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PubMed1988

Stimulus properties of 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDA) analogs.

Using a standard two-lever operant procedure, groups of rats were trained to discriminate intraperitoneal doses of the phenylisopropylamines (+)amphetamine (1.0 mg/kg) or racemic 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM; 1.0 mg/kg) from saline using a VI 15-sec schedule of reinforcement for food reward. Once trained, the animals were administered doses of several methylenedioxy analogs (MDAs) of phenylisopropylamine including the N-monomethyl [S(+)MDMA and R(-)MDMA], N-monoethyl [(+/-)MDE, S(+)MDE, and R(-)MDE], and the N-hydroxyl [(+/-)N-OH MDA] derivatives. The DOM-stimulus did not generalize to any of these agents. The amphetamine-stimulus generalized to S(+)MDMA, S(+)N-ethylamphetamine and (+/-)N-hydroxyamphetamine, but not to R(-)MDMA, (+/-)MDE, S(+)MDE, R(-)MDE, or N-OH MDA. The present results are consistent with other reports in the literature suggesting that the psychoactive effects of certain MDA derivatives may be other than simply amphetamine- or DOM-like.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1998

A dominant-negative inhibitor of CREB reveals that it is a general mediator of stimulus-dependent transcription of c-fos.

Several studies have characterized the upstream regulatory region of c-fos, and identified cis-acting elements termed the cyclic AMP (cAMP) response elements (CREs) that are critical for c-fos transcription in response to a variety of extracellular stimuli. Although several transcription factors can bind to CREs in vitro, the identity of the transcription factor(s) that activates the c-fos promoter via the CRE in vivo remains unclear. To help identify the trans-acting factors that regulate stimulus-dependent transcription of c-fos via the CREs, dominant-negative (D-N) inhibitor proteins that function by preventing DNA binding of B-ZIP proteins in a dimerization domain-dependent fashion were developed. A D-N inhibitor of CREB, termed A-CREB, was constructed by fusing a designed acidic amphipathic extension onto the N terminus of the CREB leucine zipper domain. The acidic extension of A-CREB interacts with the basic region of CREB forming a coiled-coil extension of the leucine zipper and thus prevents the basic region of wild-type CREB from binding to DNA. Other D-N inhibitors generated in a similar manner with the dimerization domains of Fos, Jun, C/EBP, ATF-2, or VBP did not block CREB DNA binding activity, nor did they inhibit transcriptional activation of a minimal promoter containing a single CRE in PC12 cells. A-CREB inhibited activation of CRE-mediated transcription evoked by three distinct stimuli: forskolin, which increases intracellular cAMP; membrane depolarization, which promotes Ca2+ influx; and nerve growth factor (NGF). A-CREB completely inhibited cAMP-mediated, but only partially inhibited Ca2+- and NGF-mediated, transcription of a reporter gene containing 750 bp of the native c-fos promoter. Moreover, glutamate induction of c-fos expression in primary cortical neurons was dependent on CREB. In contrast, induction of c-fos transcription by UV light was not inhibited by A-CREB. Lastly, A-CREB attenuated NGF induction of morphological differentiation in PC12 cells. These results suggest that CREB or its closely related family members are general mediators of stimulus-dependent transcription of c-fos and are required for at least some of the long-term actions of NGF.

Amino Acid Sequence↗
PubMed1996

Discriminative stimulus control with olanzapine: generalization to the atypical antipsychotic clozapine.

The present study was conducted to determine if the putative atypical antipsychotic olanzapine could be established as a discriminative stimulus in rats. Seven rats were successfully trained to discriminate olanzapine (0.5 mg/kg, IP) from vehicle in a two-lever drug discrimination procedure (mean number of acquisition sessions = 39.3). Generalization testing with olanzapine (0.0625-2.0 mg/kg) yielded an ED50 of 0.170 mg/kg (95% confidence interval = 0.118-0.246 mg/kg). The atypical antipsychotic clozapine (0.156-10.0 mg/kg) fully substituted for olanzapine in all rats at the 2.5 mg/kg dose with 99.0% drug-lever responding, in six rats at the 0.625 mg/kg dose, and in five rats at the 1.25 and 5.0 mg/kg doses (ED50 = 0.259 mg/kg, 95% confidence interval = 0.089-0.755 mg/kg). This study is the first demonstration that rats can be trained to discriminate olanzapine from vehicle in a two-lever drug discrimination procedure and that the olanzapine discrimination cue generalizes to clozapine.

Animals↗
PubMed2002

Further characterization of the stimulus properties of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline.

