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PubMed1985

Mechanistic studies on DOM as a discriminative stimulus.

Ten rats were trained to discriminate racemic DOM (1.0 mg/kg, IP) from saline using a standard two-lever operant procedure. Once responding was stable, these animals were administered doses of lisuride and the purported 5-HT1 agonist 8-OH DPAT in tests of stimulus generalization. DOM-stimulus generalization occurred with lisuride, but not with 8-OH DPAT. These animals were also administered doses of LY-53,857, ritanserin, CP-52,215, and THT in tests of stimulus antagonism. Each of these agents possesses a significant affinity for 5-HT2 binding sites, and each effectively attenuated the DOM-stimulus. These results, coupled with our earlier findings, support the hypothesis that DOM may be producing its stimulus effects via a 5-HT2-related mechanism.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1992

Mechanistic investigation of the stimulus properties of 1-(3-trifluoromethylphenyl)piperazine.

Using a standard two-lever operant procedure with rats trained to discriminate 1-(3-trifluoromethylphenyl)piperazine (TFMPP) (0.5 mg/kg) from saline, tests of stimulus antagonism and stimulus generalization were performed to better understand the stimulus properties of this agent. The agents examined for ability to antagonize the TFMPP stimulus were prazosin, quipazine, zacopride, buspirone, 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), 1-(2-methoxyphenol)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190), haloperidol, and 1-(2-pyrimidinyl)piperazine (1-PP); only buspirone attenuated the response to TF-MPP. In separate experiments, the lowest nondisrupting dose of buspirone (1.2 mg/kg) caused a rightward shift of the TFMPP dose-response curve (TFMPP alone, ED50 = 0.19 mg/kg; TFMPP + buspirone, ED50 = 0.43 mg/kg). In addition, 3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo[3,2-b]pyrid-5-one (CP 93, 129), 7-trifluoromethyl-4-(4-methyl-1-piperazinyl)pyrolo[1,2-a]quinox ali ne (CGS 12066B), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), 3-chlorophenylbiguanide (mCPBG), NAN-190, nisoxetine, zacopride, 1-PP, (+)-N-allylnormetazocine ((+)-NANM), and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) were analyzed in tests of stimulus generalization. The TFMPP stimulus generalized only to CGS 12066B (ED50 = 4.2 mg/kg) and (+)-NANM (ED50 = 8.8 mg/kg). Tests with DOI and MDMA resulted in partial generalization. Up to doses that disrupted behavior, all other agents had little effect on TFMPP-appropriate responding. The results of these and other published studies suggest roles for 5-hydroxytryptamine 1B (5-HT1B), 5-HT1C, and, possibly, sigma-receptors in the mediation of the TFMPP stimulus and indicate a lack of involvement of 5-HT1A, 5-HT2, dopaminergic, and adrenergic mechanisms in this behavior.

Animals↗

PubMed1991

The discriminative stimulus effects of diazepam in rats at two training doses.

Two groups of rats were trained to discriminate either a low (1 mg/kg) or a high (10 mg/kg) intraperitoneal dose of diazepam from vehicle injections in a two-lever, food-reinforcement procedure. Comparison of the dose-response curves demonstrated a difference in the intensity of the stimulus effects. A number of benzodiazepine agonists and partial agonists were tested for stimulus generalization. The stimulus effect in both groups of rats generalized fully to triazolam, alprazolam, adinazolam and pentobarbital. Ro 17-1812 occasioned nearly full generalization in both groups of rats with a shallow dose-response slope. The low-, but not the high-dose stimulus effect generalized to the following compounds: CL 218872, ZK 91296 (ethyl-5-benzyloxy-4-methoxymethyl-B-carboline-3-carboxylate), CGS 20625 (2-(4-methoxyphenyl)-2,3,5,6,7,8,9,10-octahydrocyclohepta(b)pyrazo lo(3,4- d)pyridin-3-one) and U-78875 (3-(5-cyclo-propyl-1,2,4-oxadiazol-3-yl)-5-(1- methylethyl)imidazol(1,5-a)quinoxalin-4(5H)-o-ne). Flumazenil, FD-7142 (N-methyl-beta-carboline-3-carboxamide), buspirone and morphine occasioned predominantly vehicle-appropriate responses in both groups of rats. In the low-dose group, pretreatment with flumazenil (10 mg/kg) reduced responding on the diazepam-lever for the following compounds: diazepam, Ro 17-1812 (cyclopropylmethyl-(S)-8-chloro-12,12a-dihydro- 9-oxo-9H,11H-aceto(2,1-C)imidazo(1,5-a)(1,4)benzo-diazepine-1-carboxylat e), ZK 91296, CGS 20625, CL 218872 and U-78875.(ABSTRACT TRUNCATED AT 250 WORDS)

