Variations in coralligenous assemblages from local to biogeographic spatial scale.

The present study aims at contributing to the knowledge of the spatial variability of coralligenous reefs through the evaluation of patterns ranging from local to biogeographic scale around the island of Sardinia. The coralligenous reef assemblages of six areas were studied through a hierarchical sampling design: three sites per area were selected, in each site three plots were sampled and in each plot ten photographic samples were collected. The structure of coralligenous reefs across closed biogeographic regions is described, highlighting that nearly pristine assemblages, although characterized by similar high diversity, can be either dominated by animals, such as gorgonians and bryozoans, or macroalgae. The observed variations seem largely related to biogeographic patterns rather than spatial distance, supporting the need to identify specific reference conditions to assess the ecological quality of this habitat depending on the biogeographic area to be monitored.

Discriminative stimulus effects of morphine in squirrel monkeys: stimulants, opioids, and stimulant-opioid combinations.

Morphine and other mu opioids mimic and/or modulate the discriminative stimulus (DS) effects of cocaine, possibly reflecting mutual stimulation of mesolimbic dopamine activity. Less is known about the capacity of cocaine and related stimulants to modulate the DS effects of morphine. The present study investigated the effects of cocaine, amphetamine, and reference drugs, administered alone and with morphine, in squirrel monkeys trained to discriminate morphine from vehicle. Additional studies determined the ability of opioid and dopamine receptor antagonists to attenuate the DS effects of morphine and the morphine-like effects of other drugs. The DS effects of morphine were mimicked by the mu-opioid agonist fentanyl but not the delta-opioid agonists SNC 80 and BW 373U86 or the kappa-opioid agonist U50,488H, and were antagonized by the opioid antagonist naltrexone but not the dopamine antagonist flupenthixol. In three of five monkeys, the DS effects of morphine also were mimicked by cocaine, amphetamine, and the dopamine transport inhibitor GBR 12909 but not the norepinephrine transport inhibitor talsupram or the serotonin transport inhibitor fluoxetine, and were antagonized by flupenthixol but not naltrexone. In this subgroup, pretreatment with cocaine or amphetamine enhanced the DS effects of morphine, whereas in the other two monkeys pretreatment with either stimulant attenuated the DS effects of morphine. The results demonstrated individual differences in morphine-like DS effects of stimulants that are mirrored by individual differences in their interactions with morphine. Furthermore, different mechanisms appear to mediate the DS effects of morphine and the morphine-like DS effects of cocaine and amphetamine.

Zolpidem physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons.

The current study examined behavioral effects and possible development of physical dependence after once-daily doses of zolpidem (0, 1.0, 3.2, 10.0, 32.0 mg/kg intragastrically [i.g.]) in three baboons. Each dose was administered for 17 days and then the dose was increased; the 32.0 mg/kg dose was administered for 27 days. Baboons had access to food pellets for 20 hr/day beginning 15 min after dosing. Each day, baboons were presented with a fine motor task. Observation sessions were conducted 1 hr after dosing on days 1, 10, 12 and 14 of each dose condition and after termination of drug dosing. On days 10 and 14 of each dose condition, vehicle and flumazenil (5 mg/kg i.m.) were administered, respectively. Zolpidem increased the number of pellets obtained by two of three baboons. Vomit and/or retch and grimace (signs believed to be indicative of abdominal discomfort) were observed in one or two baboons during all zolpidem dose conditions (1.0-32.0 mg/kg). Time to complete the fine motor task increased dose-dependently in all three baboons, and incoordination was observed during the task in two baboons at 10.0 and 32.0 mg/kg. Analysis of blood plasma showed that measurable levels of zolpidem were present 24 hr after dosing in all drug conditions. The signs of flumazenil-precipitated withdrawal were summarized on a 9-point scale. Scores ranged from 1 to 5 in the 1.0 mg/kg condition, from 2 to 5 in the 3.2 and 10.0 mg/kg conditions and from 4 to 6 in the 32.0 mg/kg condition. Signs that were considered intermediate in severity were observed. Specifically, tremor, jerk and/or rigidly braced posture was observed in one baboon at 1.0 mg/kg, two baboons at the next two doses and all three baboons at 32.0 mg/kg. Vomit and/or retch also occurred in two baboons at dose conditions above 1.0 mg/kg. Discontinuation of zolpidem dosing after 78 to 79 days resulted in mild withdrawal signs (e.g., number of pellets obtained were lower and number of 1-min intervals increased in which eyes were closed, or in which lying down, head lower than torso posture and/or withdrawn posture were observed) on the first day in two baboons. The peak withdrawal scores were 4 or 5 on days 5 to 10; two baboons vomited and/or retched and all three baboons showed tremor, jerk and/or rigidly braced posture. Thus, zolpidem produced physical dependence under once-daily dosing conditions, and the severity of the withdrawal syndrome can be characterized as intermediate.

