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T U Järbe

Publications and source records attributed to T U Järbe.

At least 19 recordsLinked to original sources
PubMed2001

(R)-methanandamide and Delta 9-THC as discriminative stimuli in rats: tests with the cannabinoid antagonist SR-141716 and the endogenous ligand anandamide.

RATIONALE AND OBJECTIVES: (R)-methanandamide (AM-356), a metabolically more stable chiral analog of the endocannabinoid ligand anandamide, was used as a representative of fatty acid ethanolamide CB1 receptor ligands to characterize the discriminative stimulus functions of anandamides. METHODS: Rats discriminated between 10 mg/kg (R)-methanandamide and vehicle administered IP 15 min prior to session onset. Another group of rats was initially trained to discriminate between 3 mg/kg Delta9-THC and vehicle given IP 30 min prior to session onset; for anandamide testing, the animals were retrained with 1.8 and 5.6 mg/kg Delta9-THC. A two lever operant methodology (FR10) was used. RESULTS: Delta9-THC was more potent than (R)-methanandamide at both 15 and 30 min post-injection, irrespective of the training drug used. Additional tests with 10 and 18 mg/kg (R)-methanandamide suggested that the effects were declining by 1 h. The cannabinoid antagonist SR 141716 (0.3 and 1 mg/kg) produced rightward shifts in the Delta9-THC dose-response curve for Delta9-THC-appropriate responding and for (R)-methanandamide-appropriate responding (surmountable antagonism). SR-141716 (0.3 and 1 mg/kg) antagonized the ability of (R)-methanandamide to occasion either Delta9-THC-appropriate responding or (R)-methanandamide-appropriate responding. This antagonism was surmountable only at a dose of 0.3 mg/kg SR-1421716 in the (R)-methanandamide-trained rats. SR-141716 did not antagonize the rate-decreasing effects of (R)-methanandamide in either the Delta9-THC or the (R)-methanandamide trained rats. Response suppression precluded testing doses higher than 30 mg/kg (R)-methanandamide. Tests with SR-141716 (1 and 10 mg/kg) alone resulted in <3% Delta9-THC-appropriate responding. With 10 mg/kg SR-141716, response rate was significantly lower as compared to the rate observed during a vehicle test. Tests with anandamide (10 and 18 mg/kg) resulted in 41% and 85% (R)-methanandamide-appropriate responding at a 3-min pre-treatment time, but in a maximum of 15% (R)-methanandamide-appropriate responding at a longer (15 min) pre-treatment time. In the Delta9-THC (1.8 and 5.6 mg/kg) trained rats, anandamide never produced more than about 20% Delta9-THC-appropriate responding. CONCLUSION: The results add to a growing body of evidence indicating that there are both similarities and dissimilarities between classical cannabinoids such as THC and endogenous fatty acid ethanolamides.

Adjuvants, Immunologic↗
PubMed2001

Effects of fluvoxamine on ethanol-reinforced behavior in the rat.

Serotonergic deficiencies have been associated with alcoholism, and increasing serotonin function has been reported to decrease ethanol consumption. In this study, we examined the effects of the selective serotonin reuptake inhibitor, fluvoxamine, upon ethanol self-administration in the rat, and as a test of specificity also examined the effects of fluvoxamine upon food-maintained behavior. Fluvoxamine decreased ethanol-maintained (0.1 ml per dipper presentation, 4-32% w/v ethanol) behavior at lower doses than the doses needed to decrease food-maintained (2 x 45-mg pellet) behavior. Examination of the behavioral interactions of ethanol and fluvoxamine upon food-maintained behavior showed that these observations did not result from synergistic behavioral actions that would occur during ethanol-maintained, but not food-maintained, behavior. Also, fluvoxamine did not alter the potency or efficacy of ethanol to occasion ethanol-appropriate responding in rats trained to discriminate 1.2 g/kg ethanol from vehicle. These findings suggest that fluvoxamine has specific actions upon the reinforcing effects of ethanol.

