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PubMed1981

Maintenance diet and the effects of furosemide on hamsters.

Experiment 1 indicated that furosemide, a diuretic, was ineffective in causing hamsters to excrete more urinary sodium when they were fed a sodium-replete diet. Neither the experimental nor the control animals showed any appreciable change in urinary sodium concentration when injected while maintained on Purina lab chow. However, experimental animals that were fed a sodium-deficient diet and then were injected with furosemide showed an increase in urinary volume as well as in sodium concentration in comparison with controls. Experiment 2 assessed the effect of furosemide on the hamsters' intake of saline when they were presented with either 0.9% NaCl and water or 2.0% NaCl solution and water. The results indicated that this diuretic increased the animals' intake of 0.9% saline but not of 2.0% NaCl. Ten days after this experiment, the same hamsters were then tested in a situation where they were presented with both 0.9% and 2.0% saline (Experiment 3). When these animals were injected with furosemide, both groups showed increased intake of 2.0% saline but not of 0.9% NaCl. These results indicate that the outcome of two-bottle preference tests is influenced by the combinations upon which the hamster is making the paired comparison. Experiment 4 involved the comparison of the single-stimulus and double-stimulus methods in assessing the effects of furosemide injections on the saline intake of different groups of hamsters. In general, the double-stimulus method appears to be more sensitive in detecting the natriorexigenic effects of furosemide.

Animals↗
PubMed1988

A comparison of the stimulus effects of codeine in rhesus monkeys under the contingencies of a two lever discrimination task and a cross self-administration paradigm: tests of generalization to pentazocine, buprenorphine, tilidine, and different doses of codeine.

The stimulus effects of codeine were assessed in three monkeys trained to perform first under the contingencies of a cross self-administration paradigm and then under a two lever discrimination task. Codeine-trained monkeys generalized to pentazocine, buprenorphine, and codeine under both procedures in doses different from the training dose. Codeine-trained monkeys did not generalize to tilidine. These results indicate that monkeys do not behave in a qualitatively different way when presented with the study drugs under both contingencies. However, there were marked quantitative differences between the generalization effects of doses of pentazocine, buprenorphine, and codeine to doses other than that used in training between the two paradigms. Much higher doses of codeine and pentazocine, but not of buprenorphine, were necessary for inducing generalization effects in the two lever task than in the cross self-administration procedure. The possible reasons for these quantitative differences are discussed. It is concluded that the cross self-administration procedure is more sensitive for the assessment of opioid-like stimulus properties of drugs than the two lever discrimination task.

Animals↗
PubMed1995

Discriminative stimulus properties of flesinoxan: effects of enantiomers, (S)-UH301 and WAY-100635.

Rats were trained to discriminate the specific 5-HT1A receptor agonist (+)-flesinoxan (R(+)-N(-)[2[4-(2,3-dihydro-2-2-hydroxy-methyl-1,4- benzodioxin-5-yl)-1-piperazinyl]ethyl]-4-fluorobenzoamide) (1.5 mg/kg p.o.) from water in a two-lever operant procedure. Generalization tests were conducted with the enantiomers and racemate of flesinoxan and the 5-HT1A receptor antagonists (S)-UH301 ((S)-5-fluoro-8-hydroxy-2-(dipropylamino)-tetralin) and WAY-100635 ((N(-)[2(-)[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide trihydrochloride). (S)-UH301, WAY-100635 and fentanyl were investigated for their antagonistic properties. The (+)-flesinoxan stimulus generalized to (-)-flesinoxan and the racemate. The ED50 values for generalization corresponded well with the affinities of the enantiomers and the racemate for the 5-HT1A receptor. The flesinoxan cue could not be mimicked by (S)-UH301 or WAY-100635, but (S)-UH301 reduced response rates. Antagonism tests showed that both (S)-UH301 and WAY-100635 dose dependently antagonized the flesinoxan cue, with ID50 values of 0.52 and 0.03 mg/kg s.c., respectively. Fentanyl had no significant antagonistic properties. It is concluded that rats can learn to discriminate orally administered (+)-flesinoxan from water. The generalization of flesinoxan to the (-)-enantiomer and the antagonism of flesinoxan's cue by specific 5-HT1A receptor antagonists are further evidence for the involvement of flesinoxan's 5-HT1A receptor agonistic properties in its discriminative stimulus effects.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1966

Long temporal gradient of retrograde amnesia for a well-discriminated stimulus.