The discriminative stimulus effects of muscimol in rats.

To evaluate the discriminative stimulus effects of a direct-acting GABAA agonist, seven rats were trained to discriminate 1 mg/kg IP muscimol from saline under a two-lever fixed ratio (FR) 20 schedule of food reinforcement. The direct GABAA agonist THIP (4,5,6,7-tetrahydro-isoxazolo [5, 4,c]-pyridin-3-ol) produced increases in muscimol lever responding and substituted for muscimol in all subjects. Unlike results with muscimol, the highest levels of muscimol lever responding following THIP administration were often produced at doses which also decreased rates of responding. The GABAB agonist baclofen and the indirect-acting GABAA agonists pentobarbital and midazolam produced substitution for muscimol in some subjects, but not in others. The non-competitive NMDA antagonist phencyclidine (PCP) produced mixed results in these rats, from partial to full substitution (both dose-dependently and exhibiting in lack of dose-dependence) in some animals and a complete failure to substitute in another. The selective GABAA antagonist bicuculline dose-dependently blocked the muscimol discriminative stimulus in a majority of subjects. This study is the first report of successful training of a drug discrimination in rats using muscimol. Evidence is provided from substitution and antagonism testing with THIP and bicuculline, respectively, that the muscimol discrimination was mediated by actions at the GABA binding site on the GABAA receptor-ionophore complex. Results, also suggest that drug stimulus control by muscimol is weak compared to that of other types of GABA agonists previously studied using drug discrimination procedures in rodents.

Self-administration of D1 receptor agonists by squirrel monkeys.

Dopaminergic mechanisms are believed to play a prominent role in the self-administration of cocaine and other abused stimulants. The contribution of D2 receptors is now well established, but less is known about the role of D1 receptors in the reinforcing effects of these drugs. To help clarify the role of D1 mechanisms in stimulant self-administration, agonists differing in D1 receptor selectivity (SKF 81297 > SKF 82958 > SKF 77434) and efficacy (SKF 82958 > SKF 81297 > SKF 77434) were studied for their ability to maintain IV self-administration in squirrel monkeys previously trained to self-administer cocaine. Up to a 100-fold range of doses of each D1 agonist was studied under both a fixed-ratio (FR) and a second-order fixed-interval (FI) schedule of reinforcement. Parallel studies were conducted with the D2 receptor agonists, (+)-PHNO and quinpirole, under the second-order FI schedule. Of the three D1 agonists, only SKF 82958 maintained consistent self-administration under both the FR and second-order FI schedules and had dose-related effects that were qualitatively similar to those of (+)-PHNO and quinpirole under the latter condition. SKF 81297, which has high selectivity at D1 receptors and intermediate agonist efficacy, maintained self-administration in the majority of monkeys under the FR schedule, but did not maintain self-administration under the second-order FI schedule. SKF 77434, which has moderate selectivity at D1 receptors and low agonist efficacy, did not maintain self-administration under either schedule. The results suggest that the ability of D1 agonists to maintain IV self-administration in squirrel monkeys depends both on the type of schedule and on the pharmacological properties (i.e. selectivity and efficacy) of the particular drug. These results are also consistent with the view that D1, in addition to D2, receptor mechanisms play a role in the self-administration of abused stimulants.

Behavioral pharmacology of two novel substituted quinoxalinedione glutamate antagonists.

