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V J Hruby

Publications and source records attributed to V J Hruby.

At least 163 records · Page 9Linked to original sources
PubMed1989

Designing molecules: specific peptides for specific receptors.

Peptides are the largest class of mediators of intercellular communication in the central nervous system. These molecules pose special problems in design for potential medical applications because of the high degree of flexibility, lack of high receptor selectivity, and ready biodegradation or clearance. The global and local use of conformational constraints has overcome these difficulties. Structure-biological activity relationships, molecular modeling, conformational analysis, conformational calculations, and molecular dynamics simulations can all be used to derive suitable lead structures and conformational models. Often, a single, constrained peptide analogue can be designed, which will have many of the desired biological and biophysical properties, and will serve as a template. Peptide analogues with high potency, exquisite receptor selectivity, and biological stability can be obtained. The approach is illustrated by the design of cyclic enkephalin-agonist analogues with exceptional delta-opioid-receptor selectivity, and of constrained somatostatin analogues that have become opioid peptides and possess potent opioid antagonist activities and exceptional selectivity for mu-opioid receptors.

Chemical Phenomena↗
PubMed1989

Antidiarrheal properties of supraspinal mu and delta and peripheral mu, delta and kappa opioid receptors: inhibition of diarrhea without constipation.

We evaluated the ability of mu [morphine, Tyr-Pro-N-MePhe-D-Pro-NH2 (PLO17)], delta (Tyr-D-Pen-Gly-Phe-D-Pen) (DPDPE) and kappa [U50,488H, (trans-3,4-dichloro-N-methyl-N-(2-(1-pyr-rolidinyl) cyclo-hexyl)benzeneacetamine)] opioid receptor selective agonists to inhibit diarrhea induced by castor oil (0.6 ml p.o.) in mice after supraspinal (i.c.v.) and peripheral (s.c.) administration. The antidiarrheal potency of each compound was compared to its analgesic and gastrointestinal antitransit potency when given by the same route of administration. When administered i.c.v., morphine, PLO17 and DPDPE inhibited diarrhea in a dose-related fashion. The mu agonists, morphine and PLO17, given i.c.v, inhibited diarrhea at doses much lower than those needed to produce analgesia or to inhibit gastrointestinal transit. DPDPE (i.c.v.) was equipotent in inhibiting diarrhea and in eliciting analgesia, but did not effect the rate of transit. U50,488H (i.c.v.) inhibited diarrhea only at extremely high doses which also caused profound postural-motor incapacitance. U50,488H given i.c.v. had no effect on transit at any dose. When given peripherally, morphine, PLO17, DPDPE and U50,488H all inhibited diarrhea in a dose-related fashion. All four compounds inhibited diarrhea at doses much below those needed to cause analgesia. Morphine s.c. and PLO17 s.c. both inhibited diarrhea at doses lower than those required to inhibit transit. DPDPE s.c. and U50,488H s.c. had no effect on transit at any dose. The antidiarrheal effects of i.c.v. morphine, i.c.v. PLO17 and i.c.v. DPDPE were antagonized by pretreatment with 1 microgram i.c.v. of naltrexone.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

[3H]-[H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2] ([3H]CTOP), a potent and highly selective peptide for mu opioid receptors in rat brain.

