l-Serine induces sedative and hypnotic effects acting at GABA(A) receptors in neonatal chicks

Intracerebroventricular injection of l-serine has been shown to have sedative and hypnotic effects on neonatal chicks exposed to acute stressful conditions. However, the mechanism by which l-serine induces these effects is unclear. The present study was conducted to clarify the mechanism by l-serine. The involvement of gamma-aminobutyric acid (GABA)(A) receptors on the effect of l-serine was investigated using the GABA(A) receptor antagonist picrotoxin. Co-administration of picrotoxin attenuated the sedative and hypnotic effect of l-serine. Further, we also investigated the involvement of glycine receptors since l-serine is suggested to act as the alpha-homomeric glycine receptor agonist. Glycine similarly induced sedative and hypnotic effects in chicks, but its effect was attenuated by the glycine receptor antagonist strychnine. Therefore, whether the effect of l-serine was mediated through the glycine receptor was investigated using l-serine and strychnine. The effect of l-serine was inhibited by picrotoxin, but not strychnine. It appears that l-serine induces sedative and hypnotic effects by enhancing inhibitory neurotransmission via GABA(A) receptors.     

Discriminative stimulus properties of phenazepam and lorazepam: specificity and role of GABA A receptors

Rats were trained to distinguish the injections of phenazepam (PZ, 2 mg/kg, i.p.) and lorazepam (LZ, 2 mg/kg, i.p.) from saline in the same dose in the two-lever liquid-reinforced operant drug-discrimination (DD) paradigm experiment. A very similar level of stimulus control was obtained in both PZ- and LZ-trained animals throughout the 14 and 19-day duration of the study, respectively, the accuracy of the appropriate lever responses being no less than 80% in both cases. The principal similarity of the dynamics of PZ-saline and LZ-saline stimulus discrimination in different operant behavior schedules, their generalization profiles and the results of cross-substitution testing are indicative of the identity of the interoceptive DD properties of PZ and LZ. The results of cross-substitution tests with phenobarbital (40-100 mg/kg, i.p.), pentobarbital (10 mg/kg, i.p.), muscimol (1 mg/kg, i.p.), calcium valproate (20 mg/kg, i.p.), and pregnanolone (2 mg/kg, i.p.) as well as the tests for antagonism with bicuculline (10 mg/kg, i.p.) and picrotoxin (2 mg/kg, i.p.) showed that the DD properties of LZ strongly depend on the functional activity of GABA receptors and to a much lesser extent on the picrotoxin-binding receptor component of the GABA-receptor complex, which is additional evidence for the principal similarity of the interoceptive effects of PZ and LZ.     

Agonists and antagonists acting at P2X receptors: selectivity profiles and functional implications

P2X receptors are nucleotide-gated cation channels composed of homomeric or heteromeric assemblies of three subunits. In the past 7 years, an extended series (P2X1-7) of P2X subunits has been cloned from vertebrate tissues. In this rapidly expanding field, one of the main current challenges is to relate the cloned P2X receptor subtypes to the diverse physiological responses mediated by the native P2X receptors. However, the paucity of useful ligands, especially subtype-selective agonists and antagonists as well as radioligands, acts as a considerable impediment to progress. Most of the ligands available are highly limited in terms of their kinetics of action, receptor-affinity, subtype-selectivity and P2X receptor-specificity. Their suspected ability to be a substrate for ecto-nucleotidases or to inhibit these enzymes also complicates their use. A number of new antagonists at P2X receptors have recently been described which to some degree are more potent and more selective than earlier antagonists like suramin or pyridoxal-5'-phosphate-6-azophenyl 2',4'-disulfonate (PPADS). This work moves us closer to the ideal goal of classifying the recombinant and native P2X receptor subtypes on the basis of antagonist profiles. This review begins with a brief account of the current status of P2X receptors. It then focuses on the pharmacological properties of a series of key P2 receptor agonists and antagonists and will finish with the discussion of some related therapeutic possibilities.     

Modulation of 5-hydroxytryptamine-induced head-twitch response by drugs acting at GABA and related receptors.