Animals↗
PubMed2000

Effects of Delta 9-tetrahydrocannabinol, (R)-methanandamide, SR 141716,and d-amphetamine before and during daily Delta 9-tetrahydrocannabinol dosing.

We examined the effects of Delta 9-tetrahydrocannabinol (Delta 9-THC), (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide ((R)-methanandamide, AM 356), SR 141716, and d-amphetamine on fixed-ratio (FR) responding maintained by food in rats before and during daily dosing with Delta 9-THC. Rats responded under a FR 10 schedule of food reinforcement. Cumulative dose-response curves for the various drugs were determined before and during daily Delta 9-THC administration. All four drugs dose-dependently decreased responding both before and during daily dosing with Delta 9-THC (18 mg/kg/day). The dose-response curves for both Delta 9-THC and (R)-methanandamide were shifted to the right with daily dosing with Delta 9-THC, indicating tolerance to the effects of Delta 9-THC and cross-tolerance to the effects of (R)-methanandamide. The doses of d-amphetamine examined produced similar effects both before and during daily dosing with Delta 9-THC. The effects of SR 141716 were not consistently altered by daily Delta 9-THC administration. These results indicate that tolerance develops to the effects of Delta 9-THC, when Delta 9-THC is administered repeatedly. These results also indicate that cross-tolerance to (R)-methanandamide develops with repeated Delta 9-THC administration.

Animals↗
PubMed2000

Delta9-THC training dose as a determinant for (R)-methanandamide generalization in rats: a systematic replication.

Järbe et al. (1998a) trained rats to discriminate between (-)-delta9-tetrahydrocannabinol (delta9-THC) and vehicle, using different training doses in order to create assays with different efficacy demands, to examine whether (R)-methanandamide, an analog of the endogenous ligand anandamide, had lower efficacy than delta9-THC. Rats were initially trained with 3 mg/kg delta9-THC, then tested with (R)-methanandamide and delta9-THC. Thereafter, the rats were split into two groups and retrained with either 1.8 or 5.6 mg/kg delta9-THC, followed by additional tests with the two agonists. The current study systematically replicated this study in two groups of rats, trained from the outset to discriminate between vehicle and either 1.8 or 5.6 mg/kg delta9-THC, respectively. Two-lever operant drug discrimination procedures were used. The outcomes in the two studies were similar. In tests with (R)-methanandamide, full substitution occurred in the low-dose delta9-THC training group, whereas substitution was partial in the high-dose delta9-THC training group. (R)-Methanandamide in higher doses exerted marked suppression of lever pressing. In tests with delta9-THC, full substitution occurred in both delta9-THC-trained groups, and rates of responding were comparable to those observed during regular drug training sessions. In conclusion, both sets of data indicate that cannabinoid agonists either can have varying degrees of efficacy at a receptor site, or may produce their behavioral actions through multiple mechanisms, or both. Prevailing training-dose condition rather than prior training-dose history is the major determinant for the substitution pattern.

Animals↗
PubMed1999

Discriminated taste aversion and context: a progress report.

The research described here concerns the interaction between the environment (context), the organism, and the effects of opiates, focusing on how conditioning and contextual cues affect drug controlled behaviors. This analysis applies the powerful tool of drug discrimination to a respondent conditioning procedure (discriminated taste aversion, DTA). Data show that the use of DTA is feasible in that it is sensitive to morphine dose and saccharin concentration. Swifter control over DTA was achieved by increasing the LiCl dose (UCS magnitude). It is also clear that morphine alone can serve as a discriminative stimulus not requiring saccharin as a contextual element (which has been the case for most DTA studies to date), or saccharin being part of a compounded stimulus. Pharmacological specificity was demonstrated in substitution tests with delta-9-tetrahydrocannabinol. This research continues a systematic experimental analysis of the interaction between drug-controlled behavior and context.

Animals↗
PubMed1999

Effects of lithium dose (UCS) on the acquisition and extinction of a discriminated morphine aversion: tests with morphine and delta9-THC.