The cyclic, conformationally restricted octapeptide [3H]-[H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2] ([3H]CTOP) was synthesized and its binding to mu opioid receptors was characterized in rat brain membrane preparations. Association rates (k+1) of 1.25 x 10(8) M-1 min-1 and 2.49 x 10(8) M-1 min-1 at 25 and 37 degrees C, respectively, were obtained, whereas dissociation rates (k-1) at the same temperatures were 1.93 x 10(-2) min-1 and 1.03 x 10(-1) min-1 at 25 and 37 degrees C, respectively. Saturation isotherms of [3H]CTOP binding to rat brain membranes gave apparent Kd values of 0.16 and 0.41 nM at 25 and 37 degrees C, respectively. Maximal number of binding sites in rat brain membranes were found to be 94 and 81 fmol/mg of protein at 25 and 37 degrees C, respectively. [3H]CTOP binding over a concentration range of 0.1 to 10 nM was best fit by a one site model consistent with binding to a single site. The general effect of different metal ions and guanyl-5'-yl-imidodiphosphate on [3H]CTOP binding was to reduce its affinity. High concentrations (100 mM) of sodium also produced a reduction of the apparent mu receptor density. Utilizing the delta opioid receptor specific peptide [3H]-[D-Pen2,D-Pen5]enkephalin, CTOP appeared to be about 2000-fold more specific for mu vs. delta opioid receptor than naloxone. Specific [3H]CTOP binding was inhibited by a large number of opioid or opiate ligands.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Novel peptidic mu opioid antagonists: pharmacologic characterization in vitro and in vivo.

A series of six synthetic octapeptides, structurally related to somatostatin, demonstrate high affinity and selectivity for mu opioid receptors in radioligand binding assays. The compounds, D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), D-tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (D-Tic-CTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (D-Tic-CTOP) and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (D-Tic-CTAP), were tested in vitro and in vivo for agonist and antagonist potency and selectivity. In vitro bioassays included the guinea pig ileum, mouse vas deferens and rabbit vas deferens. In vivo tests included hotplate antinociception and gastrointestinal transit inhibition, performed in mice. In vitro, all six derivatives were competitive, highly selective mu antagonists (pA2 values from 6.4-7.9). The compounds demonstrated varying degrees of intrinsic agonist activity especially in the mouse vas deferens, the least active being CTAP and D-Tic-CTAP, which showed no mu or kappa agonist actions, and delta activity only at very high (greater than 3 microM) concentrations. In vivo, none of these compounds showed antinociceptive actions when administered i.c.v. in mice. All were competitive mu antagonists in the hotplate antinociception test.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Antagonist activity of the cyclic somatostatin analogue CTP at mu- but not delta- and kappa-opioid receptors involved in presynaptic inhibition of neurotransmitter release.

In the present study the opioid receptor antagonist properties of the conformationally constrained cyclic octapeptide D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP), which is derived from somatostatin, were investigated, using in vitro functional paradigms of central mu-, delta- and kappa-opioid receptors. Activation of mu-opioid receptors by the enkephalin analogues DADLE or DAGO resulted in a strong inhibition (by 60-70%) of the (electrically evoked) release of [3H]noradrenaline (NA) from superfused cortical slices. This inhibitory effect was antagonized by CTP in a competitive fashion (pA2 value 7.7-7.9). Activation of kappa-opioid receptors by bremazocine selectively inhibited (by 45-50%) the release of [3H]dopamine (DA) from striatal slices, whereas activation of delta-opioid receptors by DADLE caused an inhibition (by 55-60%) of striatal [14C]acetylcholine (ACh) release, but neither of these inhibitory effects was affected by CTP. By itself, CTP inhibited cortical [3H]NA release (by 35-40%), but it did not affect the release of [3H]DA nor that of [14C]ACh from striatal slices. The inhibitory effect of CTP was not antagonized by naloxone. The data indicate that CTP selectively antagonizes mu-opioid receptors, involved in presynaptic inhibition of NA release in the brain. In addition, the peptide by itself causes an inhibition of NA release via a non-opioid receptor-mediated process.

Adrenergic alpha-Agonists↗
PubMed1988

Cyclic lactam analogues of Ac-[Nle4]alpha-MSH4-11-NH2.