This experiment tested the general validity of recent findings that retrograde amnesia can be produced by electroconvulsive shock only if the shock is administered within 10 to 30 seconds after the learning trial. Precautions were taken to avoid confusion of other shock effects with retrograde amnesia. A temporal gradient of elec- troconvulsive shock-produced retrograde amnesia, extending up to at least 1 hour, for a well-discriminated stimulus, was demonstrated in mice in a one-trial learning passive avoidance situation.

Amnesia↗
PubMed1997

Dopamine ligands and the stimulus effects of amphetamine: animal models versus human laboratory data.

Studies with laboratory animals have consistently demonstrated a role for dopamine in mediating the discriminative stimulus (i.e., interoceptive) effects of amphetamine. For example, D2 dopamine agonists mimic the discriminative stimulus effects of amphetamine and D1 and D2 dopamine antagonists generally block them. The discriminative stimulus effects of drugs in animals are believed to parallel their subjective effects in humans. Therefore, it is often assumed that dopamine plays a role in amphetamine-induced subjective effects in humans and it would be reasonable to expect that dopamine antagonists would block the subjective effects of amphetamine. Few studies have tested this hypothesis directly, and those that have have yielded inconsistent results. This paper will review data regarding the effects of dopamine agonists and antagonists on the discriminative stimulus effects of amphetamine in animals and its subjective effects in humans. Possible explanations for the discrepancies between animal and human data will be discussed, and classical assumptions underlying the use of animal models of drug effects will be examined.

Amphetamine↗
PubMed1980

Positive conditioned suppression: Transfer of performance between contingent and noncontingent reinforcement situations.

Five homing pigeons were trained on concurrent variable-interval schedules. A fixed-duration stimulus was occasionally presented on one key; and, in various conditions, this stimulus terminated (a) without reinforcement, (b) in noncontingent reinforcement, (c) with reinforcement contingent on a response on the key on which the stimulus was presented, and (d) with reinforcement contingent on a response on the key on which the stimulus was not presented. Initially, a stimulus terminating in noncontingent reinforcement generally produced decreased response rates on both keys during the stimulus. Contingencies, however, reliably produced increased rates during the stimulus on the key on which the contingency was arranged, relative to the rate on the concurrently available key. Contingency conditions were followed by noncontingency conditions in which the separation of rates caused by contingencies was maintained. When rates during the stimulus were compared with response rates on the same keys in the absence of the stimulus, contingency-caused rate increases and decreases were again found, but only the rate decreases were maintained in subsequent noncontingency conditions. Further data suggested that the contingency-caused rate changes were not maintained when the stimulus terminated without reinforcement, and that they were unaffected by a threefold decrease in the reinforcement rate provided by the baseline schedules. The results support the suggestion that performance in the positive conditioned suppression procedure results from concurrent and multiple schedule interactions. They further suggest that the production of either acceleration or suppression is dependent on adventitious and historical contingencies.

Journal Article↗
PubMed2001

The effects of perinatal exposure to lead on the discriminative stimulus properties of cocaine and related drugs in rats.

