Effects of naloxone and diprenorphine on spontaneous activity in rats and mice

The narcotic antagonist naloxone has been reported to decrease locomotor activity in the rat, presumably by blocking endogenous opiate systems. Naloxone has a greater affinity for receptors which preferentially bind morphine and other opiate alkaloids as compared to receptors that bind endogenous opioid peptides. Diprenorphine, another pure opiate antagonist, binds with equal affinity to both receptor subtypes. Therefore, the effects of the narcotic antagonists naloxone and diprenorphine on spontaneous activity were compared in rats and mice, tested individually and in pairs. Only naloxone (10 mg/kg) affected spontaneous activity in rats tested individually, decreasing both gross and fine activity. In rats tested in pairs, naloxone (1.0 and 10 mg/kg) decreased both fine and gross activity, while diprenorphine (10 mg/kg) produced significant decreases only in fine activity. In mice tested individually, naloxone produced modest (nonsignificant) decreases in activity while diprenorphine (10 mg/kg) significantly enhanced activity. Neither opiate antagonist produced consistent effects on activity in paired mice. These results illustrate the species and situation dependence of the effects of opiate antagonists and point out the need for testing more than one narcotic antagonist in research designed to provide inferential information concerning possible physiological functions of endogenous opioid peptides.     

Nucleus accumbens opiate-dopamine interactions and locomotor activation in the rat: evidence for a pre-synaptic locus

Locomotor activation produced by the indirect dopamine (DA) agonist amphetamine is reversed by the opiate-receptor antagonist naloxone. Since amphetamine-stimulated locomotion results from the release of DA within the nucleus accumbens (N.Acc.), it is possible that these effects of naloxone result either from a decrease in the pre-synaptic release of DA within the N.Acc. or from a disruption of the effects of DA at, or distal to, the post-synaptic DA receptor. In the present study, we investigated the effects of naloxone on the locomotor-activating properties of dopamine injected directly into the nucleus accumbens. Naloxone (0-2 mg/kg) had no significant effect of DA-stimulated locomotion; the lowest dose of naloxone tested (0.5 mg/kg) was shown to significantly disrupt the locomotor activation produced by amphetamine (0.5 mg/kg). In separate animals, very high doses of naloxone (5.0 mg/kg) had no significant effect on locomotor activation produced by the DA receptor agonist apomorphine in rats following 6-hydroxydopamine (6OHDA) denervation of the N.Acc. These results indicate that naloxone must disrupt amphetamine-stimulated locomotion through its action presynaptic to N.Acc. DA receptors.     

Effects of naloxone on heroin-, amphetamine- and caffeine-stimulated locomotor activity in the rat

We investigated the effects of naloxone on the locomotor activating properties of heroin (0.25 mg/kg SC), d-amphetamine (0.25 mg/kg SC) and caffeine (7.5 mg/kg SC). Naloxone eliminated heroin-stimulated locomotion at doses approximately six times lower than those that blocked amphetamine-stimulated locomotion. Caffeine-induced locomotor activation was insensitive to naloxone at all doses tested. These results suggest that central opiate systems are differentially involved in the behavioral activation produced by heroin, amphetamine and caffeine.     

Differential effects of naloxone and diprenorphine on defensive behaviour in rats

Two opiate antagonists, naloxone and diprenorphine, were used to examine the proposed involvement of endogenous opioid mechanisms in the modulation of shock-induced defensive behaviour patterns in rats. Naloxone was found to exert a biphasic influence on defensive fighting, with small dose (0.1 mg/kg) facilitation and large dose (10 mg/kg) inhibition. This compound also induced a dose-dependent inhibitory effect on shock-elicited threat whilst facilitated escape/avoidance behaviour was observed with the largest doses only. None of these influences could be attributed to alterations in electric shock thresholds. In contrast to the effects of naloxone, diprenorphine (0.1–10 mg/kg) was largely ineffective in modifying shock-induced defensive behaviour. These data suggest that endogenous opioid mechanisms may not be involved in the effects of naloxone on defensive fighting and cast some doubt upon the general hypothesis of the involvement of endorphins in the regulation of innate defence patterns.     