Two side-chain cyclic lactam analogues of the 4-11 fragment of alpha-melanocyte-stimulating hormone (alpha-MSH), Ac-[Nle4,D-Orn5,Glu8]alpha-MSH4-11-NH2 and Ac-[Nle4,D-Orn5,D-Phe7,Glu8]alpha-MSH4-11-NH2, were prepared on p-methylbenzhydrylamine resin by using a combination of N alpha-Boc and N alpha-Fmoc synthetic strategies with diphenyl phosphorazidate mediated cyclization. The melanotropin activities of these two analogues were examined and compared relative to those of alpha-MSH, Ac-[Nle4]alpha-MSH4-11-NH2, and Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. In the frog (Rana pipiens) skin bioassay, the L-Phe7 17-membered ring cyclic analogue was slightly more potent than the linear Ac-[Nle4]alpha-MSH4-11-NH2 and exhibited prolonged melanotropic bioactivity (greater than or equal to 4 h). In this same assay, the D-Phe7 cyclic analogue was more than 100-fold less potent than the L-Phe cyclic analogue and was 10,000 times less potent than linear Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. In the lizard skin (Anolis carolinensis) bioassay, the L-Phe7 cyclic analogue was 100-fold less potent than Ac-[Nle4]alpha-MSH4-11-NH2, while the D-Phe7 cyclic analogue was 10,000-fold less potent than both Ac-[Nle4]alpha-MSH4-11-NH2 and the D-Phe7 linear derivative Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. The solution conformation of these two cyclic analogues in dimethyl sulfoxide-d6 was examined by 1D and 2D 500-MHz 1H NMR spectroscopy. Our analysis suggests an H bond stabilized C10 (or C13) turn for the D-Phe7 cyclic structure while the L-Phe7 analogue is more conformationally flexible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Alpha-melanocyte-stimulating hormone structure-activity studies: comparative analysis of melanotropic and CNS bioactivities.

The structure-activity relationships in vitro of alpha-MSH (alpha-melanocyte-stimulating hormone, alpha-melanotropin) analogs as determined on normal and transformed (melanoma cell) melanocyte bioassays are summarized. Specifically, the characterization of potent and metabolically stable melanotropic agonist analogs and a newly discovered antagonist of alpha-MSH are highlighted. Comparison of these data versus the known structure-activity relationships of alpha-MSH related to CNS bioactivities suggests the existence of nonclassical alpha-MSH receptor-mediated pathways or, perhaps, a yet undefined endogenous neuropeptidergic pathway(s) having different selectivities for alpha-MSH analogs. In summary, several of the alpha-MSH analogs reported here may be useful molecular probes in future strategies aimed at the identification and systematic characterization of both peripheral and central alpha-MSH receptors.

Amino Acid Sequence↗
PubMed1988

Toxicologic studies of a superpotent alpha-melanotropin, [Nle4, D-Phe7]alpha-MSH.

A toxicology study was performed in mice given a superpotent alpha melanocyte stimulating hormone (MSH) analog. This 13 amino acid derivative, [Nle4, D-Phe7]alpha-MSH or NDP-MSH, is a melanotropin which is very slowly biodegraded in vivo and is active at 1/1,000 the concentration of natural alpha-MSH. Mice were administered up to 2 mg/kg of the analog daily and weekly over 4 or 12 weeks by both topical application (in 90% DMSO) or by IP injections (in physiologic saline). At the end of this period, no toxic effects were observed in various organs, on hematologic indices, or on weight gain. A slight increase in triglyceride and platelet levels were noted in mice given the analog weekly for 12 weeks. There was no evidence of an effect on behavior nor ACTH-like endocrine actions such as elevated serum cortisol levels. Transdermal drug delivery studies performed in vitro showed reproducible diffusion of the NDP-MSH analog through full-thickness mouse skin. Approximately 0.002% to 0.05% of a 10(-4) M preparation was transdermally delivered using a DMSO/water solution or a PEG/alcohol cream base, respectively. This superpotent analog is now entering a Phase I clinical trial with possible therapeutic applications for the treatment of hypomelanotic disorders such as vitiligo and for pharmacologic tanning without the need for sunlight exposure.

Administration, Cutaneous↗
PubMed1988

Quantitative autoradiography of [3H]CTOP binding to mu opioid receptors in rat brain.

