinetic parameters were estimated. ZK 93 426 in both doses was well tolerated and exhibited no side effects. A decrease in peripheral skin temperature and heart rate was observed. In a general estimation of behavioural changes, volunteers experienced a stimulant and activating effect of the drug. An improvement in performance was observed in two cognitive tasks, the logical reasoning task and pictures differences task which estimated concentration and attention, respectively. No effects were found in time estimation. Plasma levels 5 min after intravenous administration of ZK 93 426 were 16±10 ng/ml and 52±31 ng/ml for 0.01 mg/kg and 0.04 mg/kg, respectively. Total clearance was calculated as 46±22 ml/min/kg (0.04 mg/kg).     

Centralα-2 adrenoceptors are responsible for a clonidine-induced cue in a rat drug discrimination paradigm

Clonidine produces an interoceptive discriminative stimulus or cue in rat drug discrimination studies. This cue may be mediated by its-2 adrenoceptor agonist properties and/or its affinity for the non-adrenoceptor imidazoline preferring receptor. Six rats were trained to respond differentially after receiving clonidine (0.02 mg kg^–1, IP) or a saline vehicle. The-2 adrenoceptor agonists clonidine, UK14, 304 and rilmenidine, which bind to the imidazoline preferring receptor, and guanabenz which does not, dose-dependently substituted for (i.e. > 80% total responding was clonidine associated) the clonidine-induced cue in doses up to 0.02, 0.16, 1.25 and 0.32 mg kg^–1, respectively. Furthermore, the cue was blocked when clonidine was given in combination with 30-min pretreatments of the highly selective-2 adrenoceptor antagonists RX811059 (2.5 mg kg^–1) and fluparoxan (3 mg kg^–1). Since the clonidine-induced cue was substituted for by guanabenz, which does not act at the imidazoline-preferring receptor, and antagonised by RX811059 and fluparoxan it appears to be mediated by-2 adrenoceptors. Moreover, abolition of the clonidine-induced cue did not occur with the peripherally acting-2 adrenoceptor antagonist L659, 066 suggesting it involves central as opposed to peripheral sites.     

Comparison of several benzodiazepine receptor ligands in two models of anxiolytic activity in the mouse: an analysis based on fractional receptor occupancies

This study compared the effects of the -carboline anxiolytic, abecarnil, with other benzodiazepine receptor (BZR) ligands, including the full agonists diazepam and alprazolam, and the partial agonists ZK 95962 and bretazenil (Ro 16-6028), and alpidem, in the mouse four-plate test and plus-maze. The efficacy and potency of each compound was related to the fraction of BZR occupied by the drug. Abecarnil was efficacious in both tests and showed anxiolytic effects comparable with alprazolam and diazepam. In the four-plate test, abecarnil, bretazenil, and ZK 95962 had selective effects on releasing exploratory locomotor activity suppressed by footshock (punished crossings). None of these compounds significantly altered non-punished crossings. In contrast, diazepam and alprazolam increased both unpunished and punished crossings at low to medium doses (receptor occupancies of approximately 20–60%). The number of punished and unpunished crossings fell to control levels or below at higher, more sedative doses (approximately 80% receptor occupancy). Alpidem had very weak anxiolytic-like effects in this test and markedly reduced unpunished crossings at relatively low receptor occupancies (> 15%). In the plus-maze, abecarnil increased the time spent in the open arms and the percentage open arm entries to an extent equal to that observed following diazepam or alprazolam administration. Bretazenil and ZK 95962 had weak effects on the measures of anxiolytic activity in this test. Alpidem also had little anxiolytic-like activity in the plus-maze but markedly reduced the total number of arm entries. The fractional BZR occupancies required to increase the time spent in the open arms of the maze to 250% of control levels were approximately 45% for abecarnil and alprazolam, 60% for diazepam, and 100% for ZK 95962. Bretazenil did not reach this potentiation at the doses tested (up to 89% receptor occupancy). Abecarnil appeared to act as a full agonist on the measures of anxiolytic activity in both tests (i.e. required low fractional BZR occupancies) but on the measures of stimulation or sedation was more similar to the BZR partial agonists (i.e. had no significant effects even at receptor occupancies approaching 100%). On this basis abecarnil could be described as a selective agonist. In general, the four-plate test was more sensitive than the plus-maze. For example, lower BZR occupancies were needed to produce significant anxiolytic effects in the four-plate test than in the plus-maze. In addition, the partial agonists bretazenil and ZK 95962, which both produced weak effects in the plus-maze, had similar anxiolytic potencies to the full BZR agonists, diazepam and alprazolam, in the four-plate test.     