Alprazolam↗

PubMed1986

Discriminative stimulus properties of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT).

Using a two-lever operant procedure, eleven rats were trained to discriminate 0.2 mg/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT) from saline using a variable-interval 15 sec schedule of reinforcement. Once trained, these animals were used in a series of stimulus generalization and stimulus antagonism studies. The 8-OH DPAT-stimulus did not generalize to the 5-HT1B agonist 1-(3-trifluoromethylphenyl) piperazine (TFMPP) or the 5-HT2 agonist 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM), nor could it be attenuated by pre-treatment of the animals with the 5-HT2 antagonist ketanserin. Low doses of spiperone and propranolol were without effect on 8-OH DPAT-appropriate responding, whereas higher doses of these agents resulted in disruption of behavior. Some preliminary structure-activity data were also obtained using several related tetralin analogs. The results of this study demonstrate that the serotonin agonist 8-OH DPAT serves as a discriminative stimulus in rats and that it produces stimulus effects that are probably not 5-HT1B or 5-HT2-mediated.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1991

Inverse agonist properties of the THBC discriminative stimulus: asymmetrical generalization with FG 7142.

Male rats were trained to discriminate the stimulus properties of the beta-carbolines 1,2,3,4-tetrahydro-beta-carboline (THBC) (15.0 mg/kg) or FG 7142 (5.0 mg/kg) from vehicle in a two-lever, food-motivated operant task. Consistent with the serotonergic properties of THBC, administration of the 5HT1B agonists TFMPP and mCPP to THBC-trained rats resulted in THBC-appropriate responding. Norharmane, a beta-carboline metabolite of THBC, also mimicked the THBC discriminative stimulus. In contrast, the benzodiazepine receptor partial inverse agonist FG 7142, the anxiogenic/convulsant pentylenetetrazole (PTZ), two physiological stressors and the alpha 2 adrenergic antagonists yohimbine and idazoxan failed to produce THBC-appropriate responding. In the FG 7142-trained rats, THBC and norharmane dose-dependently mimicked the FG 7142 discriminative stimulus. This generalization was not based upon the serotonergic properties of THBC and norharmane since administration of the serotonin agonist mCPP to FG 7142-trained rats failed to produce FG 7142-appropriate responding. The ability of THBC to substitute for the FG 7142 discriminative stimulus was antagonized by the benzodiazepine receptor mixed agonist/antagonist CGS 9896 and the benzodiazepine receptor antagonist RO 15-1788, indicating that THBC produces an inverse agonist stimulus in FG 7142-trained rats. These results suggest that THBC produces a discriminative stimulus which consists of both serotonergic and inverse agonist components.

Animals↗

PubMed1999

Analysis of D2 and D3 receptor-selective ligands in rats trained to discriminate cocaine from saline.