[3H]H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 ([3H]CTOP), a potent and highly selective mu opioid antagonist, was used to localize the mu receptors in rat brain by light microscopic autoradiography. Radioligand binding studies with [3H]CTOP using slide-mounted tissue sections of rat brain produced a Kd value of 1.1 nM with a Bmax value of 79.1 fmol/mg protein. Mu opioid agonists and antagonists inhibited [3H]CTOP binding with high affinity (IC50 values of 0.2-2.4 nM), while the delta agonist DPDPE, delta antagonist ICI 174,864, and kappa agonist U 69, 593 were very weak inhibitors of [3H]CTOP binding (IC50 values of 234-3631 nM). Light microscopic autoradiography of [3H]CTOP binding sites revealed regions of high density (nucleus of the solitary tract, clusters in the caudate-putamen, interpeduncular nucleus, superior and inferior colliculus, subiculum, substantia nigra zona reticulata, medial geniculate, locus coeruleus and dorsal motor nucleus of the vagus) and regions of moderate labeling (areas outside of clusters in the caudate-putamen, cingulate cortex, claustrum and nucleus accumbens). The cerebral cortex (parietal) showed a low density of [3H]CTOP binding.

Animals↗
PubMed1988

Transdermal delivery of a melanotropic peptide hormone analogue.

We previously reported that topical application of [Nle4,D-Phe7]alpha-MSH, a superpotent analogue of alpha-melanocyte stimulating hormone, to mice induces a darkening of follicular melanocytes throughout the skin. We now report that the melanotropin analogue can be delivered across mouse but not rat skin in an in vitro model system. Passage of the analogue from the topically applied vehicle (polyethylene glycol) across the skin into a subcutaneous receiving vessel was demonstrated by both bioassay as well as by radioimmunoassay. The bioassay data demonstrate that percutaneous absorption of the melanotropin did not result in loss of biological activity of the peptide. The differential penetration of the peptide across rodent skin reveals that one cannot predict percutaneous absorption of a substance across the stratum corneum from studies on a single species. The present results are the first to demonstrate, by direct quantitative measurements, that a bioactive peptide can be delivered across the vertebrate integument in vitro. These studies point out the potential of a topically applied melanotropin for tanning of the skin and possibly for treatment of certain hypopigmentary disorders.

Administration, Cutaneous↗
PubMed1988

Perifused precision-cut liver slice system for the study of hormone-regulated hepatic glucose metabolism.

A nonrecirculatory perfusion system for precision-cut rat liver slices has been developed and utilized for investigating hormone-regulated hepatic glucose metabolism. In this system, slices are cultured in a highly controlled environment and exhibit excellent retention of viability as judged by their maintenance of intracellular potassium and glycogen contents. Using this system, the complex physiological phenomenon of hormone-regulated glycogenolysis was investigated at both extra- and intracellular sites. Specifically, the sensitive responses of intracellular cyclic AMP (cAMP) production, activation of cyclic AMP-dependent protein kinase, and production of glucose upon glucagon stimulation have been measured. The maximal responses observed for these parameters were either equal to or greater than those previously reported for either isolated hepatocytes or perfused livers, demonstrating the sensitivity of this technique. Upon dose-response examination of glucagon challenge, it was observed that high doses of glucagon (greater than 16 nM) stimulate glucose production by activating the cAMP-second messenger cascade. In contrast, low doses (less than 4 nM) stimulate this process without production of intracellular cAMP or activation of cAMP-dependent protein kinase, suggesting the operation of cAMP-independent messenger. Since this system permits measurements of parameters common to many cellular processes, this methodology is suitable for addressing both pharmacological and toxicological questions.

Animals↗
PubMed1988

Ventral tegmental oxytocin induces grooming.