RATIONALE: Developmental lead exposure may alter responsiveness to cocaine well into adulthood, and ultimately influence drug-use patterns. OBJECTIVES: The present study examined the effect of perinatal lead exposure on the discriminative stimulus properties of cocaine. METHODS: Female rats were treated with 0, 8, or 16 mg lead daily for 30 days before breeding with untreated males. This exposure regimen continued through gestation and until postnatal day (PND) 21, i.e., weaning. At PND 60 male pups were trained to discriminate between saline and cocaine (5 mg/kg) injections. After acquisition, a series of generalization/substitution tests were performed using a cumulative dosing procedure. RESULTS: Developmental lead exposure produced subsensitivity to SKF-82958 (D1-like dopamine receptor agonist), quinpirole (D2-like dopamine receptor agonist), and apomorphine (mixed D1-like/D2-like dopamine receptor agonist); but no differences were evident among lead-treatment groups on generalization/substitution tests with cocaine, d-amphetamine, or GBR-12909. Furthermore, when the kappa-opioid receptor agonist U69,593 was administered prior to cocaine (5 mg/kg), generalization to the cocaine stimulus decreased in control rats, but generalization in lead-exposed rats was not altered. Group differences were not evident in tolerance or recovery of tolerance to cocaine following repeated cocaine administration (60 mg/kg per day for 14 days). Furthermore, no differences were found across groups in concentrations of lead in brain, although pups exposed to 16 mg lead had slightly elevated blood lead concentrations (<7 microg/dl). CONCLUSIONS: These results further a growing research literature that suggests developmental lead exposure can produce long-lasting changes in drug responsiveness, even after exposure to the toxicant has been discontinued.

Animals↗
PubMed1994

Evaluation of deprenyl for cocaine-like discriminative stimulus effects in rats.

The antiparkinsonian agent l-deprenyl is metabolized to l-methamphetamine and l-amphetamine and, at higher doses, can facilitate the release and inhibit the reuptake of dopamine. Since l-deprenyl can affect dopamine release and reuptake it was important to evaluate it for cocaine-like discriminative stimulus effects. Male Fisher rats were trained to discriminate cocaine (10 mg/kg, i.p.) from saline in a two-lever, operant-conditioning procedure using schedules of food-delivery or stimulus-shock termination. l-Deprenyl (17 mg/kg, i.p.) produced full generalization to cocaine under the food-delivery schedule but this or higher doses produced only partial generalization to cocaine under the stimulus-shock termination schedule. d-Deprenyl produced full generalization to cocaine under both schedules at i.p. doses of 5.6 to 10 mg/kg. These cocaine-like discriminative stimulus effects occur only at doses that are well above the clinically relevant dose range for l-deprenyl.

Animals↗
PubMed1999

Discriminative stimulus effects of ethanol: neuropharmacological characterization.

Generally, compounds discriminated by animals possess psychotropic effects in animals and humans. As with many other drugs of abuse, strength of the ethanol discriminative stimulus is dose related. The majority of studies show that doses close to 1.0 g/kg are close to the minimum at which the discrimination can be learned easily. Substitution studies suggest that anxiolytic, sedative, atactic, and myorelaxant effects of ethanol all play an important role in the formation of its intercoeptive stimulus. Low doses of ethanol produce more excitatory cues, similar to amphetamine-like subjective stimuli, whereas higher doses produce rather sedative/hypnotic stimuli similar to those elicited by barbiturates. Substitution studies have shown that the complete substitution for ethanol may be exerted by certain GABA-mimetic drugs acting through different sites within the GABA(A)-benzodiazepine receptor complex (e.g., diazepam, pentobarbital, certain neurosteroids), gamma-hydroxybutyrate, and antagonists of the glutamate NMDA receptor. Among the NMDA receptor antagonists both noncompetitive (e.g., dizocilpine) and competitive antagonists (e.g., CGP 40116) are capable of substituting for ethanol. Further, some antagonists of strychnine-insensitive glycine modulatory sites among the NMDA receptor complex (e.g., L-701,324) dose-dependently substitute for the ethanol discriminative stimulus. On the other hand, neither GABA-benzodiazepine antagonists nor NMDA receptor agonists produce contradictory effects (i.e., reduce the ethanol discriminative stimulus). There is influence of a particular training dose of ethanol on the substitution pattern of different compounds. For example, 5-HT(1B/2C) agonists substitute for intermediate (1.0 g/kg) but not higher (2.0 g/kg) ethanol training doses. Discrimination studies with ethanol and drugs acting on NMDA and GABA receptors consistently indicate asymmetrical generalization. For example, ethanol is able to generalize to barbiturates and benzodiazepines, but neither the benzodiazepine nor barbiturate response generalizes to ethanol. Only a few drugs are able to antagonize, at least to some extent, the discriminative stimulus of ethanol (e.g., partial inverse GABA-benzodiazepine receptor antagonist Ro 15-4513 and the opioid antagonist naloxone). The ethanol stimulus effect may be increased (i.e., stronger recognition) by N-cholinergic drugs (nicotine), dopaminergic drugs (apomorphine), and 5-HT3 receptor agonists (m-chlorophenylbiguanide). Thus, the ethanol stimulus is composed of the several components, with the NMDA receptor and GABA(A) receptor complex being of particular importance. This suggests that a drug mixture may be more capable of substituting for ethanol (or block its stimulus) than a single compound. The ability of drugs to substitute for the ethanol discriminative stimulus is frequently, although not preclusively, associated with the reduction of voluntary ethanol consumption. The examples of positive correlation are gamma-hydroxybutyrate, possibly memantine and certain serotonergic drugs such as fluoxetine. However, it remains uncertain to what extent the discriminative stimulus of ethanol can be seen as relevant in the understanding of the complex mechanisms of dependence.