The effects of varying the lithium dose (unconditioned stimulus [UCS]; LiCl range 30-180 mg/kg) on the acquisition and extinction of stimulus control by 5.6 mg/kg of morphine in a discriminated taste aversion (DTA) procedure were examined in rats. In addition, pharmacological specificity was examined by substituting (-)-delta-9-tetrahydrocannabinol (delta9-THC) for morphine during a test phase intervening between acquisition and extinction. DTA acquisition was more rapid at higher LiCl doses. The lowest dose of LiCl, 30 mg/kg, did not robustly maintain a DTA. Two groups treated with 60 mg/kg LiCl, differing only in the type of drinking nozzle used (ball-bearing vs standard non-ball-bearing), behaved similarly. Suppression of drinking was related to the morphine dose, in an orderly manner (dose range 0.3-10 mg/kg), in rats for which morphine was followed by LiCl. No significant decline in drinking occurred for rats for which morphine was followed by saline, except perhaps at the 10 mg/kg test dose of morphine. The control of drinking was pharmacologically specific; both experimental and control animals were equally affected in tests with delta9-THC (0.3-10 mg/kg). Low doses of delta9-THC increased water consumption; this did not occur with morphine. During extinction the reinstitution of drinking was similar across groups that had been effectively conditioned, i.e. there was no apparent effect of lithium dose on extinction. After extinction, a much attenuated reaction occurred to morphine in tests with 3 and 10 mg/kg. These doses of morphine had significantly suppressed drinking before the extinction phase. Collectively, these data add to the formal similarities between sensory and drug discriminative stimuli.

Animals↗
PubMed1998

Discriminative stimulus functions of CNS sedative drugs assessed by drug versus drug discrimination procedures in gerbils.

This study is concerned with dissecting out differences in the discriminative stimulus attributes between drugs from broader pharmacological categories such as sedative/hypnotics where generalization tests often indicate shared stimulus effects. To this end, the discriminative stimulus effects of three to five doses of either chlordiazepoxide (CDP), chlormethiazole (CMZ), ethanol (ETOH), and pentobarbital (P-barb) were studied with gerbils in a two-choice, T-maze task. When the discrimination was based upon the presence versus the absence of drug administration, speed of acquiring the discrimination increased dose-dependently for all four drugs with log of sessions to criterion being a linear function of log dose. The slopes of all four lines were similar. The acquisition of a discrimination based on different doses of the training drug was then examined. A two-to-one ratio of high to low doses was used. Discriminative control developed with CMZ, ETOH, and P-barb, but not with CDP. The side of the T-maze that correlated with the lower training dose was always selected in tests with saline. Gerbils were then trained to discriminate between two drugs using at least two different dose combinations. The CDP versus CMZ, CDP versus ETOH, CMZ versus P-barb, CMZ versus ETOH discriminations were acquired. The CDP versus P-barb discrimination was obtained across doses only after an additional training procedure was instituted such that the P-barb dose was incremented gradually from low to higher doses during discrimination training; the CDP training doses were 20 and 30 mg/kg in two different groups of gerbils, respectively and the dose of P-barb was incremented by 2.5 mg/kg until the final dose of 20 mg/kg was reached with the barbiturate. Thus, although often shown to share similar stimulus effects, members of the broad pharmacological class of CNS sedatives/hypnotics nonetheless were shown to be discriminable from one another. Non-drug tests (vehicle) were used to assess stimulus control between pairs of drugs, equal control being implicated when responding was evenly distributed across the two training conditions.

Animals↗
PubMed1998

Delta9-THC training dose as a determinant for (R)-methanandamide generalization in rats.

The objective of this study was to examine if (R)-methanandamide, a metabolically stable chiral analog of the endogenous ligand anandamide, is a cannabimimetic with a lower efficacy than delta9-THC. Employing a two-lever choice drug discrimination procedure, rats were trained to discriminate between 1.8, 3.0, or 5.6 mg/kg delta9-tetrahydrocannabinol (delta9-THC) and vehicle. Different training doses were used in order to create assays with different efficacy demands. Generalization tests with 18 mg/kg (R)-methanandamide yielded around 90% delta9-THC responses in the two lower delta9-THC training dose conditions. However, only around 60% delta9-THC responses occurred in the 5.6 mg/kg delta9-THC training dose condition in tests with 18 mg/kg (R)-methanandamide; a higher dose (30 mg/kg) produced even fewer delta9-THC-appropriate responses in this group. Morphine did not substitute for delta9-THC. In conclusion, the data with delta9-THC and (R)-methanandamide indicate that cannabinoid agonists can have varying degrees of intrinsic activity at a receptor site, or may produce their behavioral actions through multiple mechanisms, or both.