Two novel quinoxalinedione glutamatergic antagonists, with in vitro selectivity for the glycine modulatory site on the N-methyl-d-aspartate (NMDA) receptor, were evaluated in a number of behavioral tests primarily designed to compare their effects to those of the noncompetitive NMDA antagonist phencyclidine (PCP). The compounds evaluated were 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) and 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021). In rats, both ACEA-1011 and ACEA-1021 were completely devoid of PCP-like discriminative stimulus effects, although behavioral activity, in the form of response rate suppression, was seen at the higher doses tested (6-25mg/kg, i.p.). ACEA-1011 and ACEA-1021 were also ineffective as antagonists of PCP discrimination in rats. ACEA-1021 failed to substitute in rhesus monkeys trained to discriminate PCP from sham injection, although in the monkeys minimal effects were observed on rates of responding even at the highest dose tested (10.2mg/kg, i.v.). ACEA-1021 also failed to produce ethanol-like discriminative stimulus effects in rats under test conditions where PCP has been shown to produce substantial levels of substitution for ethanol. Both ACEA-1011 and ACEA-1021 were also evaluated as antagonists of NMDA discrimination in rats. ACEA-1011 produced some decreases in NMDA-lever responding, with the largest effect at one intermediate dose (3mg/kg, i.p.). ACEA-1021 was ineffective as an antagonist of NMDA discrimination. Unlike results reported for PCP-like NMDA antagonists, neither ACEA-1011 nor ACEA-1021 disrupted prepulse inhibition of the acoustic startle reflex in rats. It was not possible to establish ACEA-1021 (10 or 15.6mg/kg) as a discriminative stimulus in rats. In conclusion, the novel glutamate antagonists ACEA-1011 and ACEA-1021 did not produce a profile of behavioral effects similar to that of PCP-like noncompetitive NMDA antagonists. These results are consistent with an emerging body of evidence showing differences in the behavioral effects of different classes of glutamate antagonists.

Discriminative stimulus effects of excitatory amino acid agonists in rats.

Sixteen male Sprague-Dawley rats were trained to discriminate 30 mg/kg i.p. NMDA from saline using a 2-lever operant procedure. Responding was maintained under a FR 32 schedule of food reinforcement. Substitution tests were completed with NMDA (3-56 mg/kg) and other putative excitatory amino acids, L-glutamate (30-560 mg/kg), L-aspartate (30-300 mg/kg), L-homocysteic acid (100-1500 mg/kg), L-cysteine (30-1000 mg/kg), monosodium glutamate (100-3000 mg/kg), kainic acid (0.1-3 mg/kg) and the selective NMDA receptor agonist, D,L-(tetrazol-5-yl)glycine (LY 285265) (0.01-1.0 mg/kg). LY 285265 fully substituted for NMDA and was approx 100-fold more potent than NMDA for producing NMDA-like discriminative stimulus effects. Partial substitution occurred with monosodium glutamate, L-glutamate and L-homocysteic acid, resulting in mean maximum levels of 49-59% NMDA-lever responding, however response rate decreases were only obtained with 3000 mg/kg monosodium glutamate, suggesting that behaviorally active doses of the other compounds may not have been fully studied. L-Cysteine, kainic acid and L-aspartate failed to substitute for NMDA or produce decreases in response rates. Unlike with other excitatory agonists tested, full substitution occurred only with LY 285265, providing evidence that selective NMDA receptor activation is the basis for the NMDA discriminative stimulus. These results also suggest that LY 285265 is a potent, systemically active, selective agonist for the NMDA receptor.

Discriminative stimulus effects of presynaptic GABA agonists in pentobarbital-trained rats.

The discriminative stimulus effects of indirect-acting GABAergic drugs were compared to those of pentobarbital (PB) and midazolam in rats trained to discriminate 5 mg/kg PB from saline under a two-lever fixed-ratio 32 schedule of food reinforcement. PB and midazolam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Valproic acid, an antiepileptic drug and GABA transaminase inhibitor, substituted for PB but only at a dose that produced response rate suppression. Vigabatrin, an irreversible GABA transaminase inhibitor, failed to substitute for PB, but did produce a dose-dependent decrease in response rates. The GABA uptake inhibitors, 1-[2-[bis[4-(trifluoromethyl)phenyl]-methoxy]ethyl]-1,2,5,6- tetrahydro-3-pyridinecarboxylic acid (CI-966) and (R(-)-N-[4,4-bis(3-methylthien-2-yl)but-3-enyl] nipecotic acid HCl (tiagabine), produced no greater than 40% PB-lever responding. Aminooxyacetic acid (AOAA), which is described as a nonselective presynaptic GABA agonist, yielded a maximum of 43% PB-lever responding. These results indicate that the discriminative stimulus effects of the indirect GABAA agonists, PB and midazolam, although similar to one another, differ from those of presynaptic GABAergic drugs. Differences in the discriminative stimulus properties of GABA transaminase inhibitors and uptake inhibitors also exist, indicating that not all presynaptic GABA agonists have similar behavioral profiles. These results contribute to a further understanding of the similarities and differences in the behavioral effects of drugs that enhance GABAergic neurotransmission.