The effects of drugs acting at the gamma-aminobutyric acid (GABA) receptors and other chloride ionophore-related sites have been studied for their ability to modulate the head-twitch induced by 1-5-hydroxytryptophan (5-HTP) in the mouse. The GABAa receptor agonists, muscimol, imidazoleacetic acid and 3-aminopropanesulphonic acid, produced a dose-related potentiation, while bicuculline inhibited the head-twitch. The GABAb receptor agonist, baclofen, produced dose-related inhibition. Diazepam potentiated the head-twitch while the 'inverse' benzodiazepine receptor agonist ethyl-beta-carboline-3-carboxylate inhibited the head-twitch. The antagonist Ro15-1788 also produced inhibition. Ro05-4864, a ligand for the benzodiazepine 'acceptor' site, potentiated the head-twitch. Pentobarbitone and pentylenetetrazol potentiated the 5-HTP-induced head-twitch at low doses, changing to inhibition as the dose was increased. Picrotoxin in subconvulsant doses, produced only potentiation. More than one site may be involved in the action of these substances. GABA, amino-oxyacetic acid and 1-2-4-diaminobutyric acid inhibited the head-twitch, while the GABA-depletor, 3-mercaptopropionic acid potentiated it. Of all the agents tested, only muscimol produced head-twitching when given alone. It was concluded that both GABAa and GABAb receptors modulate the head-twitch response to 5-HTP.     

Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site

With the exception of obsessive compulsive disorder, benzodiazepines (BZs) remain a major first line treatment for anxiety disorders. However, as well as being anxiolytic, BZs also cause sedation acutely, related to the fact that BZs are also used as hypnotics, and chronically may have abuse potential as well as cause physical dependence which manifests itself as the demonstration of a number of adverse events upon discontinuation. The molecular mechanisms of BZs are now well defined in that they enhance the actions of the inhibitory neurotransmitter GABA by binding to a specific recognition site on GABA(A) receptors containing alpha1, alpha2, alpha3 and alpha5 subunits. Compounds that bind at this modulatory site and enhance the inhibitory actions of GABA are classified as agonists, those that decrease the actions of GABA are termed inverse agonists whereas compounds which bind but have no effect on GABA inhibition are termed antagonists. The clinically used BZs are full agonists and between the opposite ends of the spectrum, i.e. full agonist and full inverse agonist, are a range of compounds with differing degrees of efficacy, such as partial agonists and partial inverse agonists. Attempts have been made to develop compounds which are anxioselective in that they retain the anxiolytic properties of the full agonist BZs but have reduced sedation and dependence (withdrawal) liabilities. Such compounds may interact with all four (i.e. alpha1-, alpha2-, alpha3- and alpha5-containing) GABA(A) receptor subtypes and have partial rather than full agonist efficacies. Examples of nonselective partial agonists include bretazenil, imidazenil, FG 8205, abecarnil, NS 2710, pagoclone, RWJ-51204 and (S)-desmethylzopiclone. Alternatively, a compound might have comparable binding affinity but different efficacies at the various subtypes, thereby preferentially exerting its effects at subtypes thought to be associated with anxiety (alpha2- and/or alpha3-containing receptors) rather than the subtype associated with sedation (alpha1-containing receptors). Examples of efficacy selective compounds include L-838417, NGD 91-3 and SL651498. For each compound, preclinical and where available clinical data will be reviewed. Emerging themes include the lack of definitive intrinsic efficacy data for certain compounds (e.g. abecarnil, ocinaplon, pagoclone) and the difficulty in translating robust anxiolysis and a separation between anxiolytic and sedative doses of non-selective partial agonists in preclinical species into consistent clinical benefit in man (e.g. bretazenil, abecarnil, pagoclone). With respect to efficacy selective compounds, NGD 91-3 was not anxiolytic in man but in the absence of efficacy data, these results are difficult to interpret. Nevertheless, efficacy selective compounds represent a novel approach to targeting specific subtypes of the GABA(A) receptor, the ultimate test of which will be evaluation in the clinic.     

Contribution of GABA(A) and GABA(B) receptors to the discriminative stimulus produced by gamma-hydroxybutyric acid.

The present study examined the involvement of GABA(A) and GABA(B) receptors in the discriminative stimulus effects of gamma-hydroxybutyric acid (GHB). Rats were trained to discriminate either 300 or 700 mg/kg GHB IG from water using a T-maze, food-reinforced drug-discrimination procedure. The direct GABA(B) agonist, baclofen, substituted completely for both training doses of GHB; its potency to substitute for GHB increased moderately as the training dose of GHB was increased. The positive GABA(A) modulator, diazepam, substituted partially for 300 mg/kg GHB, but failed to elicit GHB-appropriate responding in rats trained with the higher GHB dose. Finally, the GABA(B) antagonist, CGP 35348, completely blocked the discriminative stimulus effects of the high training dose of GHB, but only partially antagonized the effects of the low training dose. These results suggest that (a) GHB produces a compound stimulus, and (b) both GABA(B)- and GABA(A)-mediated cues are prominent components of this compound stimulus; the contribution of each component, however, appears to vary as the training dose of GHB is increased.     