Diprenorphine and naloxone in squirrel monkeys with enhanced sensitivity to opioid antagonists

The effects of diprenorphine and naloxone were examined in squirrel monkeys responding under a multiple fixed-ratio 30, fixed-interval 5-min schedule of food presentation. Dose-response curves for diprenorphine and naloxone were determined prior to and following chronic administration of 10.0 mg/kg naloxone once daily for at least 21 days. Prior to the chronic regimen, naloxone (0.1–10.0 mg/kg) had little effect on performance. At the highest dose examined, rates of responding were decreased only slightly. Diprenorphine (0.003–0.1 mg/kg) produced dose-dependent decreases in rates of responding under both components of the multiple schedule. Subsequent to the chronic naloxone regimen, doses of both naloxone and diprenorphine produced greater decreases in rates of responding. This suggests that frequent exposure to naloxone enhances its own rate-decreasing effects as well as those of diprenorphine.     

General pharmacological properties of YJA20379-8, a new H+/K(+)-ATPase inhibitor with anti-ulcer activities

The general pharmacological properties of YJA20379-8 (3-butyryl-4-[(R)-1-methylbenzylamino]-8-ethoxy-1,7-naphthyridine, CAS 187654-40-6), a new H+/K(+)-ATPase inhibitor with anti-ulcer activities, were investigated in mice, rats and guinea pigs. YJA20379-8 at oral doses of 25, 50 and 100 mg/kg did not affect the locomotor activity, hexobarbital hypnosis and motor coordination in mice. The drug did not have analgesic action and anticonvulsant action at the doses of 100 mg/kg p.o. The respiration and blood pressure were not affected at 10 mg/kg i.v. in rats. YJA20379-8 at 2 x 10(-4) g/ml did neither produce any contraction nor relaxation of isolated organs, such as guinea pig ileum, rat fundus, rat uterus and guinea pig vas deferens, and the drug antagonized the contractile responses to several spasmogens, such as acetylcholine, histamine, serotonin, L-phenylephrine, oxytocin and BaCl2. The drug up to 100 mg/kg p.o. did not affect pupil size and the intestinal propulsion of mice. And it did not show an anticarrageenan action at 100 mg/kg. In this general pharmacology study, hypothermic effect in mice, retardation in gastric emptying in rats, decreases in urine excretion in rats at oral doses of 50 and 100 mg/kg of YJA20379-8 and the spasmolytic activity could be found. However, no other effects were exhibited at a high oral dose of 100 mg/kg in animals in this study.     

General pharmacology of the new antiviral agent SK 1899

The general pharmacological properties of 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine (CAS 247081-81-8, SK 1899), a new potential antiviral agent, were investigated in mice, rats, guinea pigs, rabbits, and dogs. The oral administration of 50, 150, and 500 mg/kg of SK 1899 had no effects on the central nervous system except that it slightly increased the spontaneous locomotor activity in mice at a dose of 500 mg/kg. SK 1899 did not disturb either the spontaneous motility or contractor-induced contraction of the isolated organs such as guinea pig ileum, rat uterus, guinea pig vas deferens, and guinea pig trachea at concentrations up to 10(-4) mol/l. It slightly increased the contractile force in the isolated guinea pig atrium at a concentration of 10(-4) mol/l. Following intravenous infusion of 5, 15, and 50 mg/kg of SK 1899 to anesthetized dogs, it did not change the mean arterial pressure, heart rate, left ventricular systolic pressure (LVSP), and respiratory rate, while it slightly increased the left ventricular positive dP/dtmax (LV + dP/dtmax) at a dose of 50 mg/kg. SK 1899 did not induce any significant changes in the intestinal charcoal meal transit in mice, basal gastric juice secretion in rats, and renal function in rats. It did not affect the blood coagulation system and phenolsulfonphthalein secretion in rats. These findings suggest that SK 1899 has a very low potential to induce any adverse pharmacological effects at the doses showing antiviral activity.     

GR46611 potentiates 5-HT1A receptor-mediated locomotor activity in the guinea pig.