Alcoholism↗
PubMedDate not supplied

Discriminative stimulus properties of toluene in the rat.

Rats were trained to discriminate toluene (100 mg/kg, IP) from vehicle in a two-lever operant task. Acquisition of the discrimination required a range of 85-219 training days. Injections of either methohexital (0.5-10 mg/kg) or oxazepam (0.5-20 mg/kg) produced toluene-lever responding in a dose-dependent fashion in most animals. The discriminative stimulus properties of toluene were not found to generalize to chlorpromazine (0.3-10 mg/kg). These results are consistent with those obtained in the mouse and provide further evidence that toluene has stimulus properties similar to those of CNS depressant drugs. These results further suggest that toluene may have drug abuse potential of the CNS depressant type.

Animals↗
PubMed1976

The discriminative stimulus properties of nicotine, d-amphetamine and morphine in dopamine depleted rats.

Rats permanetly depleted of central dopamine (DA) via 6-OHDA neonatally were studied in relation to their ability to discriminate various psychoactive drugs from saline using a two-bar operant procedure. DA rats learned to discriminate both morphine (4 mg/kh) and d-amphetamine (0.9 mg/kg) as rapidly as controls and exhibited similar sensitivity when dose-generalization studies were conducted. However, DA rats appeared to tolerate higher doses of the same drug better than controls indicating that they were more tolerant to behavioral disruption. It was suggested that the behavioral disruption. It was suggested that the behavioral disruption usurons. DA rats had more difficulty learning to discriminate nicotine than controls. In fact the peripherally injected nicotine stimulus generalized to hippocampal (Hp) injections in controls but was not observed in DA rats. These data suggest that part of nicotine's discriminative stimulus properties may be contingent upon the integrity of a Hp-DA connection.

Animals↗
PubMed1988

Prolonged noxious mechanical stimulation of the rat's tail: responses and encoding properties of dorsal horn neurones.