This study examined the role of dopamine D3 receptors in the stimulus generalization produced by 7-OH-DPAT and PD 128907 in rats trained to discriminate cocaine from saline. Twelve male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg) from saline in a two-choice operant procedure using a FR20 schedule of water reinforcement. Stimulus generalization tests were administered with the D3-preferring agonists (+/-)-7-OH-DPAT (0.01-0.3 mg/kg), (+)-7-OH-DPAT (0.01-0.3 mg/kg), and PD 128907 (0.01-0.3 mg/kg), and the selective D2 agonist PNU-39156 (0.01-0.3 mg/kg). Complete generalization to cocaine was observed with (+/-)-7-OH-DPAT at doses that markedly suppressed response rate. Only partial stimulus generalization was observed with (+)-7-OH-DPAT and PD 128907 when these compounds were administered intraperitoneally, although subcutaneous injections of these compounds produced complete substitution. Response rate was also significantly reduced by these compounds. The selective D2 agonist, PNU-91356 also fully substituted for the cocaine cue and suppressed response rate in a dose-dependent manner. To ascertain the importance of D3 receptor actions in the stimulus generalization produced by (+/-)-7-OH-DPAT (0.1 mg/kg) and PD-128907 (0.3 mg/kg), the fairly selective D3 antagonist, PNU-99194A (2.5-20 mg/kg) was also tested in combination with these compounds. Although PNU-99194A partially attenuated the stimulus generalization produced by (+/-)-7-OH-DPAT, it failed to block PD-128907 substitution for cocaine. These results indicate at least some involvement of D3 receptors in the stimulus effects of (+/-)-7-OH-DPAT, although further investigations are clearly warranted. The present results also suggest that the cue properties of cocaine may be dissociated from the locomotor activating effects of this drug, because D3/D2 receptor agonists suppress locomotor activity but produce stimulus generalization to cocaine.

Animals↗

PubMed1988

Site-selective serotonin agonists as discriminative stimuli.

Various direct- and indirect-acting serotonin (5-HT) agonists serve as training drugs in tests of stimulus control of behavior; such agents include: 5-hydroxytryptophan, 5-methoxy-N,N-dimethyltryptamine, and fenfluramine. However, with the recent discovery of multiple populations of central 5-HT binding sites, the concept of site-selective serotonergic agents needs to be addressed. Certain 4-substituted 1-(2,5-dimethoxyphenyl)-2-aminopropanes such as DOM (4-methyl), DOB (4-bromo), and DOI (4-iodo) appear to be 5-HT2-selective agonists and serve as effective training drugs in rats. Stimulus generalization occurs among these agents regardless of which is used as the training drug, although stimulus generalization does not occur with 5-HT1A-selective agonists [e.g., 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH DPAT)] or with 5-HT1B-selective agonists [e.g., 1-(3-trifluoromethylphenyl)piperazine (TFMPP)]. 8-OH DPAT and TFMPP also serve as training drugs; the 8-OH DPAT-stimulus generalizes to other 5-HT1A agonists, but not to 5-HT1B or 5-HT2 agonists, whereas the TFMPP-stimulus generalizes to other 5-HT1B agonists, but not to 5-HT1A or 5-HT2 agonists. Classical serotonin antagonists, most of which are rather selective for 5-HT2 sites, and 5-HT2-selective antagonists are able to block the stimulus effects of DOM, DOB, and DOI, but not those of 8-OH DPAT or TFMPP. The results of such studies reveal that, in rats, site-selective 5-HT agonists produce stimulus effects that are also selective; although generalization may occur with nonselective 5-HT agonists, animals trained to discriminate site-selective 5-HT agonists apparently do not recognize other 5-HT agonists that are selective for a different site. Animals trained to discriminate such agents from saline might be useful for the identification and/or investigation of novel site-selective agonists and antagonists (for example, the 8-OH DPAT-stimulus generalizes to members of a new class of anxiolytics that display high affinity for 5-HT1A binding sites), and might also aid in the overall understanding of central serotonergic mechanisms.

Animals↗

PubMed1998

The dopamine D3 receptor antagonist PNU-99194A fails to block (+)-7-OH-DPAT substitution for D-amphetamine or cocaine.