Animals↗
PubMed1998

Effects of delta-9-tetrahydrocannabinol and (R)-methanandamide on open-field behavior in rats.

This study compared the effects of (R)-methanandamide, an analog of the mammalian brain constituent anandamide, and delta-9-tetrahydrocannabinol on the open-field behavior of male Sprague-Dawley rats. Rats were individually housed with free access to food and water. Animals were treated with 0, 1, 3, and 5.6 mg/kg delta-9-tetrahydrocannabinol given i.p. 30 min pre-session; and 0, 3, 10, and 18 mg/kg (R)-methanandamide, 15 min pre-session. The behavioral categories recorded were ambulation (the number of squares crossed), rearing (the number of times the rat stood erect on its hind-legs), latency (the time in seconds to leave the starting area, the circle in the center of the field), circling (the number of times the animal turned around its vertical axis, 0.5 point given for each 180 degrees turn), grooming (the number of cleaning bouts), urination and defecation (the number of urination spots and fecal boli deposited during the 5 min observation period). Delta-9-tetrahydrocannabinol was more potent than (R)-methanandamide, but otherwise the effects of delta-9-tetrahydrocannabinol and (R)-methanandamide were similar, with one exception; whereas delta-9-tetrahydrocannabinol produced dose-related increases in circling, (R)-methanandamide did not increase circling over the doses examined. The delta-9-tetrahydrocannabinol-induced increase in circling was blocked by the central cannabinoid receptor CB1 antagonist SR 141716. The differential effects with regard to circling may indicate that there are qualitative behavioral differences in the effects of delta-9-tetrahydrocannabinol and (R)-methanandamide.

Analysis of Variance↗
PubMed1997

Multielemental stimulus control: effects of saccharin concentration on a discriminated morphine-saccharin taste aversion.

The effects of saccharin concentration on the stimulus control by a compound stimulus consisting of morphine, saccharin (0.01, 0.03, or 0.10%, wt/vol), and a ball bearing drinking nozzle in a discriminated taste aversion (DTA) procedure were examined in rats (Rattus norvegicus). In paired rats injections of lithium followed presentation of this compound stimulus, whereas in unpaired rats saline injections followed this stimulus. DTA acquisition was more rapid at higher saccharin concentrations. In testing with each individual stimulus element, stimulus control was clearly exerted by all 3 stimulus elements. When another stimulus element was presented jointly with saccharin, behavioral control was similar to that of saccharin alone. Behavioral control by saccharin increased with saccharin concentration. However, behavioral control by the 2 other stimulus elements was relatively unaffected when the saliency of the saccharin element was increased.

Animals↗
PubMed1994

Discriminative stimulus- and open-field effects of the enantiomers of 11-hydroxy-delta-8-tetrahydrocannabinol in pigeons and gerbils.

The cannabimimetic activity of the two enantiomers of 11-hydroxy-delta-8-tetrahydrocannabinol (11-OH-delta-8-THC) was evaluated in pigeons trained to discriminate between the presence and absence of (-)-delta-9-tetrahydrocannabinol [(-)-delta-9-THC]. (-)-11-OH-Delta-8-THC exhibited cannabimimetic activity with a potency (ED50, 0.17 mg/kg) similar to that of delta-9-THC. The duration of action for (-)-11-OH-delta-8-THC was shorter than that observed for delta-9-THC. No cannabimimetic activity was seen after administrations of (+)-11-OH-delta-8-THC, indicating enantiomeric selectivity for the discriminable effects. A dose-related decrease in response rate occurred with (-)-11-OH-delta-8-THC, but not with (+)-11-OH-delta-8-THC; the latter compound produced an increase in responding at 3 mg/kg. Open-field behavior in Mongolian gerbils indicated marked suppression of rearing (vertical activity) after treatments with (-)-delta-9-THC and (-)-11-OH-delta-8-THC; this did not occur after (+)-11-OH-delta-8-THC. The results support the notion of cannabimimetic enantiospecificity.