1. Single-unit electrical activity has been recorded from dorsal horn neurones in the sacral (S1-S2) segments of the spinal cord of barbiturate-anaesthetized rats. Fifty-two neurones responding to a manually applied pinch of their receptive fields in the tail were selected. They were subsequently tested for their responses to four successive 2 min pinches at noxious intensities delivered by a feed-back-controlled mechanical device. 2. Neurones were tested with both innocuous (i.e. brushing and stroking) and noxious (i.e. pinching, pin-prick, and in some cases heating about 45 degrees C) stimulation of their cutaneous receptive fields. Three of the tested cells were driven exclusively by innocuous skin stimulation (mechanoreceptive or class 1), thirty-six were driven by both innocuous and noxious skin stimulation (multireceptive or class 2) and thirteen were driven exclusively by noxious skin stimulation (nocireceptive or class 3). 3. All of the multireceptive and nocireceptive neurones responded to the 2 min noxious pinch with an initial phasic discharge followed by sustained firing that showed little evidence of adaptation throughout the stimulus period. The three mechanoreceptive neurones responded to the 2 min noxious pinch with a short discharge at the stimulus onset, but were silent for the remainder of the stimulus period. 4. Thirty-one cells were tested with successive 2 min pinches of 4, 6 and 8 N (and in some cases, a further 4 N pinch) applied at 10 min intervals. Different encoding properties were observed during the sustained part of the neuronal response according to: (i) the afferent fibre input characteristics of the cell; (ii) whether or not the tail had received a test series of pinches earlier in the same experiment. 5. None of the multireceptive cells with only an A-fibre afferent input encoded the stimulus strength. However, the multireceptive cells with both an A- and a C-fibre afferent input and all nocireceptive cells did encode the stimulus strength, providing that no previous noxious test stimuli had been applied to the tail. The encoding nocireceptive neurones had in general a steeper stimulus-response curve than the encoding multireceptive neurones, though the two groups overlapped to some extent. 6. Three encoding cells (two multireceptive and one nocireceptive) were tested with a second series of pinches (4, 6, 8 and 4 N), 40 min subsequent to the initial test series. These cells did not encode this second test series, but were more excitable, producing a greater response to a given test force.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1992

Forgetting of stimulus attributes: methodological implications for assessing associative phenomena.

Differential responding to changes in the stimulus situation, long central to the concept of stimulus control, also provides the implicit conceptual basis for assessing the nature of a variety of associative relationships. However, there is substantial evidence that the perception of stimulus similarity is not a static property. Generalization gradients to contextual as well as discriminative stimuli flatten over time, and this increase in perceived similarity presumably reflects forgetting of the detailed characteristics or attributes of stimuli. Methodologically, the flattening of the gradient imposes an important constraint: The effect of a stimulus shift will be highly sensitive to the length of the delay interval between training and testing. Conceptually, the loss of memory for stimulus attributes also implies that the sources of interference in retention can increase over time.

Animals↗
PubMed1986

A Hypothesis to Explain Divergent Findings Among Studies Comparing the Efficacy of Unilateral and Bilateral ECT in Depression.

This article explains divergent reports on the relative efficacy of unilateral and bilateral electroconvulsive therapy (ECT) by hypothesizing a therapeutic effect of both seizure and electrical stimulus, with the seizure's effect based on its intensity and generalization. The effect of the stimulus is normally obscured by the seizure but emerges with reduced electrical dosage or elevated threshold. These circumstances favor a therapeutic advantage for bilateral ECT, which introduces more electrical charge into a larger and differently distributed volume of brain and induces greater seizure generalization, more diencephalic stimulation, and a relative decrease in left relative to right hemisphere electroencephalographic (EEG) frequencies.

Journal Article↗
PubMed1992

Evidence for noradrenergic involvement in mediating the FG 7142 discriminative stimulus.

Rats were trained to discriminate the stimulus properties of the benzodiazepine receptor partial inverse agonist beta-carboline-3-carboxylate acid methyl amide (FG 7142) (5.0 mg/kg) or the alpha 2-adrenergic receptor antagonist 17 alpha-hydroxyyohimban-16 alpha-carboxylic acid methyl ester (yohimbine) (3.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. These compounds have in common a beta-carboline structure and anxiogenic behavioral profiles. The yohimbine discriminative stimulus was mimicked by the alpha 2-adrenergic receptor antagonist idazoxan and antagonized by the alpha 2-adrenergic receptor agonist clonidine, indicating that the yohimbine stimulus was mediated through the alpha 2-adrenergic receptor. The anxiogenic beta-carbolines FG 7142, 1,2,3,4-tetrahydro-beta-carboline (THBC), and norharmane, the anxiogenic/convulsant agent pentylenetetrazole (PTZ), and two physiological stressors failed to mimic the yohimbine discriminative stimulus. In contrast, both yohimbine and idazoxan dose responsively mimicked the anxiogenic FG 7142 stimulus. The present results demonstrate that an asymmetrical generalization exists between the discriminative stimuli produced by yohimbine and FG 7142. Furthermore, these data suggest that yohimbine can produce a multicomponent discriminative stimulus, part of which may be anxiogenic in nature. The ability of alpha 2-adrenergic receptor antagonists to mimic the FG 7142 cue suggests that activation of the noradrenergic system may underlie cues produced by benzodiazepine receptor inverse agonists.