This investigation is based on the premise that conformational restriction of abused phenylalkylamines in a tetrahydroisoquinoline conformation alters their pharmacology in such a manner that their original action is lost and that a new action emerges. TDIQ or 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline, is a conformationally constrained phenylalkylamine that serves as a discriminative stimulus in animals. Although TDIQ bears structural resemblance to phenylalkylamine stimulants (e.g., amphetamine), hallucinogens (e.g., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane [DOM]), and designer drugs (e.g., N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane [MDMA], N-methyl-1-(4-methoxyphenyl)-2-aminopropane [PMMA]), the TDIQ stimulus failed to generalize to (+)amphetamine or MDMA. In the present investigation, further evaluations were made of the stimulus nature of TDIQ. Specifically, the stimulus similarities of TDIQ, PMMA, and DOM were examined. In no case was stimulus generalization (substitution) observed. The results confirm that TDIQ produces stimulus effects distinct from those of the abovementioned phenylalkylamines. We also examined the structure-activity relationships of a series of TDIQ analogs, including several that might be viewed as conformationally restricted (CR) analogs of phenylalkylamine hallucinogens, stimulants, and designer drugs. These agents were examined in rats trained to discriminate either DOM (1.0 mg/kg), (+)amphetamine (1.0 mg/kg), MDMA (1.5 mg/kg), or TDIQ (5.0 mg/kg) from saline vehicle. Whereas we have demonstrated that none of these agents retains their respective phenylalkylamine stimulus actions, several of these agents were found to substitute for TDIQ. N-Methylation abolished TDIQ-stimulus action. These results, coupled with previous findings, imply that TDIQ derivatives represent a novel class of phenylalkylamines analogs with unique stimulus properties. Preliminary radioligand binding studies suggest that an alpha2-adrenergic mechanism might underlie the stimulus effects produced by TDIQ.

Animals↗
PubMed1984

Defective stimulus set attention in generalized epilepsy.

This study examined auditory selective attention in primary generalized and complex-partial (temporal lobe) epileptics using binaural and dichotic versions of the Continuous Performance Test. The patient groups did not differ from normal controls when only one channel was presented or when divided attention (simultaneously monitoring two channels) was required. However, generalized epileptics had significantly depressed hit rates when directed attention (responding to critical stimuli in only one channel) was required. These results suggest a contribution of brain stem "arousal" mechanisms to stimulus set attention. In addition, right ear perceptual advantages were found on these dichotic monitoring tasks, lending support to the contention that short-term auditory memory and verbal report are not required for the dichotic ear effect.

Adult↗
PubMed1985

One-way generalization of clonidine to the discriminative stimulus produced by cocaine.

Rats were trained to discriminate the stimulus properties of either cocaine or clonidine using a food reinforced two-lever choice paradigm. After training, cocaine was generalized to the cocaine lever in a dose-dependent manner, and clonidine was generalized to the clonidine lever in a dose-dependent manner. Yohimbine, an alpha-2 antagonist, blocked the clonidine stimulus but not the cocaine stimulus. Cocaine was not generalized to the clonidine stimulus; however, clonidine was generalized to the cocaine stimulus, and this generalization was blocked by yohimbine. The one-way generalization of clonidine to cocaine suggests that clonidine has at least two discrete stimulus components: a major component that is not cocaine-like, and a minor component that can be detected by cocaine-trained subjects. In addition, the yohimbine blockade data suggest that both components of the clonidine stimulus are mediated via alpha-2 receptors.

Animals↗
PubMed1978

Movement discrimination capacities in the cat.

Cats were trained to discriminate moving from nonmoving targets or one direction of movement from another. Various stimulus changes, e.g., size, direction, and rate, were then introduced as a test for generalization of the dimension of movement. Thresholds for detection for minimal movement were also determined. The results showed that (a) for cats, discrimination of movement is more difficult than discriminations based on brightness; (b) the dimension of movement is completely generalized across stimulus configuration but incompletely generalized for direction of movement; (c) the mean movement detection threshold was found to be 3.3 degrees/sec; (d) the thresholds for minimal movement and direction of movement were essentially identical; and (e) stimulus-viewing strategies were found to play an important role in the threshold determinations. The results of the generalization tests are consistent with the physiological properties of neurons found to be sensitive to movement in the cat visual system. The movement threshold values were found to lend support to the view that resolution and slow movement thresholds are correlated.

Animals↗
PubMed1994

Learning-related alterations in the visual responsiveness of neurons in a memory system of the chick brain.