The present study examined the role of dopamine D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate either D-amphetamine or cocaine from saline. Twelve male Sprague-Dawley rats were trained to discriminate D-amphetamine (1.0 mg/kg) and 12 rats were trained to discriminate cocaine (5.0 mg/kg) from saline in a two-choice, water-reinforced operant procedure. Stimulus generalization tests were administered with the D3 receptor-preferring agonist, (+)-7-hydroxy-N, N-di-n-propyl-2-aminotetralin ((+)-7-OH-DPAT, 0.01-1.0 mg/kg) as well as the D3-preferring antagonist, 5,6-di-methoxy-2-(dipropylamino)indan-hydrochloride (PNU-99194A, 5-40 mg/kg). PNU-99194A (10-40 mg/kg) was also administered in combination with the training dose of D-amphetamine or cocaine to test for antagonism of each training drug cue. Finally, to assess the role of D3 receptor actions in the stimulus generalization produced by (+)-7-OH-DPAT (0.1 mg/kg), PNU-99194A (10, 20 mg/kg) was tested in combination with this compound in each training group. The results showed complete stimulus generalization with (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine, although only partial stimulus generalization was observed with this compound in rats trained to discriminate cocaine. PNU-99194A produced partial substitution for both training drugs, and failed to block the discriminative stimulus effects of either D-amphetamine or cocaine. Moreover, this compound failed to block the stimulus generalization produced by (+)-7-OH-DPAT in rats trained to discriminate D-amphetamine. These results question the importance of D3 receptor actions in the discriminative stimulus effects of psychostimulants and their similarities to (+)-7-OH-DPAT.

Amphetamine↗

PubMed1989

A developmental study of filtering in visual attention.

Children aged 4, 5, and 7 years and adults aged 20 years performed a speeded classification task designed to isolate several sources of interference in visual selective attention. On each trial, observers responded to 1 of 4 targets which were mapped to 2 responses. On some trials the targets were also flanked by distractor stimuli, which observers were asked to ignore. The interference measures examined the effects of attentional set, increases in feature number, increases in feature type, response competition, and stimulus generalization. All but 1 of the measures (stimulus generalization) produced reliable interference in the adult observers. However, only 2 of the measures (attentional set, increases in feature number) produced reliable interference in children. The implications of these findings for theories of attentional development are discussed.

Adult↗

PubMed1988

Chlorphentermine may produce dual stimulus effects: a preliminary investigation.

1. Rats were trained to discriminate injections of either (+)-amphetamine (0.75 mg/kg) or (+/-)-fenfluramine (1.5 mg/kg) from saline in a two-lever drug discrimination task. 2. After stable discrimination performances were attained in each group, stimulus generalization studies were conducted with amphetamine, fenfluramine, and chlorphentermine. 3. Stimulus generalization (substitution) did not occur between amphetamine and fenfluramine when either drug was used as the training stimulus. 4. In contrast, both the amphetamine stimulus and the fenfluramine stimulus generalized completely to chlorphentermine. 5. Taken together, the results suggest that chlorphentermine may be capable of producing dual stimulus effects in animals.

Animals↗

PubMed1999

An examination of isomeric phenylpropanolamines in (-)ephedrine-trained rats.

A total of eight isomeric phenylpropanolamines are possible when the terminal amine is either an N-monomethylamine or a primary amine: (-)ephedrine, (+)ephedrine, (+)pseudoephedrine, (-)pseudoephedrine, (-)norephedrine, (+)norephedrine, (+)cathine, and (-)cathine. Few previous studies have examined the individual optical isomers of these phenylpropanolamines and, with the exception of one report on locomotor effects, no comparative behavioral data have been published on this series of agents. Using rats trained to discriminate 4 mg/kg of (-)ephedrine (i.p.) from saline vehicle using standard operant conditioning with a VI 15-s schedule of reinforcement, all eight agents were examined in tests of stimulus generalization. The (-)ephedrine stimulus (ED50 = 0.90 mg/kg) generalized to (+)ephedrine (ED50 = 2.64 mg/kg), (+)pseudoephedrine (ED50 = 6.58 mg/kg), (-)norephedrine (ED50 = 1.86 mg/kg), (+)norephedrine (ED50 = 5.75 mg/kg), and (+)cathine (ED50 = 4.87 mg/kg). The (-)ephedrine stimulus failed to generalize to either (-)pseudoephedrine or (-)cathine; the latter agents produced a maximum of 29 and 31% (-)ephedrine-appropriate responding, respectively. Thus, (a) six of the eight phenylpropanolamines produced ephedrine-like stimulus effects, (b) (-)ephedrine was the most potent of the examined agents, and (c) where stimulus generalization occurred, ED50 values spanned less than a tenfold range.