5-HT(1B/D) receptor agonists such as GR46611 (3-[3-(2-Dimethylaminoethyl)-H-indol-5-yl]-N-(4-methoxybenzyl)acrylamide ) are known to lower body temperature in guinea pigs. Although stimulation of their functional analogs in rats, the 5-HT1B receptor induces hyperlocomotion, this effect has yet to be demonstrated with 5-HT(1B/D) receptor agonists in the guinea pig. Previous studies have shown that 5-HT1A agonists increase locomotor activity in guinea pigs. The current study set out to examine the effects of 5-HT(1B/D) receptor stimulation on locomotor activity in the guinea pig and to examine the interaction between 5-HT1A and 5-HT(1B/D) receptor stimulation on locomotor activity in that species. The full agonist at 5-HT1A receptors, 8-OH-DPAT (R(+)-8-Hydroxy-dipropylaminotetralin HBr) dose-dependently increased locomotor activity in guinea pigs (0.3-1.25 mg kg(-1) s.c.), as to a lesser extent, did the partial agonist, buspirone (8-[4-[4-(2-Pyramidinyl)-1-piperazinyl]butyl]-8-azaspiro[4.5 ]decane-7,9-dione HCl) (5.0-20.0 mg kg(-1) s.c.). The 5-HT(1B/D) receptor agonist GR46611 had no effect on locomotor activity in guinea pigs at doses up to 40 mg kg(-1) s.c. 8-OH-DPAT-induced behavioural activation was reversed by the selective 5-HT1A receptor antagonist WAY100635 (N-[-2-[4-(-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyrinidyl) cyclo hexanocarboxamide trihydro-chloride), with a minimum effective dose of 0.006 mg kg(-1), but not by the 5-HT(1B/D) receptor antagonist GR127935 (2'-methyl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-biphenyl-4-carboxyli c acid [4-methoxy-3-(4-methyl-piperazin-1-yl)phenyl]-amide) (0.25-1.0 mg kg(-1)). GR46611, at doses that were without effect given alone (0.5-2.5 mg kg(-1)), significantly enhanced the locomotor response to subthreshold doses of 8-OH-DPAT (0.5 mg kg(-1)) and buspirone (10 mg kg(-1)). The effect of GR46611 on 8-OH-DPAT-induced hyperactivity was reversed by pretreatment with GR127935 and with WAY 100635 indicating that activation of both receptors was required for the expression of locomotor hyperactivity. These findings suggest that activation of 5-HT(1B/D) receptors alone may not stimulate locomotor activity but it does potentiate the locomotion induced by 5-HT1A receptor stimulation in guinea pigs.     

Naloxone and diprenorphine reduce responding for brain self-stimulation in a fixed-ratio schedule in rats

Rats were implanted with bipolar stimulating electrodes in the midbrain-central gray area (MID-CG) and trained to lever-press for intracranial self-stimulation (ICSS) on a continuous reinforcement schedule (CRF). When behavior was stable, animals were tested in 30 min ICSS sessions following the administration of either naloxone or diprenorphine, both over the dose-range 0.001-10 mg/kg, or with vehicle. Following testing on the CRF schedule, animals were re-trained on a fixed-ratio:30 (FR:30) schedule. When behavior had again stabilized, testing with naloxone, diprenorphine and vehicle was repeated. In the CRF tests, neither naloxone nor diprenorphine had any effects on response rates over the 10,000-fold dose-range used. In the FR:30 tests, however, both drugs significantly reduced response rates at the 10 mg/kg dose, and the reduction produced by naloxone was significantly greater than that produce by diprenorphine. These results suggested that diprenorphine is qualitatively similar to naloxone in altering the rate of responding maintained by ICSS, but is less potent than the prototypical opioid antagonist in this paradigm.     