Discriminative stimulus properties of narcotic analgesic drugs.

This paper presents a comprehensive review on the experimental data relevant to the discriminative stimulus properties of narcotic analgesic drugs. The narcotic cue is defined as the discriminative stimulus complex which is exclusively associated with the specific central action(s) of narcotic analgesic drugs. The first part of this review discusses evidence that narcotics can act as a discriminative stimulus, and that this cue is an exclusive, complexly composed, and centrally originating property of narcotics. The pharmacological and biochemical specificity of the narcotic cue is supported by findings indicating (1) that chemically heterogenous narcotics generalize with narcotic agonist training drugs, (2) a close correlation between narcotic cuing and analgesic potency of narcotics, (3) that the requirement of steric specificity applies, and (4) the naloxone-reversibility of this cue. The comparative data so far available are thus consistent with the assumption that the narcotic cue in laboratory animals relates intimately to, and can serve as a preclinical model for opiate-like subjective effects in man. Further discussion is concerned with the involvement of various neurotransmitter substances in the narcotic cue; much as it appears likely that multiple and diffusely organized brain sites rather than discrete brain areas are involved, there is no evidence at this stage that any single transmitter would play a unique role in this cue. The other issues being discussed here are (1) the role of training drug dose, (2) the tolerance problem, (3) the relation between the narcotic cuing and the analgesic activity of narcotics, (4) the involvement of neuropeptides, (5) drug cue conditioning to environmental stimuli; (6) drug cues and drug states, and (7) the internal discriminative stimulus control of behavior by endogenous opioid substances.     

Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats

Rationale Tiagabine is an anticonvulsant drug which may also have sleep-enhancing properties. It acts by inhibiting reuptake at the gamma-aminobutyric acid (GABA) transporter (GAT-1). Objectives The aim of the study was to determine whether tiagabine acted as a discriminative stimulus and, if so, whether other GABAergic compounds would generalise to it. Materials and methods Rats were trained to discriminate tiagabine (30 mg/kg p.o.) from vehicle, and generalisation to drugs that modulate GABA was assessed. Results Gaboxadol (5–20 mg/kg p.o.), a selective extrasynaptic GABA_A agonist, generalised to tiagabine, although the extent of the generalisation was inconclusive. Indiplon (1 mg/kg p.o.), a benzodiazepine-like hypnotic, also partially generalised to tiagabine, although zolpidem and S-zopiclone did not. Baclofen, a GABA_B receptor agonist, and gabapentin, which increases synaptic GABA, did not generalise to tiagabine. (+)-Bicuculline (3 mg/kg i.p.), a GABA_A receptor antagonist, blocked the tiagabine cue, but the less brain-penetrant salt form, bicuculline methochloride, had no effect. Conclusions These data suggest that tiagabine generates a discriminative stimulus in rats, and provides a central GABA-mediated cue, but is distinct from the other GABAergic compounds tested.     

Subunit selectivity of topiramate modulation of heteromeric GABA(A) receptors

Topiramate (TPM) is an anticonvulsant of novel chemical structure whose mechanism of action remains elusive. Reports of TPM modulation of ligand- and voltage-gated ion channel functions are variable and often inconsistent. In fact, TPM has been found to produce enhancement, inhibition, and no effect on GABA-currents of cultured neurons and GABA(A) receptors expressed in Xenopus laevis oocytes. To identify possible causes for the variable effects of TPM on GABA(A) receptors, multiple combinations of recombinant GABA(A) receptor subunits were expressed in Xenopus oocytes. TPM modulation of GABA-currents was sensitive to GABA concentrations and the beta subunit isoform co-expressed in heteromeric GABA(A) receptors. TPM potentiated and directly activated heteromeric receptors containing either beta(2) or beta(3) subunit. TPM's direct activation was most effective on receptors comprised of alpha(4)beta(3)gamma(2S) subunits and activated approximately 74% of the peak GABA-current. TPM modulation of beta(1)-containing heteromeric receptors depended on the co-expressed alpha subunit isoform (i.e., either TPM enhancement or inhibition). Depolarized potentials decreased TPM enhancement and increased TPM inhibition depending on the beta subunit present. These results suggest that the effects of TPM on GABA(A) receptor function will depend on the expression of specific subunits that can be regionally and temporally distributed, and altered by neurological disorders.     