Pharmacological specificity of N-methyl-D-aspartate discrimination in rats.

The purpose of this study was to provide further information on the usefulness of N-methyl-D-aspartate (NMDA) discrimination in rats as a behavioral model for NMDA receptor activation. The pharmacological specificity of the NMDA discriminative stimulus was examined in rats trained to discriminate 30 mg/kg, i.p. NMDA from saline using a 2-lever fixed-ratio (FR) 32 food reinforcement schedule. Pharmacologically diverse centrally-acting agents were examined for their ability to substitute for NMDA. Morphine did not substitute for NMDA; neither did the central stimulants, caffeine and (+)-amphetamine, which produced a maximum mean of only 16 and 35% NMDA-lever responding, respectively. Pentylenetetrazol and picrotoxin also did not substitute for NMDA. Compounds interacting with cholinergic neurotransmission including nicotine, physostigmine, arecoline and mecamylamine, produced at best, only intermediate levels of NMDA-lever responding (32-61%), with the highest levels of NMDA-lever responding generally occurring at doses that also reduced rates of responding. These results suggest that the discriminative stimulus properties of NMDA are dissimilar from those of a number of centrally-acting drugs. Combined with the results of studies indicating that the NMDA discriminative stimulus can be antagonized by competitive NMDA antagonists, these results provide further evidence that NMDA receptor activation is the basis of NMDA discrimination and that this model may be useful for studying site-selective NMDA agonists and antagonists.

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats.

The discriminative stimulus effects of direct and indirect-acting GABAergic drugs were investigated in rats trained to discriminate 5 mg/kg pentobarbital (PB) from saline under a two-lever fixed ratio (FR) 32 schedule of food reinforcement. PB and diazepam produced dose-dependent substitution for the training dose of PB with response rate reduction only at doses above those producing full substitution. Muscimol, thiomuscimol and 4,5,6,7-tetrahydroisoxazolo [5,4-c]-pyridin-3-ol (THIP) produced intermediate levels of pentobarbital-lever responding (40-60%), accompanied by dose-dependent decreases in rates of responding following THIP and muscimol administration. The GABAA agonist progabide and its metabolite 4-([(4-chlorophenyl) (5-fluoro-2-hydroxyphenyl)methylene]amino)] butyric acid (SL 75102) also partially substituted for PB, producing means of 39-73% PB-lever responding. The GABAB agonist, baclofen, completely failed to substitute for PB even at doses that decreased rates of responding. These results show that the discriminative stimulus effects of indirect GABAA agonists, PB and diazepam, although similar to one another, differ from those of direct GABAA receptor agonists, which produced only partial substitution for PB. The GABAB agonist, baclofen, can be distinguished by lacking any ability to substitute for PB. These results contribute to a further understanding of the similarities and differences in the behavioral effects of different types of GABA agonists.

Drug discrimination analysis of ethanol as an N-methyl-D-aspartate receptor antagonist.

Ethanol has been shown to antagonize N-methyl-D-aspartate (NMDA) receptor-mediated neurotransmission in a number of in vitro systems. Drug discrimination procedures in rats were used to evaluate ethanol as an antagonist of NMDA discrimination and for its ability to produce discriminative stimulus effects similar to those of competitive and noncompetitive NMDA antagonists. Ethanol (300-1500 mg/kg i.p.) failed to antagonize the stimulus effects of 30 mg/kg NMDA, nor did it substitute fully for either the competitive antagonist NPC 12626 nor the noncompetitive antagonist phencyclidine (PCP). A maximum average of 55.4% PCP-lever responding provided evidence for partial substitution in this model. The effects of ethanol on NMDA discrimination are distinct from those previously reported for competitive NMDA antagonists but similar to those of noncompetitive antagonists. On the other hand, ethanol can be distinguished from both competitive and PCP-like noncompetitive NMDA antagonists using drug discrimination procedures.