Effects of morphine,ethylketocyclazocine,N-allylnormetazocine and naloxone on locomotor activity in the rabbit

Locomotor activity was studied in the rabbit following injections of morphine, ethylketocyclazocine andN-allylnormetazocine. All three drugs produced only depression of activity. The opioid antagonist naloxone antagonized the effects of both morphine and ethylketocyclazocine. Naloxone (0.1 mg/kg) did not antagonize the effects ofN-allylnormetazocine. Naloxone alone depressed locomotor activity at doses above 0.3 mg/kg. This effect of naloxone was partially antagonized by 0.1 mg/kg ethylketocyclazocine, but not by 0.1 mg/kg morphine. The GABA agonist muscimol (0.1 and 1.0 mg/kg) also did not antagonize the effect of naloxone on locomotor activity. Finally, amphetamine did not produce a great deal of locomotor activation in the rabbit, which may indicate that increasing activity in the rabbit by drug intervention may be inherently difficult. These results indicate that the opioids have effects in the rabbit that are clearly different from those observed in rodents, where morphine andN-allylnormetazocine have been reported to produce locomotor activation, and naloxone typically has little effect. In addition, the effects of the opioids on locomotor activity were clearly distinguishable from their effects on learning in the rabbit. While morphine and ethylketocyclazocine were approximately equipotent in depressing locomotor activity, morphine is much less potent than ethylketocyclazocine in retarding acquisition of the classically conditioned nictitating membrane response in the rabbit.     

General pharmacological properties of YJA 20379-1, a novel proton pump inhibitor with antiulcer activities

The general pharmacological properties of YJA 20379-1 (2-amino-4,5-dihydro-8-phenylimidazo[2,1-b]thiazolo[4,5-g]benzo thi azole), a novel proton pump inhibitor with antiulcer activities, were investigated in mice, rats, guinea pig and rabbits. YJA 20379-1 at oral doses of 50, 100 and 200 mg/kg did not affect the general behaviour, hexobarbital hypnosis, motor coordination and body temperature in mice. The drug does not have analgesic and anticonvulsant action at 200 mg/kg p.o. The locomotor activity was not affected at 100 mg/kg p.o., but at 200 mg/kg, the activity was suppressed. YJA 20379-1 (at 2 x 10(-4) g/ml) did neither produce any contraction nor relaxation of isolated organs such as rat fundus, rat uterus, guinea pig ileum and guinea pig vas deferens, and the drug did not antagonize the contractile response to several spasmogens, such as histamine, acetylcholine, serotonin and oxytocin, and the drug up to 200 mg/kg p.o. did not affect pupil size of mice. The intestinal propulsion in mice was not affected up to 200 mg/kg p.o. The gastric emptying in rats was not affected at 100 mg/kg p.o., even if retardation in gastric emptying occurred at 200 mg/kg. YJA 20379-1 did not show anti-inflammatory action nor did it affect urinary excretion up to 200 mg/kg p.o. From these results, it is suggested that YJA 20379-1 at the high dose of 100 mg/kg p.o. may not exert any adverse effects.     

KC-404: A POTENTIAL ANTI-ALLERGIC AGENT WITH ANTAGONISTIC ACTION AGAINST SLOW REACTING SUBSTANCE OF ANAPHYLAXIS

The mode of action of a novel compound, 3-isobutyryl-2-isopropylpyrazolo [1,5-a]pyridine (KC-404), as a potential anti-allergic agent has been investigated. KC-404 was shown to have a direct bronchodilator activity in guinea pig trachea in vitro and in anesthetized guinea pig in vivo. In addition, KC-404 had a fairly selective antagonistic action against slow reacting substance of anaphylaxis (SRS-A) on guinea pig ileum in vitro. In anesthetized guinea pigs, ED50 values for intravenously and intraduodenally injected KC-404 to inhibit SRS-A-induced bronchoconstriction were 0.0014 and 0.0065 mg/kg, respectively. Much higher doses were required to inhibit bronchospasms produced by histamine or particularly by acetylcholine. Orally administered KC-404, 0.001 to 0.1 mg/kg, also showed a selective inhibitory effect on increased vascular permeability by intradermal SRS-A in guinea pigs and rats. KC-404 inhibited the immunological release of mediators, notably SRS-A from sensitized guinea pig chopped lung in vitro at 10⁻⁸ to 10⁻⁴ g/ml. In vivo, the release of SRS-A, but not of histamine, mediated by a nonreaginic antibody in the peritoneal cavity of sensitized rats was inhibited by KC-404 at oral doses above 3 mg/kg. In a similar anaphylactic reaction but mediated by a reaginic antibody, KC-404 also inhibited SRS-A release at intraperitoneal doses of 2.5 to 10 mg/kg. The inhibitory activity on histamine release was less than half of that on SRS-A release. These results indicate that KC-404 is an orally active compound with a unique mode of action to inhibit preferentially both the effects and immunological release of SRS-A.     