Animals↗

PubMed1988

A preliminary investigation of the psychoactive agent 4-bromo-2,5-dimethoxyphenethylamine: a potential drug of abuse.

4-Bromo-2,5-dimethoxyphenethylamine (alpha-desMe DOB) is a psychoactive agent that may possess significant abuse potential. Because of its structural similarity to the established hallucinogen 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB), and because almost no pharmacological data are available on this agent, we undertook this preliminary investigation. alpha-DesMe DOB (Ki = 1 nM), like DOB itself (Ki = 0.79 nM), displays a high affinity for [3H]DOB-labeled central 5-HT2 serotonin receptors. However, unlike DOB, the alpha-desmethyl derivative also binds with significant affinity to 5-HT1A, 5-HT1B, and 5-HT1C serotonin receptors and, as such, is less selective than DOB. In drug discrimination studies using rats trained to discriminate either DOM (i.e., the 4-methyl analog of DOB) or R(-)DOB from saline, stimulus generalization occurred in both groups of animals. However, stimulus generalization was associated with extensive disruption of behavior, alpha-DesMe DOB may produce stimulus effects similar, but not identical, to those of DOM and R(-)DOB; in addition, this agent may be capable of producing other, as yet undefined, central effects at comparable doses. These other effects may be reflective of the lack of selectivity of alpha-desMe DOB for 5-HT2 serotonin receptors. Because other hallucinogenic agents display high affinity for 5-HT2 serotonin receptors and result in stimulus generalization in DOM- and/or DOB-trained animals, it is tentatively concluded that alpha-desMe DOB is a psychoactive agent with at least some hallucinogenic or DOB-like properties.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1976

State-dependent learning produced by chlordiazepoxide and its transfer at different dose levels.

In Experiment I, the rat was given 15 mg/kg of chlordiazepoxide (CDP) and trained on a black-white discrimination task, motivated by electric shocks; the same animal, when given saline, was treated similarly with the reversed cue relationship on different and usually alternate sessions. Training was continued until a learning criterion under both drug and saline states and then tested with only one of five testing CDP doses (2.5, 5, 10, 20 and 25 mg/kg). During training, the rat made more errors under drug than under saline but there were little differences in starting and running times at least during the last sessions. In the transfer test, choice responses showed a bi-directional gradient around the training dose as in stimulus generalization gradient. Experiment II was identical to Experiment I, except that the same drug was tested at all five transfer doses and the resulting transfer gradient was a simple monotonic increasing function of dose levels. Discrepancy between the two experiments was discussed.

Animals↗

PubMed1978

Narcotic cuing and analgesic activity of narcotic analgesics: associative and dissociative characteristics.

By using a discrete-trial, two-lever, food-reinforced discrimination learning paradigm, rats were trained to discriminate the narcotic analgesic fentanyl (0.05 mg/kg) from saline. Stimulus generalization experiments with lower fentanyl doses (0.0025 to 0.02 mg/kg) were carried out to generate individual threshold doses. The latter were compared with the sensitivity of the same rats to the analgesic effect of fentanyl, and it was found that there is no correlation between these two sets of data. In a time-effect experiment, the duration of fentanyl's cuing effect was compared with that of its analgesic effect, and it was found that the time-effect characteristics of the narcotic cue are similar to those of analgesia. Again, however, there was no correlation between the duration of both effects within the same group of animals. The results further deliniate the associative and dissociative characteristics of the narcotic cue and narcotic analgesia.

Analgesics↗

PubMed1976

Conditioned suppression of an operant response using d-amphetamine as the conditioned stimulus.