Adrenergic alpha-Antagonists↗
PubMed2001

Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.

1. In addition to inhibiting the dopamine transporter, cocaine affects a variety of other neurotransmitter systems. In the present study, the involvement of both dopaminergic and the nondopaminergic systems in the behavioral effects of cocaine was studied using an intravenous drug discrimination procedure. 2. One group (Group 1) of rats were trained to discriminate cocaine (1 mg/kg, i.v.) from saline, while a second group (Group 2) of rats were trained to discriminate the same dose of cocaine from both GBR-12909 (1 mg/kg i.v.), a dopamine-selective uptake inhibitor, and saline. 3. Following training, substitution tests with different doses of cocaine and several drugs pharmacologically related to cocaine were conducted. When cocaine dose was varied, there was a dose-dependent generalization to the cocaine-training stimulus in both groups of rats. Conversely, GBR-12909 and GBR-12935, another dopamine-selective uptake inhibitor, generalized to the cocaine-training stimulus in Group 1, but there was minimal or no generalization in Group 2 4. The norepinephrine-selective uptake inhibitors, desipramine and nisoxetine, and the serotonin-selective uptake inhibitor, zimeldine, produced little or no generalization to the cocaine-training stimulus in either group of rats. The sodium channel blocker, dimethocaine which has a relatively high affinity for the dopamine transporter fully generalized to the cocaine stimulus in both groups of rats, while procaine which has a low affinity for the dopamine transporters only partially generalized to the cocaine-training stimulus in both groups of rats 5. Finally, lidocaine, which has negligible affinity for the dopamine transporter, did not generalize to the cocaine-training stimulus in either group of rats. The findings suggest similarities as well as subtle, but important, differences between the discriminative stimulus effects of cocaine and the dopamine uptake inhibitors, GBR-12909 and GBR12935.

Adrenergic Uptake Inhibitors↗
PubMed1998

Artificial neural networks as models of stimulus control.

We evaluate the ability of artificial neural network models (multilayer perceptrons) to predict stimulus-response relationships. A variety of empirical results are considered, such as generalization, peak shift (supernormality) and stimulus intensity effects. The networks were trained on the same tasks as the animals in the experiments considered. The subsequent generalization tests on the networks showed that the model replicates correctly the empirical results. We conclude that these models are valuable tools in the study of animal behaviour. (c) 1998 The Association for the Study of Animal Behaviour.

Journal Article↗
PubMedDate not supplied

A drug discrimination analysis of ethanol-induced behavioral excitation and sedation: the role of endogenous opiate pathways.

The drug discrimination technique was used to characterize the biphasic behavioral effects of ethanol (ETOH) and examine the role of opiate pathways in mediating ETOH's excitatory (EX) and sedative (SED) phase effects. Forty Sprague-Dawley rats were trained to perform ETOH vs. saline discriminations during either ETOH's EX (6 min post-dose) or SED (30 min post-dose) phase of action in a double-lever food reinforced operant paradigm. After animals had achieved the required performance criterion, dose-response and phase-generalization tests were conducted in each group. In addition, preliminary studies were conducted to examine the effect of naloxone (NLX) pretreatment on discrimination of ETOH's EX and SED phase stimulus effects. Results of generalization testing demonstrate that discrimination of ETOH was dose-dependent and there was no generalization between phases regardless of the initial training condition. NLX pretreatment significantly attenuated discrimination of ETOH's EX phase effects but was ineffective in antagonizing ETOH's SED effects. These data demonstrate that the stimulus properties of ETOH are phase-dependent and suggest that opiate pathways are critical for the expression of ETOH's EX phase behavioral effects.

Animals↗