The effects of cyclopentane and cyclopentene analogues of GABA at recombinant GABA(C) receptors.

The pharmacological effects of the enantiomers of cis-3-aminocyclopentanecarboxylic acids ((+)- and (−)-CACP), the enantiomers of trans-3-aminocyclopentanecarboxylic acids ((+)- and (−)-TACP), and the enantiomers of 4-aminocyclopent-1-ene-1-carboxylic acids ((+)- and (−)-4-ACPCA) were studied on human homomeric ρ₁ and ρ₂ GABA_C receptors expressed in Xenopus oocytes using two-electrode voltage clamp methods. These compounds are conformationally restricted analogues of γ-aminobutyric acid (GABA) held in a five-membered ring. (+)-TACP (EC₅₀ (ρ₁)=2.7±0.2 μM; EC₅₀ (ρ₂)=1.45±0.22 μM), (+)-CACP (EC₅₀ (ρ₁)=26.1±1.1 μM; EC₅₀ (ρ₂)=20.1±2.1 μM) and (−)-CACP (EC₅₀ (ρ₁)=78.5±3.5 μM; EC₅₀ (ρ₂)=63.8±23.3 μM) were moderately potent partial agonists at ρ₁ and ρ₂ GABA_C receptors, while (−)-TACP (100 μM inhibited 56% and 62% of the current produced by 1 μM GABA at ρ₁ and ρ₂ receptors, respectively) was a weak partial agonist with low intrinsic activity at these receptors. In contrast, (+)-4-ACPCA (K_i (ρ₁)=6.0±0.1 μM; K_i (ρ₂)=4.7±0.3 μM) did not activate GABA_C ρ₁ and ρ₂ receptors but potently inhibited the action of GABA at these receptors, while (−)-4-ACPCA had little effect as either an agonist or an antagonist. The affinity order at both GABA_C ρ₁ and ρ₂ receptors was (+)-TACP>(+)-4-ACPCA(+)-CACP>(−)-CACP(−)-TACP(−)-4-ACPCA. This study shows that the cyclopentane and cyclopentene analogues of GABA affect GABA_C receptors in a unique manner, defining a preferred stereochemical orientation of the amine and carboxylic acid groups when binding to GABA_C receptors. This is exemplified by the partial agonist, (+)-TACP, and the antagonist, (+)-4-ACPCA.     

Discriminative stimulus properties of CGS 9896: interactions within the GABA/benzodiazepine receptor complex

Male rats were trained to discriminate the stimulus effects of CGS 9896 (30.0 mg/kg) from its vehicle. Once trained, discriminative performance was observed to be dose-responsive in the 3.75-30.0 mg/kg range and analysis of the dose-response curve generated an ED50 of 6.44 mg/kg. Generalization testing with chlordiazepoxide and pentobarbital produced CGS 9896-appropriate responding, whereas administration of the GABA agonists SL 75 102 resulted in 75% (intermediate) generalization to the CGS 9896 discriminative stimulus. Although full antagonism of the CGS 9896 cue was obtained following administration of Ro15-1788 and pentylenetetrazole, the inverse agonist DMCM failed to provide complete antagonism. These results suggest that the discriminative properties of CGS 9896 are consistent with its activity as a benzodiazepine receptor agonist.     

Discriminative stimulus effects of (-)-ephedrine in rats: analysis with catecholamine transporter and receptor ligands