The use of a drug state as a conditioned stimulus (CS) in a classical conditioning paradigm was investigated. Suppression of a single-lever food-reinforced response (variable-interval 60 s) served as an index of a classically conditioned response (conditioned suppression). d-Amphetamine (0.8 mg/kg) injections were paired with a series of inescapable shocks. Following drug-shock pairing, the effects of d-amphetamine on operant response totals was compared to effects obtained in control subjects which had received unpaired d-amphetamine and shock exposures. d-Amphetamine administered during daily operant sessions unaccompanied by shock was an effective CS for conditioned suppression of the operant response. Administration of cocaine hydrochloride (7.5 mg/kg) also produced a decrease in total responses, suggesting stimulus generalization from the shock-paired drug to a novel drug.

Animals↗

PubMed1985

Drug discrimination training with a single choice trial per session.

All drug discrimination procedures share in common the practice of providing for multiple choice opportunities per training session. This practice allows nondrug cues (presence or absence of reinforcement) to mediate choice behavior during that portion of the session following the initial choice. Investigators who have acknowledged this problem typically use only first-trial choice performance to evaluate discriminative control by the drug cue, and consider additional choice training following the delivery or nondelivery of the first reinforcer to be facilitatory in establishing drug-mediated discriminative control. In this experiment, rats were trained to discriminate 4.0 mg/kg morphine from saline in a novel procedure that employed a single choice trial per training session. Choice performance was characterized during discrimination acquisition and in subsequent stimulus generalization testing. The results indicated that when all reinforcers are made contingent on correct performance during a single choice trial, rapid and stable control of drug-mediated choice behavior, is observed. In addition, the results demonstrated that additional choice training following the delivery or nondelivery of the first reinforcer is not a necessary antecedent toward establishing drug-mediated discriminative control.

Animals↗

PubMed2001

Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.

RATIONALE: Inhibitors of neuronal dopamine uptake, such as GBR 12909, decrease IV cocaine self-administration by laboratory animals and have been proposed as potential therapeutic agents for abuse of psychomotor stimulant drugs. OBJECTIVES: This study was performed to determine how GBR 12909 alters the discriminative stimulus effects of methamphetamine and cocaine. METHODS: Rats were trained to discriminate between IP injections of 10 mg/kg cocaine and saline and were tested for stimulus generalization to cocaine, GBR 12909, and methamphetamine. Based upon the ED50 of the individual drugs, combinations of GBR 12909 and either cocaine or methamphetamine were tested that comprised a) 1 part GBR 12909 and 2 parts cocaine or methamphetamine, or b) 2 parts GBR 12909 and 1 part cocaine or methamphetamine. RESULTS: GBR 12909 and cocaine were equipotent and 30-fold less potent than methamphetamine in producing cocaine-like discriminative effects. GBR 12909 and cocaine produced cocaine-like discriminative effects synergistically in the ratio of 1 part GBR 12909:2 parts cocaine (0.16+0.32 to 1.92+ 3.87 mg/kg) and nearly synergistically in the ratio of 2 parts GBR 12909:1 part cocaine (0.32+0.16 to 3.92+ 1.91 mg/kg). GBR 12909 and methamphetamine (0.32+0.02 to 3.20+0.22 mg/kg or 0.65+0.01 to 6.53+0.1 mg/kg) were simply additive in both sets of fixed-ratio dose combinations. CONCLUSIONS: The synergy of GBR 12909 and cocaine and the additivity of GBR 12909 and methamphetamine run counter to the presumed mechanisms of action of these drugs at dopamine nerve terminals, which might have implications for the use of GBR 12909 in the treatment of addiction to cocaine or amphetamines.

Animals↗

PubMed1982

Treatment of an abnormal avoidance of fluid consumption.

Adipsia is an uncommon, life-threatening condition which refers to an absence of thirst or an abnormal avoidance of fluid consumption. A behavioral intervention was successfully used in the treatment of severe adipsia in a multi-handicapped adolescent whose water intake was almost entirely limited to the water content of the foods he consumed. Using edible reinforcement and a set of commercial measuring utensils (from 1/4 teaspoon to 1 cup), milk consumption was established through a behavior shaping regimen. Follow-up results over 1 year indicated that the behavioral progress was maintained, problems with dehydration were eliminated, and stimulus generalization to several other fluids occurred.

Adolescent↗