Animals↗
PubMed1993

Repeated testing within drug discrimination learning: time course studies with cocaine, amphetamine, and 3-PPP.

Pigeons were trained to discriminate between 3 mg/kg cocaine and saline. Tests with cocaine and amphetamine were conducted at different intervals after administration to compare the time course of the discriminative stimulus (DS) effects. Tests were of two kinds: a) separate, that is, only one dose and interval were examined on each separate test day; and b) repeated, that is, all three intervals were assessed after a single administration of the drug dose during 1 test day. Separate and repeated determinations of the time course yielded similar estimates. The duration of the DS effects of amphetamine were longer than those of cocaine. No apparent difference, either with regard to duration of effect or potency, existed between (+)- and (-)-amphetamine. The potency of cocaine was similar to that of the amphetamine isomers. The dopamine autoreceptor blockers (+)- and (-)-3-(hydroxyphenyl)-N-n-propylpiperidine (3-PPP) (1-10 mg/kg) engendered less than 44% cocaine-associated responding for the repeatedly examined intervals (15, 60, and 120 min after administration). The results of this study encourage the use of repeated testing methodology to assess the duration of action of the DS effects of drugs.

Amphetamine↗
PubMed1993

Discriminative stimulus effects and receptor binding of enantiomeric pairs of cannabinoids in rats and pigeons; a comparison.

The cannabimimetic activity of two enantiomeric pairs of compounds structurally different from the classical cannabinoids was evaluated in rats and pigeons, trained to discriminate between the presence and absence of (-)-delta-9-tetrahydrocannabinol (THC). One pair of enantiomers [compounds (+)-HU-249 and (-)-HU-250] has a 5-membered oxygen-containing benzofuran ring; the second pair [(+)-HU-253 and (-)-HU-254] does not have an oxygen-containing ring. The onset of cannabimimetic activity was slower, and duration of action was longer for the test compounds than for THC. HU-250 exhibited cannabimimetic activity with a potency similar to THC in both species; HU-249 was 22 times less active than THC. The pattern of response rate and THC-like responding obtained with HU-249 were dissociated; THC-like responding occurred during the later test intervals when suppression of response rate was reduced. HU-250 bound to the cannabinoid receptor with a Ki of 47.6 nM, essentially identical to that of THC. HU-249 was much less active, with a Ki of 28.3 microM. The triacetate enantiomers, HU-253 and HU-254, occasioned THC-like responding in both species, HU-254 being about 4.5 times less potent than THC and 3 to 4 times more potent than HU-253. In binding, HU-253 was also less potent than HU-254. The corresponding triols were considerably more potent than the acetates; (-)-HU-256 had a Ki of 198 nM, whereas (+)-HU-255 had a Ki of 43.8 nM, comparable to that of THC.

Animals↗
PubMed1992

A novel probe for the cannabinoid receptor.

The 1,1-dimethylheptyl (DMH) homologue of 7-hydroxy-delta 6-tetrahydrocannabinol (3) is the most potent cannabimimetic substance reported so far. Hydrogenation of 3 leads to a mixture of the epimers of 5'-(1,1-dimethylheptyl)-7-hydroxyhexahydrocannabinol or to either the equatorial (7) or to the axial epimer (8), depending on the catalysts and conditions used. Compound 7 discriminates for delta 1-THC (2) in pigeons (ED50 = 0.002 mg/kg, after 4.5 h), at the potency level of 3, and binds to the cannabinoid receptor with a KD of 45 pM, considerably lower than the Ki of 180 pM measured for compound 3 and the Ki of 2.0 nM measured for CP-55940 (1), a widely employed ligand. Tritiated 7 was used as a novel probe for the cannabinoid receptor.