The intermediate and medial hyperstriatum ventrale (IMHV) of the chick brain is known to be essential for the learning process of imprinting. The activity of neurons was recorded from the left IMHV of 2-day-old unanaesthetized chicks while the chicks were free to move in a running wheel. The chicks were either raised in complete darkness or visually trained (imprinted) with a set duration of exposure to a visual image. The first group of these birds was trained by exposure for 100 min to a rotating red box and the second was trained by similar exposure to a rotating blue cylinder. A third group was left untrained. Training more than doubled the proportion of sites that responded to the stimulus used to train the bird, relative to the proportion of sites responsive to the other stimulus and to the proportion of sites responsive in the untrained birds; the learning-related increase was selective and highly significant. Behavioural monitoring indicated that the enhanced responsiveness could not be explained by overt differences in the alertness, attentiveness or movements of the birds. No significant effect of training was found on the proportion of sites responsive to a rotating stuffed jungle fowl or to the sound of a maternal call. The response at certain sites selectively signalled the presence of the training stimulus, while at others the response showed generalization across stimulus shape or colour. There was a non-specific effect of training upon the pattern of spontaneous discharges of the neurons: the numbers of spikes occurring in clusters (bursts) was significantly reduced in trained birds compared with the dark reared controls.

Acoustic Stimulation↗
PubMed1984

Teaching of labels: an analysis of concrete and pictorial representations.

The relationship between the use of concrete objects and pictorial representations of those objects when teaching noun labels to 3 autistic boys was analyzed. A multiple baseline design, counterbalanced for the type of stimulus presentation, was used to teach four sets of five objects and their pictorial representations to the youngsters. Although results indicated no consistent functional relationship between the two types of stimulus presentation, there were varying degrees of generalization between the two conditions. Findings suggest that there is a need to facilitate greater and more consistent generalization from pictures to the realities they represent.

Autistic Disorder↗
PubMed1999

Noribogaine generalization to the ibogaine stimulus: correlation with noribogaine concentration in rat brain.

The discriminative stimulus effects of ibogaine and noribogaine in rats have been examined in relation to their concentrations in blood plasma and brain regions and to receptor systems through which they have been proposed to act. Rats were trained to discriminate ibogaine (10 mg/kg i.p.), the NMDA antagonist dizocilpine (0.08 mg/kg i.p.) or the kappa-opioid agonist U50,488 (5 mg/kg i.p.) from vehicle in a standard two-lever operant conditioning procedure with a tandem VI-FR schedule of food reinforcement. Only rats trained on ibogaine generalized to noribogaine, which was approximately twice as potent as the parent compound. Noribogaine was detected in plasma and brain after administration of ibogaine and noribogaine. At the ED50 doses for the discriminative effect, the estimated concentrations of noribogaine in plasma, cerebral cortex, and striatum were similar regardless of whether ibogaine or noribogaine was administered. The findings suggest that the metabolite noribogaine may be devoid of NMDA antagonist and kappa-opioid agonist discriminative effects and that it may play a major role in mediating the discriminative stimulus effect of ibogaine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

Symmetrical generalization between the discriminative stimulus effects of gamma-hydroxybutyric acid and ethanol: occurrence within narrow dose ranges.

Gamma-hydroxybutyric acid (GHB) has been shown to reduce ethanol consumption and suppress ethanol withdrawal syndrome both in laboratory animals and humans. The present study was designed to assess the similarity between the discriminative stimulus effects, or subjective feelings, of GHB and ethanol using a T-maze, food-reinforced drug discrimination procedure. Three groups of rats were trained to discriminate ethanol (1.0 or 2.0 g/kg; p.o.) or GHB (300 mg/kg; p.o.) from water. In the 1.0 g/kg ethanol-trained rats, substitution for ethanol was an inverted U-shape function of GHB dose, with only 300 mg/kg GHB resulting in complete substitution for ethanol. No dose of GHB elicited selection of ethanol-appropriate arm higher than 10% in the 2.0 g/kg ethanol-trained group. In the 300 mg/kg GHB-trained rats, complete substitution for GHB occurred only at the dose of 1.0 g/kg ethanol. Doses of ethanol lower or higher than 1.0 g/kg did not substitute for GHB. The results of the present study indicate that symmetrical generalization between ethanol and GHB occurred within narrow dose ranges. They are discussed in terms of common neurotransmitter systems involved in the mediation of GHB and ethanol effects.

Alcohol Drinking↗
PubMed1992

Naloxone as a stimulus in drug discrimination learning: generalization to other opiate antagonists.