Bilateral microinjection of oxytocin (OXY) into the ventral tegmental area (VTA) of rat brain produced a significant increase in grooming behaviors at doses from 100 pg to 400 ng. Sites in the caudal region of the VTA were sensitive to lower doses of OXY than sites in the rostral region of the VTA. The time course of action of OXY in the grooming paradigm indicated onset beginning immediately after injection, and termination at 60-75 minutes after injection. Comparison of OXY-induced grooming in male, female, and ovariectomized, estrogen-treated female rats showed no differences in potency for OXY among these groups, suggesting that the grooming effects of OXY are not regulated by sex steroids. Analysis of locomotor activity in rats microinjected with OXY 200 ng bilaterally into the caudal VTA revealed that OXY had no effect on ambulatory locomotion, suggesting that this peptide may activate neurons within the VTA which mediate grooming but not locomotion. The OXY receptor antagonist, [Pen1, pMePhe2, Thr4, Orn8]-OT, blocked OXY-induced grooming when both were simultaneously microinjected into the VTA. The dopamine D-2 receptor antagonist, haloperidol, and the D-1 receptor antagonist, SCH 23390, when microinjected into the VTA five minutes before microinjection of OXY into the VTA, did not block OXY-induced grooming, suggesting that OXY is not working through a dopamine autoreceptor on the VTA neurons. Systemic pretreatment with haloperidol and SCH 23390 effectively blocked grooming induced by OXY in the VTA, suggesting that OXY is directly stimulating OXY receptors on VTA neurons to release dopamine at postsynaptic sites regulating grooming behaviors.

Animals↗
PubMed1988

The effects of glucagon and TH-glucagon on steroid metabolism in isolated rat hepatocytes.

Glucagon decreases the activity of steroid-metabolising enzymes in isolated rat liver cells at physiological concentrations. Higher concentrations are less effective. TH-glucagon (1-N-alpha-trinitrophenylhistidine-12-homoarginine-glucagon) also reduces enzyme activity but does not lose activity at higher concentrations. The effects of the two hormones mimic closely their reported effects on phosphatidylinositol-4,5-bisphosphate breakdown. It is, thus, likely that the effect of glucagon on steroid metabolism is mediated via breakdown of this phospholipid. The calcium ionophore, A23187, had no effect on steroid metabolism whereas the phorbol ester 4 beta-phorbol-12-myristate-13-acetate (PMA) mimicked the effect of glucagon, showing that activation of protein kinase C but not Ca2+ mobilization may be involved in glucagon's action on hepatic steroid metabolism.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed1988

Design and synthesis of somatostatin analogues with topographical properties that lead to highly potent and specific mu opioid receptor antagonists with greatly reduced binding at somatostatin receptors.

A series of conformationally restricted, cyclic octapeptides containing a conformationally stable tetrapeptide sequence related to somatostatin, -Tyr-D-Trp-Lys-Thr-, as a template, were designed and synthesized with the goal of developing highly potent and selective mu opioid antagonists with minimal or no somatostatin-like activity. Three distinct structures of the peptide became targets of chemical modifications and constraints; the N- and C-terminal amino acids and the cyclic 20-membered ring moiety. Based on the conformational analysis of active and inactive analogues of the parent peptide D-Phe1-Cys2-Tyr3-D-Trp4-Lys5-Thr6-Pen7+ ++-Thr8-NH2, CTP (Kazmierski, W.; Hruby, V. J. Tetrahedron 1988, 44, 697-710), we designed analogues to include the tetrahydroisoquinolinecarboxylate (Tic) moiety as the N-terminal amino acid instead of D-Phe, since Tic can exist only as a gauche (-) or a gauche (+) conformer. In this series, the following peptides were synthesized and pharmacologically evaluated: D-Tic-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (TCTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (TCTOP), and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (TCTAP). In rat brain membrane opioid radioligand binding assays, all three peptides displayed high affinity for mu opioid receptors (IC50 = 1.2, 1.4, 1.2 nM, respectively), and exceptional mu vs delta opioid receptor selectivity: 7770, 11,396, and 1060, respectively. TCTOP and TCTAP also possess exceptional mu vs somatostatin receptor selectivity: 14,574 and 28,613, respectively. In the peripheral in vitro GPI bioassay, TCTP, TCTOP, and TCTAP were highly effective antagonists of the potent mu opioid receptor agonist PL017, with pA2 = 8.69 for TCTAP, 8.10 for TCTP, and 7.38 for TCTOP. Our results show that a 10-fold higher affinity and selectivity for mu opioid receptors (in both central and peripheral studies) over delta and somatostatin receptor was gained as a result of the D-Tic1 substitution. These three peptides, TCTP, TCTOP, and TCTAP, are the most potent and selective mu opioid antagonists known. CTP has been shown to possess prolonged biological action, much longer than that of naloxone. This renders these analogues potentially useful ligands for investigating the physiological functions of the mu opioid receptor. Analogues of TCTP in which the 20-membered disulfide ring was contracted by deletion of D-Trp4, and/or Lys5, and/or Thr6 led to compounds with greatly reduced potency at the mu opioid receptor.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acids↗
PubMed1988