A drug discrimination procedure was used to examine the neuropharmacology of (−)-ephedrine (5 mg/kg), a sympathomimetic amine found in a variety of dietary supplements. (−)-Ephedrine has caused concern because of its use as a precursor in the manufacture of street drugs (e.g. methamphetamine) and its potential for abuse and toxicity. In the present study, the catecholamine reuptake inhibitors mazindol and nomifensine, the norepinephrine (NE) reuptake inhibitor desipramine, and the dopamine D₂-like (e.g. D₂, D₃ and D₄) agonist quinpirole substituted for (−)-ephedrine (80% (−)-ephedrine-lever responding). The NE reuptake inhibitor nisoxetine, the D₁-like (e.g. D₁ and D₅) agonists (±)-SKF 38393 and SKF 82958, and the mixed D₁-/D₂-like agonist apomorphine occasioned intermediate levels of responding (50–79% (−)-ephedrine-lever responding). The (−)-ephedrine cue was antagonized by the D₁-like antagonist SCH 23390 and the ₁-adrenoceptor antagonist prazosin as well as the D₂-like antagonists (−)-eticlopride and haloperidol, although only at doses that disrupted responding in some rats. The discriminative stimulus effects of a small dose of (−)-ephedrine (1.25 mg/kg) were enhanced by the ₂-adrenoceptor antagonist idazoxan and to a lesser extent by the β-adrenoceptor antagonist (−)-propranolol. However, the ₂-adrenoceptor agonist clonidine (0.04 mg/kg) did not attenuate the (−)-ephedrine stimulus. These results suggest that D₁-, D₂-like, and ₁-adrenergic receptors mediate the discriminative stimulus effects of (−)-ephedrine. Substitution of desipramine for (−)-ephedrine and not for some other stimulants suggests that NE transmission is a prominent feature of the (−)-ephedrine discriminative stimulus, and that NE underlies therapeutic and abuse-related effects of (−)-ephedrine that diverge from those of other stimulants.     

Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors

Although neurosteroids have rapid effects on GABA(A) receptors, study of steroid actions at GABA receptors has been hampered by a lack of pharmacological antagonists. In this study, we report the synthesis and characterization of a steroid analog, (3alpha,5alpha)-17-phenylandrost-16-en-3-ol (17PA), that selectively antagonized neurosteroid potentiation of GABA responses. We examined 17PA using the alpha1beta2gamma2 subunit combination expressed in Xenopus laevis oocytes. 17PA had little or no effect on baseline GABA responses but antagonized both the response augmentation and the direct gating of GABA receptors by 5alpha-reduced potentiating steroids. The effect was selective for 5alpha-reduced potentiating steroids; 5beta-reduced potentiators were only weakly affected. Likewise, 17PA did not affect barbiturate and benzodiazepine potentiation. 17PA acted primarily by shifting the concentration response for steroid potentiation to the right, suggesting the possibility of a competitive component to the antagonism. 17PA also antagonized 5alpha-reduced steroid potentiation and gating in hippocampal neurons and inhibited anesthetic actions in X. laevis tadpoles. Analogous to benzodiazepine site antagonists, the development of neurosteroid antagonists may help clarify the role of GABA-potentiating neurosteroids in health and disease.     

Discriminative stimulus effects of prototype opiate receptor agonists in monkeys

Angiotensin receptor binding interactions of the angiotensin agonist, 125I-angiotensin II (125I-AII), and antagonist, 125I-[sarcosine1,leucine8]angiotensin II (125I[Sar1,Leu8]AII), are differentially affected by sodium ion concentration. 125I-AII binding to calf cerebellar cortex or adrenal cortex is increased 25 or 2.5 fold respectively when sodium ion concentration is increased from 10 to 150 mM. In brain membranes increasing sodium concentration accelerates the association and slows the dissociation of 125I-AII. 125I[Sar1,Leu8]AII binding to these tissues is much less sensitive to changes in sodium ion concentration. In rabbit uterine homogenates, neither 125I-AII nor 125I[Sar1,Leu8]AII binding is significantly altered by changes in sodium ion concentration. The sodium elicited increase in 125I-AII binding to calf cerebellum is correlated with cationic size and is not an ionic strength effect. The effect of sodium on potencies of angiotensin analogues in competing for 125I[Sar1,Leu8]AII binding does not correlate with agonist or antagonist properties, but is largest for peptides with aspartic acid at position one in the peptide structure.     