Nonopiate dependent animals were trained to discriminate the opiate antagonist naloxone (1 mg/kg) from distilled water within the conditioned taste aversion baseline of drug discrimination learning. Specifically, rats injected with naloxone prior to a saccharin-LiCl pairing, and with its vehicle prior to saccharin alone, rapidly acquired the drug discrimination, avoiding saccharin following the administration of naloxone and consuming saccharin following its vehicle after only three conditioning trials. Once the discrimination was acquired, generalization tests revealed that the opiate antagonists diprenorphine and naltrexone and the mixed opiate agonist/antagonist nalorphine completely generalized to the naloxone cue at doses of 1.8, 5.6 and 18 mg/kg, respectively. That discriminative control was established with a low dose of naloxone (i.e., 1 mg/kg) and other compounds with opiate antagonist activity generalized to the naloxone cue suggest that the stimulus effects of naloxone were likely mediated through the opiate receptor. Because each of these compounds are reported to bind to the mu receptor (with varying affinities and varying degrees of selectivity), the stimulus properties of naloxone are likely mediated at this specific receptor subtype.

Animals↗
PubMed1993

Visibility of elliptical Gaussian blobs.

Contrast detection thresholds for horizontally and vertically oriented elliptical stimuli with a 2D-Gaussian luminance profile in space and a Gaussian envelope in time were measured as a function of their spatial scale parameters for two different presentation times. For slowly varying stimuli, threshold is independent of stimulus size whenever the minor axis of the stimuli exceeds 10-20 min of arc. If the presentation time is shorter, the occurrence of size invariance also depends on the area of the stimulus. In general no significant dependence of the threshold on stimulus orientation is found. Where size invariance occurs it holds that: (1) the threshold is determined by the ratio between the major and the minor axis of the stimulus; (2) the threshold is highest for circular blobs; (3) for greatly elongated blobs the threshold varies as a power of the ratio. For slowly varying stimuli, this power equals -1/2; if the stimulus varies rapidly in time, thresholds depend much less on the ratio, unless the minor axis is small. The results are predicted by a multi-layer receptive field model in which the detection units resemble circular symmetric X-type cells, and in which the total response is obtained after Pythagorean summation of the contributions of the individual units. Probability summation cannot explain our results.

Contrast Sensitivity↗
PubMed1996

Brain sites mediating the discriminative stimulus effects of nicotine in rats.

Pharmacological studies suggest that the discriminative stimulus (DS) produced by nicotine is mediated centrally. The aim of the present study was to identify neuroanatomical substrates that mediate the DS properties of nicotine. Specifically, the nucleus accumbens, a brain region known to mediate the DS effects of amphetamine and cocaine, was investigated using a two-lever operant drug discrimination paradigm. Male hooded rats were trained to discriminate nicotine (0.2 mg/kg s.c.) from saline with a tandem schedule of food reinforcement. Once stimulus control was attained, a randomised sequence of nicotine microinjections (2-8 micrograms) was tested for generalisation during brief extinction tests. It was confirmed that the stimulus produced by the systemic administration of nicotine generalized to nicotine administered bilaterally into the dorsal hippocampus, with significant decreases in overall response rates. Microinjections of nicotine (1-8 micrograms) into the nucleus accumbens failed to produce any dose-related increases in responding on the nicotine-appropriate lever although these microinjections also produced significant decreases in response rates. Smaller doses (1-4 micrograms) of nicotine administered into the fourth ventricle produced characteristic prostration responses but these microinjections failed to produce generalization in tests carried out 20 min later, when the disabling effects of prostration had dissipated. These results suggest that the DS effects of nicotine may be mediated, at least in part, through the dorsal hippocampus. Results from intra-accumbens and intraventricular injections suggest that these regions may not be important in mediating the DS effects of nicotine.

Animals↗
PubMed1982

Normal children as tutors to teach social responses to withdrawn mentally retarded schoolmates: training, maintenance, and generalization.

The findings of the three experiments reported herein indicate that normal children can successfully teach social responses (i.e., delayed imitation cooperative play, and verbalization of positive comments) to withdrawn mentally retarded peers. The effects of the intervention generalized across stimulus and response conditions, while the trained and generalized levels of responding were maintained after the end of the intervention. Moreover, the subjects developed social responding within their classrooms and play areas parallel to the intervention and continued to increase such responding after the interruption of the intervention. Direct edible reinforcement appeared to be necessary at least during the initial period of the intervention. Vicarious edible reinforcement seemed useful to prompt the appearance of responding. Vicarious social reinforcement was ineffective at the beginning of the intervention, but apparently acquired prompting power at a later stage of training. Generalization results indicated that the similarity between the response occasions used for training and those used for testing generalization played an important role. Yet, the extensiveness of training and the development of responding within the classrooms and play areas may also have had a relevant effect. The development of social responding within the classrooms and play areas appeared to be mainly the effect of new learning. This was perhaps due to vicarious and direct social reinforcement.

Adolescent↗