Animals↗
PubMed1992

Acute and chronic ethanol tolerance: operant behaviour in naive and ethanol tolerant rats.

The relationship between tolerance to ethanol and acute tolerance to ethanol was examined. One group of rats was given 1.8 g/kg ethanol, and another group was administered 18 ml/kg saline for 26 days after sessions. Animals responded under a fixed ratio ten (FR-10) schedule of food reinforcement. Thereafter, various doses of ethanol (1.3-2.5 g/kg) were examined to assess the influence of the ethanol treatment on the expression of acute tolerance. Acute tolerance was assessed by comparing the performance at equal concentrations of ethanol on the ascending and the descending limbs of the ethanol concentration curve. This was achieved by varying the time between behavioural tests since ethanol administration. Ethanol concentrations were estimated using a rebreathed air procedure. Equal concentrations of ethanol were achieved with doses of i) 1.3 g/kg (10 min post-injection, PI), and 1.8 g/kg (60 min PI), as well as with doses of ii) 2.0 g/kg (10 min PI), and 2.5 g/kg (60 min PI). Acute tolerance was demonstrated for the initially ethanol naive animals. For the animals given ethanol chronically, only doses of ethanol higher than the chronically administered dose produced evidence for acute tolerance. When the chronically dosed animals had been off ethanol for 67 days, there was evidence for acute tolerance. The present data add to the generality of the acute ethanol tolerance phenomenon, and emphasize both the appearance as well as the loss of tolerance for this effect.

Animals↗
PubMed1991

The pentylenetetrazole-cue antagonist actions of bretazenil (Ro 16-6028) as compared to midazolam.

In order to compare the potencies of bretazenil (Ro 16-6028) and midazolam (MDZ) to antagonize the pentylenetetrazole (PTZ) cue, rats were trained to discriminate between 15 mg/kg IP PTZ and saline (FR10, food reinforced). Additionally, other rats were trained to discriminate between 1.0 mg/kg IP MDZ and saline in order to investigate the degree of generalization of bretazenil to MDZ, and to test for the antagonizing effects of PTZ. Both bretazenil and MDZ were able to block the PTZ cue. Bretazenil was about 60 times more potent than MDZ in this respect. In tests for response generalization, bretazenil substituted for MDZ cue. Bretazenil did not show MDZ-antagonist actions. PTZ did block the MDZ cue and the generalization of bretazenil in the MDZ-trained animals. Assuming that the drug discriminative stimulus functions of PTZ are closely related to its anxiogenic effects, it was concluded that bretazenil may possess powerful anxiolytic properties. Bretazenil did not suppress the response rates which is consistent with previous studies reporting a lack of sedative and muscle-relaxant effects of bretazenil.

Animals↗
PubMed1990

Extinction and reacquisition of differential responding in rats trained to discriminate between chlordiazepoxide and saline.

In order to assess the resistance of drug discriminative responding to prolonged reinforcement omission, rats were trained to discriminate between either 6.0 mg/kg PO or 30.0 mg/kg PO. CDP and saline, using a food reinforced (V140-FR10) operant procedure. Dose generalization tests were conducted for both groups. Sessions were then run without reinforcement while drug (D) and saline (S) administrations were continued (extinction phase). After a maximum of 30 sessions without reinforcement, or when the rats emitted less than ten responses on either lever during three successive sessions (extinction criterion), reinforcement was reinstated. Finally, additional dose generalization tests with CDP were run. The discriminative responding controlled by the D and S administrations was not affected significantly by prolonged reinforcement omission in either group. For both groups, response rates were decreased and latencies to initiate responding were increased during the extinction phase. Response rate reduction occurred more rapidly for the drug condition in the high training dose group. This group also reached the extinction criterion sooner than the low training dose group. The reacquisition process occurred very rapidly. Response rates increased substantially after the first reinforcement had been obtained. After ten reacquisition sessions, response rates and latencies had reached values similar to those observed before extinction was initiated. Data revealed no differences between groups and the course of reacquisition did not differ between the S and D conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