Reserpine and alpha-methyldopa in the treatment of tardive dyskinesia

Thirty inpatients with evidence of tardive dyskinesia secondary to antipsychotic medications participated in this double-blind, controlled, randomized study comparing reserpine, -methyldopa and placebo. Reserpine at doses of 0.75–1.5 mg daily, or -methyldopa at doses of 750–1,500 mg daily, produced a statistically significant improvement in tardive dyskinesia symptomatology compared to the results obtained with placebo.Paper presented at the New Clinical Drug Evaluation Unit Program, Key Biscayne, Florida, May 22–24, 1979     

Effects of guanabenz and guanfacine on postsynaptic α2-adrenoceptors in the rat submaxillary and parotid glands

Summary The effects of two ₂-agonists (guanfacine and guanabenz) on both the submaxillary and parotid gland of the rat were studied. Whereas guanfacine in doses ranging between 1,000 and 30,000 g/kg i.v. produced an immediate and persistent secretion of saliva from the submaxillary gland, guanabenz in doses as high as 40,000 g/kg did not induce measurable secretion either from the parotid or the submaxillary gland. Secretion clicited by guanfacine was not modified by yohimbine (300 g/kg) but was abolished by prazosin (100 g/kg).In both glands, low doses of either guanabenz (10 g/kg) or guanfacine (100 g/kg) markedly inhibited the secretory responses induced by noradrenaline, methacholine and substance P, but not that induced by isoprenaline. The inhibition caused by the ₂-agonists was greater for noradrenaline than for either methacholine or substance P. Blockade of ₂-adrenoceptors with yohimbine (300 g/kg) did not modify the response to noradrenaline, methacholine or substance P in either gland. However, the same dose of yohimbine injected 5 min before the ₂-agonists prevented the inhibitory effects of guanfacine and guanabenz on the response induced by either one of the three sialagogic agents. Guanabenz (10 g/kg) did not modify the increase in mean blood pressure observed after the different doses of noradrenaline employed to induce salivary secretion. Guanabenz (10 g/kg) and guanfacine (100 g/kg) did not change the time course of the secretion elicited by either noradrenaline, methacholine or substance P, since the degree of inhibition was of similar magnitude at all the periods of time analyzed.The results obtained give further support to the hypothesis that activation of ₂-adrenoceptors in the submaxillary as well as parotid gland of the rat inhibits secretory responses which are mediated by either muscarine, substance P and ₁-receptors and not those elicited by -adrenoceptors.Partially supported by grants no. 3111 k/83 CONICET and Res 40-5/4/84 SUBCYT     

Is morphine-induced akinesia related to inhibition of reflex activation of flexor α-motoneurones?

Summary Unilateral injections of morphine (5–15 g) into the nucleus accumbens of non-anesthetized rats produces a decrease of locomotor activity and a catalepsy. In a similar dose-response relationship, injections of morphine into this area inhibited the reflex activation of -motoneurones by mild tetanic stimulation of the ipsilateral peroneal nerve (flexor -motoneurones) in halothane-anesthetized rats. All these effects were antagonized by systemic administration of naloxone. Our results suggest that a reduction in reflex activation of flexor -motoneurones by proprioceptive stimuli seems to be relevant for the development and/or mediation of akinesia and catalepsy, and that the nucleus accumbens plays a key role in these effects produced by morphine.     

Nasal Absorption Enhancement of 17β-Estradiol by Dimethyl-β-Cyclodextrin in Rabbits and Rats

A new formulation for nasal administration containing 17-estradiol (E₂) with dimethyl--cyclodextrin (DMC) as a solubilizer and absorption enhancer is described. Nasal administration of this E₂-DMC formulation gave a significantly higher E₂ absorption than an E₂ suspension in both rabbits and rats. Relative to an intravenous injection of the E₂-DMC formulation, absolute bioavailabilities of 94.6 and 67.2% were calculated for the nasal E₂-DMC formulation in rabbits and rats, respectively. Differences in bioavailability may have resulted from differences in experimental animal conditions. The effects on human nasal ciliary activity of the E₂-DMC formulation were studied with an in vitro method. The formulation was found to exert only a minor effect on ciliary beat frequency. Thus, nasal delivery of E₂, using a cyclodextrin inclusion formulation, may have potential for clinical application, e.g., in the therapy of postmenopausal disorders.