General pharmacological properties of the new proton pump inhibitor (+/-)-5-methoxy-2-[[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulf inyl]- 1H-imidazo[4,5-b]pyridine.

The general pharmacological profiles of a novel proton pump inhibitor, (+/-)-5-methoxy-2-[[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulfi nyl]- 1H-imidazo[4,5-b]pyridine, TU-199) on the central nervous system, cardiorespiratory system, autonomic nervous system, gastrointestinal system and renal functions were investigated. TU-199 had no effects on general signs and behavior in mice. TU-199 (300 mg/kg p.o.) decreased locomotor activity 3 h after administration in mice. TU-199 had no effect on pentobarbital-induced hypnosis, analgesic activity and electroshock-induced convulsion in mice, and on rectal temperature in rats. However, TU-199 (300 mg/kg p.o.) showed slight anticonvulsant activity on pentylenetetrazole-induced convulsion in mice. TU-199 had no effect on respiratory rate, blood pressure, heart rate, femoral blood flow and electrocardiogram in anesthetized dogs. TU-199 (10(4) M) caused the cumulative concentration-response curve obtained with acetylcholine in isolated guinea pig ileum to shift to the right. However, TU-199 showed no effect on contraction of isolated guinea pig ileum and had no effect on intestinal motility in mice, gastric emptying in rats, bile secretion in rats and carbachol-induced salivary secretion in mice. TU-199 had no effect on urinary volume and excretion of electrolytes in rats. These results suggest that TU-199 does not induce serious adverse effects on the central nervous system, cardiorespiratory system, autonomic nervous system, gastrointestinal system and renal functions with the exception of a decrease in spontaneous motor activity with high doses.     

The effects of FK506, a specific calcineurin inhibitor, on methamphetamine-induced behavioral change and its sensitization in rats

RATIONALE: FK506 inhibits calcineurin activity, resulting in the inhibition of calcium-dependent intracellular processes. Recent studies have suggested that intracellular calcium is likely to be involved in methamphetamine (MAP)-induced locomotor activity and stereotyped behavior, and in the development of sensitization to MAP. OBJECTIVES: We investigated the effects of FK506 on MAP-induced behavioral changes and the development of sensitization in rats. METHODS: In experiment 1, animals were administered IP 2 mg/kg FK506 or vehicle followed 10 min later by MAP (1, 2, 4 and 8 mg/kg, IP). Another set of animals were administered FK506 (0.1, 2, 5 and 10 mg/kg) followed by 2 mg/kg MAP. Locomotor activity and stereotyped behavior were assessed. In experiment 2, animals received repeated IP injections of 2 mg/kg MAP pretreated with 2 mg/kg FK506 or vehicle for 5 consecutive days. One week later, rats were challenged with 1 mg/kg MAP. RESULTS: Pretreatment with 2 mg/kg FK506 caused a rightward shift of the inverted U-shaped response curve of the locomotor activity induced by 1-8 mg/kg MAP. The same pretreatment significantly attenuated augmentation of the MAP-induced stereotyped behavior. FK506 at doses of 0.1-10 mg/kg dose-dependently inhibited the behavioral response induced by 2 mg/kg MAP. Coadministration of 2 mg/kg FK506 with 2 mg/kg MAP for 5 consecutive days resulted in significant suppression of the behavioral response to challenge with 1 mg/kg MAP. CONCLUSIONS: These results suggest that calcineurin plays an important role in MAP-induced behavioral changes and sensitization, especially the latter.     