Antimalarial drugs inhibit human 5-HT(3) and GABA(A) but not GABA(C) receptors

BACKGROUND AND PURPOSE: Antimalarial compounds have been previously shown to inhibit rodent nicotinic acetylcholine (nACh) and 5-HT(3) receptors. Here, we extend these studies to include human 5-HT(3A), 5-HT(3AB), GABA(A) alpha1beta2, GABA(A) alpha1beta2gamma2 and GABA(C) rho1 receptors.EXPERIMENTAL APPROACH: We examined the effects of quinine, chloroquine and mefloquine on the electrophysiological properties of receptors expressed in Xenopus oocytes.KEY RESULTS: 5-HT(3A) receptor responses were inhibited by mefloquine, quinine and chloroquine with IC(50) values of 0.66, 1.06 and 24.3 microM. At 5-HT(3AB) receptors, the potencies of mefloquine (IC(50)=2.7 microM) and quinine (15.8 microM), but not chloroquine (23.6 microM), were reduced. Mefloquine, quinine and chloroquine had higher IC(50) values at GABA(A) alpha1beta2 (98.7, 0.40 and 0.46 mM, respectively) and GABA(A) alpha1beta2gamma2 receptors (0.38, 1.69 and 0.67 mM, respectively). No effect was observed at GABA(C) rho1 receptors. At all 5-HT(3) and GABA(A) receptors, chloroquine displayed competitive behaviour and mefloquine was non-competitive. Quinine was competitive at 5-HT(3A) and GABA(A) receptors, but non-competitive at 5-HT(3AB) receptors. Homology modelling in combination with automated docking suggested orientations of quinine and chloroquine at the GABA(A) receptor binding site.CONCLUSIONS AND IMPLICATIONS: The effects of mefloquine, quinine and chloroquine are distinct at GABA(A) and GABA(C) receptors, whereas their effects on 5-HT(3AB) receptors are broadly similar to those at 5-HT(3A) receptors. IC(50) values for chloroquine and mefloquine at 5-HT(3) receptors are close to therapeutic blood concentrations required for malarial treatment, suggesting that their therapeutic use could be extended to include the treatment of 5-HT(3) receptor-related disorders.     

Antagonizing the anticonvulsant effect of ethanol using drugs acting at the benzodiazepine/GABA receptor complex

The ability of various benzodiazepine receptor ligands to antagonize the anticonvulsant action of ethanol was investigated using intravenous infusion of the GABA antagonist bicuculline. The partial inverse agonists FG 7142, RO 15-4513 and RO 15-3505 produced dose-related reductions in seizure threshold. These compounds also partially reversed the anticonvulsant action of ethanol. However, the magnitude of the effects in each case was only equivalent to the reduction in seizure threshold caused by each compound when administered alone. This is the proconvulsant effect of each compound merely subtracted from the anticonvulsant effect of ethanol. ZK 93426, a benzodiazepine receptor antagonist which alone failed to alter seizure threshold, did not affect the anticonvulsant action of ethanol. Both RO 15-4513 and RO 15-3505 also lowered the seizure threshold of barbiturate-treated mice, again in a subtractive fashion. The ability of RO 15-4513 and other inverse agonists to antagonize the anticonvulsant effect of ethanol appears to result from their intrinsic proconvulsant properties.     

Discriminative stimulus effects of H(1)-anti-histamines in cocaine-trained pigeons

Pigeons (n = 4) were trained to discriminate cocaine (3.0mg/kg, i.m.) from saline in a two-key, food-reinforced drug discrimination paradigm. After acquisition of the discrimination, the H(1)-antihistamines, chlorpheniramine, tripelennamine, diphenhydramine, promethazine and hydroxyzine, were administered before test sessions to determine if these antihistamines shared discriminative stimulus (DS) effects with cocaine. Chlorpheniramine (0.3-5.6mg/kg) and tripelennamine (0.1-1.7mg/kg) substituted, (i.e. > 80% cocaine-key responding) in all four birds. Diphenhydramine (0.1-10mg/kg) and promethazine (0.1-56mg/kg) substituted for cocaine in three and two birds, respectively, while hydroxyzine (1.0-100mg/kg) did not substitute for the training drug in any bird. These results, in conjunction with results from a previous study in which several antihistamines shared DS effects with d-amphetamine, suggest that the DS effects of some H(1)-antihistamines may be similar to those of psychomotor stimulants.     

Transduction of the discriminative stimulus effects of zolpidem by GABA(A)/alpha1 receptors

Zolpidem is an imidazopyridine with high affinity at gamma-aminobutyric acid(A) (GABA(A)) receptors expressing alpha1 subunits. In squirrel monkeys trained to discriminate a high dose of zolpidem (> or =3.0 mg/kg) from saline, zolpidem and another GABA(A)/alpha1 receptor-preferring agonist, zaleplon, substituted dose-dependently for zolpidem, whereas the non-selective agonists diazepam and triazolam were did not substitute at any dose tested. These findings offer the first evidence for a selective role of GABA(A)/alpha1 receptors in the interoceptive effects of high doses of zolpidem.     