Melanin concentrating hormone analogues: contraction of the cyclic structure. 1. Agonist activity.

Melanin concentrating hormone (MCH) is a heptadecapeptide, Asp-Thr-Met-Arg-Cys-Met-Val-Gly-Arg-Val-Tyr-Arg-Pro-Cys-Trp-Glu-Val, which is synthesized in the hypothalamus and secreted by the neurohypophysis of teleost fishes. This hormone exhibits both MCH-like as well as alpha-MSH (alpha-melanocyte stimulating hormone) like activity. We have examined the role of the disulfide bond for the two contrasting melanotropic activities of MCH. Nine analogues of the parent peptide were synthesized and characterized for biological activity. The disulfide ring was contracted from the 5-14 to the 7-14, 8-14, and 10-14 residues with concomitant substitution of alanine for Cys at position 5 in each of the heptadecapeptides. Similar substitutions were made in a series of MCH analogues. In addition, the following cyclic peptides also were synthesized: [Cys7]MCH, [Cys8]MCH, and [Cys10]MCH. The fish-skin bioassay is sensitive to MCH at a concentration of 10(-12) M. All ring-contracted analogues were inactive at 10(-6) M or lower concentrations; less than 1/1,000,000 compared to MCH (1.0) except [Ala5,Cys8]MCH (0.0008; 1/1250), [Cys10]MCH (0.000 09; 1/10,000), and [Cys8]MCH (0.000 001; 1/1,000,000). In the frog-skin bioassay, [Ala5,Cys10]MCH, although lacking MCH-like activity in the fish-skin bioassay, was equipotent to MCH in its alpha-MSH-like component of activity. Most other analogues were either inactive or much less active than MCH in stimulating melanosome dispersion. These results demonstrate that the disulfide bond between positions 5 and 14 is essential for the MCH-like activity since contraction of the ring generally leads to inactive peptides. Contraction of the disulfide bridge does not, however, have as great an effect on the MSH-like activity of MCH.

Animals↗
PubMed1988

Stimulation and antagonism of opioid delta-receptors produce opposite effects on active avoidance conditioning in mice.

The effects of opioid delta-receptor activation on conditioning in a one-way active avoidance paradigm were investigated in mice. Peripheral administration of 30 and 100 micrograms/kg of [Leu5]enkephalin (LE) and 11.6 micrograms/kg of [D-Pen2,D-Pen5]enkephalin (DPDPE), a synthetic enkephalin analog with high delta-selectivity, impaired acquisition of avoidance responding. The dose response functions for both peptides were U-shaped. Deficits in responding were also present 24 hours after training, which suggests that the impaired performance observed during training was not an impairment in the ability of the mice to perform. Also, neither LE nor DPDPE decreased footshock sensitivity or open-field activity, which rules out analgesia and decreased activity levels as likely explanations for the deficits in conditioning. Finally, antagonizing endogenous ligands with the delta-selective antagonist ICI 154,129 enhanced acquisition, an effect opposite that produced by LE and DPDPE. The results suggest that activation of delta-receptors is normally involved in the modulation of active avoidance learning.

Animals↗