Naloxone-like actions of MIF-1 do not require the presence of the pituitary

The actions of peripherally administered MIF-1 (Pro-Leu-Gly-NH₂) and naloxone in blocking the effects of morphine in the tail-flick test were measured across a wide range of five doses in hypophysectomized and intact mice. The presence of the pituitary gland failed to influence the response to MIF-1 or naloxone. Both hypophysectomized and intact mice were significantly affected by these two compounds at doses of 0.01, 0.1, 1.0, and 10.0 mg/kg IP. The greatest effect of MIF-1 occurred at 100 mg/kg, but naloxone was lethal at this dose. Preliminary experiments with other tests showed that at 10 mg/kg, naloxone, but not MIF-1, was effective in preventing the Straub-tail reflex and in precipitating withdrawal-jumping in mice implanted with morphine pellets. Only minimal activity was shown by MIF-1 in preventing blockade of electrically induced contractions of the guinea pig ileum by morphine. Neither compound was active in the frog-righting test. In summary, the results emphasize the differential actions of MIF-1 as an opiate antagonist and demonstrate that the pituitary is not required for their mediation.     

The lack of effect of opioid agonists and antagonists on some acute effects of ethanol

We studied the ability of opioid antagonists: naloxone, naltrexone and diprenorphine and an opioid agonist morphine to influence the effects of ethanol on hypothermia, sleeping time and impairment of aerial righting reflex. Naltrexone (2-16 mg/kg) and naloxone (2-16 mg/kg) were not able to attenuate effects of ethanol, while diprenorphine decreased ethanol sleeping time (4 microgram/kg) and antagonized the ethanol hypothermia (8 microgram/kg). Naltrexone in a dose of 8 mg/kg sc antagonized the ethanol impairment of aerial righting reflex. The present behavioral studies did not provide any evidence for the participation of the opioid system in the mediation of acute ethanol effects in rats.     

The effects of acetylmethadol on motor activity and schedule-controlled responding.

The effects of levo-alpha-acetylmethadol (LAAM) on locomotor activity and operant behavior were examined in rats. LAAM increased locomotor activity when given intraperitoneally (IP) at doses of 1 mg/kg and 3 mg/kg, but 10 mg/kg produced a slight decrease in motor activity over the 10-hour period. The largest increases and decreases in locomotor activity occurred 6--8 hours after administration of the drug. Other rats were trained to lever press for food pellets under a fixed-interval 90-second, fixed-ratio 10-response multiple schedule. LAAM only decreased rates of responding under the multiple schedule. Marked decreases in rates of responding under both components of the schedule occurred with LAAM was administered IP either 3 or 6 hours before the session at doses of 3 mg/kg and 10 mg/kg. The rate- decreasing effects of LAAM became greater the longer the interval between administration of the drug and initiation of the session.     

Evidence in locomotion test for the functional heterogeneity of ORL-1 receptors

1. The ORL1 agonists nociceptin and Ro 64-6198 were compared in their ability to modify spontaneous locomotor activity in male NMRI mice not habituated to the test environment. 2. Higher doses of nociceptin (>5 nmol i.c.v.) reduced whereas lower doses (<1 nmol i.c.v.) stimulated locomotor activity. Both effects were blocked by the putative ORL1 antagonists [NPhe1]nociceptin(1-13)NH2 (10 nmol i.c.v.) and UFP101 (10 nmol, i.c.v.). The effects were also blocked by naloxone benzoylhydrazone (1 mg x kg(-1) s.c.), but not by the nonselective opioid antagonist naloxone (1 mg x kg(-1) s.c.). 3 In contrast to nociceptin, the synthetic ORL1 agonist Ro 64-6198 (0.01-1.0 mg x kg(-1) i.p.) produced monophasic inhibition of locomotor activity, which was insensitive to the treatment with [NPhe1]nociceptin(1-13)NH2 or naloxone benzoylhydrazone. Treatment with UFP101 abolished the locomotor inhibition induced by Ro 64-6198 (1.0 mg x kg(-1)), whereas naloxone (1.0 mg x kg(-1), s.c.) further increased the locomotor-inhibitory effects. 4. Naloxone benzoylhydrazone (0.3; 1.0 and 3.0 mg x kg(-1) s.c.) increased locomotor activity, although the effect was statistically significant only with the highest dose used. 5. Pretreatment with the tyrosine hydroxylase inhibitor H44-68 totally eliminated the motor-stimulatory effects of low doses of nociceptin, probably via dopamine depletion. 6. The results suggest that nociceptin stimulates locomotor activity at low doses if dopamine activity is intact. High doses of nociceptin and all the tested doses of Ro 64-6198 seem to interact with a functionally different subset of ORL1 receptors. In addition, the effects of Ro 64-6198 are modulated by tonic opioid receptor activity.     