Effects of gamma-HCH and delta-HCH on human recombinant GABA(A) receptors: dependence on GABA(A) receptor subunit combination

1. Human GABA(A) receptors containing different alpha and beta subunits with or without the gamma 2S or gamma 2L subunits were expressed in XENOPUS: oocytes and the effects of the insecticides gamma- and delta-hexachlorocyclohexane (gamma-HCH and delta-HCH, respectively) on these receptor subunit combinations were examined using two electrode voltage-clamp procedures. 2. gamma-HCH produced incomplete inhibition of GABA responses on all receptor combinations examined with affinities in the range of 1.1--1.9 microM. Affinity was not dependent on subunit composition but the maximum percentage of inhibition was significantly reduced in beta 1-containing receptors. delta-HCH both potentiated GABA(A) receptors and activated them in the absence of GABA at concentrations higher than those producing potentiation. Allosteric enhancement of GABA(A) receptor function by delta-HCH was not affected by the subunit composition of the receptor, By contrast the GABA mimetic actions of delta-HCH were abolished in receptors containing either alpha 4, beta 1 or gamma 2L subunits. 4. Sensitivity to the direct actions were not restored in receptors containing the mutant beta 1(S290N) subunit, but alpha 1 beta 2 gamma 2L receptors became sensitive to the direct actions of delta-HCH when oocytes were treated for 24 h with the protein kinase inhibitor isoquinolinesulphonyl-2-methyl piperazine dihydrochloride (H-7). 5. We have shown the influence of various alpha, beta and gamma subunits on the inhibitory, GABA mimetic and allosteric effects of HCH isomers. The data reveal that neither the inhibitory actions of gamma-HCH nor the allosteric effects delta-HCH has a strict subunit dependency. By contrast, sensitivity to the direct actions of delta-HCH are abolished in receptors containing alpha 4, beta 1 or gamma 2L subunits.     

Discriminative stimulus effects of putative D3 dopamine receptor agonists in rats

Three separate groups of rats were trained to discriminate the putative D3 dopamine receptor agonists (+/-)-7-hydroxydipropylaminotetralin (7-OH-DPAT) (0.03 mg/kg), PD 128,907 (1.0 mg/kg) and quinpirole (0.03 mg/kg) from saline. Food was presented after each 10 (7-OH-DPAT and PD 128,907) or 20 (quinpirole) consecutive responses on one lever after administration of the training drug, and the other lever after the administration of saline. Once stable performances were obtained, the effects of various doses of several dopaminergic agonists were assessed during test sessions in which responses on either lever were reinforced. The substitution tests were conducted to determine if differences in potencies would be obtained, which would be suggestive of differences in the mechanisms underlying the discriminative effects of the training drugs. Non-selective agonists with activity at both D2 and D3 dopamine receptors (D2-like agonists) substituted for each of the three training drugs. In addition, the selective D2 dopamine receptor agonist U91356A also generalized to both 7-OH-DPAT and PD 128,907. The potencies of the D2-like agonists in substituting for each training drug were highly correlated with potencies in substituting for the others. SKF 82958 and SKF 81297, agonists with selectivity for D1 and D5 dopamine receptors (D1-like agonists), partially substituted for 7-OH-DPAT but not PD 128,907. The D1-like partial agonist SKF 38393 did not substitute for any of the training drugs for which it was tested. Cocaine produced intermediate substitution in 7-OH-DPAT- and PD 128,907-trained subjects and did not substitute at all in quinpirole-trained subjects. The dopamine D1-like antagonist SCH 39166 (0.001-0.03 mg/kg) did not alter the discriminative stimulus effects of PD 128,907, whereas the D2-like dopamine antagonist spiperone (0.001-0.1 mg/kg) produced at the highest dose an insurmountable antagonism of the discriminative effects of PD 128,907. In contrast, there was no appreciable antagonism of the effects of PD 128,907 on response rates. The data collected are consistent with a distinction between the effects of each of these training drugs and the indirectly acting agonist cocaine. Further, these data indicate that there are differences in the mechanisms underlying the discriminative effects of PD 128,907 and its effects on response rates. Moreover, these data indicate that each of the training drugs is distinct from drugs acting through D1 dopaminergic mechanisms. However, there were no data that clearly distinguished these training drugs from each other or from drugs acting through D2 dopaminergic mechanisms.