Effects of acute and long-term treatments with thyrotropin-releasing hormone on locomotor activity and jumping behavior in mice

The acute and chronic effects of thyrotropin-releasing hormone (TRH) on ambulation and, in combination with apomorphine, on jumping behavior were investigated in mice. A single administration of TRH (1-10 mg/kg SC) produced an initial hyperactivity in a dose-dependent manner. Following administration of TRH (1-10 mg/kg SC) for 21 successive days, the stimulatory effect on locomotion progressively increased. Haloperidol exerted a biphasic action on hyperlocomotion induced by acute and repeated TRH, i.e., stimulation at lower doses (0.01-0.02 mg/kg SC) and inhibition at higher doses (0.05-1 mg/kg SC). When TRH was administered in combination with low doses of apomorphine, locomotor activity was inhibited but jumping behavior occurred. The inhibitory effect of low doses of apomorphine on locomotion was shifted from doses of 0.1-0.25 mg/kg SC of apomorphine for acute TRH (10 mg/kg) to 0.25-0.35 mg/kg for repeated TRH (10 mg/kg), whereas the stimulatory effect of higher doses of apomorphine (0.5-1 mg/kg SC) on locomotion tended to decrease with repeated TRH. Jumping behavior induced by the combined treatment of TRH and apomorphine was proportional to the dose of TRH but exhibited an inverted-U response to the dose of apomorphine. Chronic TRH (10 mg/kg) in combination with apomorphine (0.1-1 mg/kg SC) also produced jumping behavior, but the dose-response curve for apomorphine was shifted to the right. The present results suggest that repeated treatment with TRH in mice produces hyperlocomotion, despite attenuation of both pre- and postsynaptic receptor activity, and that the inhibitory effect of repeated TRH on presynaptic receptors may be more potent than that on postsynaptic receptors.     

Antagonism of the discriminative stimulus effects of the kappa-opioid agonist spiradoline

This study compared the potency of mixed-action opioids (i.e., agonist-antagonists) and pure antagonists to block the discriminative stimulus effects of spiradoline, a kappa-opioid agonist. Rats were trained to discriminate between 3.0 mg/kg spiradoline and saline (SC) in a two-choice discrete-trial procedure. Graded doses of test drugs were administered in combination with 3.0 mg/kg spiradoline and the dose that reduced selection of the spiradoline-appropriate choice lever by 50% (AD₅₀) was calculated. Ten drugs blocked the discriminative effects of spiradoline in an orderly dose-dependent manner. They spanned a 150-fold potency range, from diprenorphine (5 times as potent as naloxone) to nalbuphine (0.03 times as potent as naloxone). Antagonism was stereoselective: 0.1–1.0 mg/kg (–)-N-allylnormetazocine (NANM) reduced spiradoline-appropriate responding by 50% whereas 3.0 mg/kg (+)-NANM did not. (–)-Pentazocine (0.1–10 mg/kg) and butorphanol (0.1–3.0 mg/kg) also did not block the discriminative effects of spiradoline. Antagonism was surmountable when graded doses of spiradoline were tested with a fixed dose of diprenorphine, naloxone, or levallorphan. Apparent pK_B values derived from the interactions between those three drugs and spiradoline were in accord with relative antagonist potencies based upon the AD₅₀s. Because the potency of a competitive antagonist is determined by its receptor affinity, the relative potencies of mixed-action opioids and pure antagonists in blocking the discriminative stimulus effects of spiradoline can provide an estimate of the relative in vivo affinities of these drugs for the kappa-opioid receptor. Present address: Weinberg Consulting Group, 1220 19th Street, Suite 300, Washington, DC 20036-2400, USA