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Paul E A Glaser

Publications and source records attributed to Paul E A Glaser.

18 recordsLinked to original sources
PubMed2006

Adderall produces increased striatal dopamine release and a prolonged time course compared to amphetamine isomers.

RATIONALE: Adderall is currently used for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) and is composed of a novel mixture of approximately 24% L-amphetamine and 76% D-amphetamine salts. There are, however, no investigations of the pharmacological effects of this combination in vivo. OBJECTIVES: The technique of high-speed chronoamperometry using Nafion-coated single carbon-fiber microelectrodes was used to study amphetamine-evoked dopamine (DA) release produced by Adderall, D-amphetamine, or D,L-amphetamine in the striatum of anesthetized male Fischer 344 (F344) rats. The amphetamine solutions were locally applied from micropipettes by pressure ejection. RESULTS: Local applications of Adderall resulted in significantly greater DA release signal amplitudes with prolonged time course of dopamine release and re-uptake as compared to D-amphetamine and D,L-amphetamine. CONCLUSIONS: These data support the hypothesis that the combination of amphetamine enantiomers and salts in Adderall has effects on DA release, which result in increased and prolonged DA release, compared to D- and D,L-amphetamine.

Amphetamine↗
PubMed2006

A low dose of aripiprazole attenuates the subject-rated effects of d-amphetamine.

Despite increased reports of amphetamine abuse and dependence, a putative pharmacotherapy has yet to be identified. In a previous study from our laboratory, 20 mg aripiprazole, an atypical antipsychotic that has partial agonist activity at D(2) receptors, attenuated many of the behavioral effects of d-amphetamine. Aripiprazole (20 mg) also impaired performance on a computerized version of the DSST when administered alone, indicating that the attenuation observed may have been functional as opposed to receptor mediated. The present experiment was conducted to determine whether a lower dose of aripiprazole (10 mg) could acutely attenuate the discriminative-stimulus, subject-rated, and physiological effects of d-amphetamine (2.5-15 mg) without impairing performance as measured with a computerized version of the DSST. The results of the present experiment indicate that 10 mg aripiprazole attenuated some abuse-related behavioral effects of d-amphetamine and was generally devoid of effects, including significant performance impairment, when administered alone. These findings suggest that 10 mg aripiprazole would be a reasonable starting dose for the treatment of stimulant abuse and dependence. Future research should examine the effects of chronic aripiprazole administration in combination with methamphetamine or cocaine.

Adult↗
PubMed2006

Cerebellar neurotransmission in attention-deficit/hyperactivity disorder: does dopamine neurotransmission occur in the cerebellar vermis?

Children and adolescents with attention-deficit/hyperactivity disorder (ADHD) have smaller cerebellar volumes, particularly in the posterior-inferior cerebellar vermis (lobules VIII-X). Functional activation of the human cerebellar vermis following stimulant administration has also been repeatedly demonstrated. There is no well-characterized dopaminergic pathway that projects to the posterior-inferior cerebellar vermis, although the dopamine transporter (DAT) and tyrosine hydroxylase (TH) have been localized in the posterior-inferior vermis in the non-human primate by immunohistochemistry. We hypothesized that DA neurotransmission may occur in localized "hot spots" in the cerebellar vermis, and if so, that differences in such neurotransmission might be relevant to the pathophysiology of ADHD. To investigate this hypothesis, cerebellar tissue was obtained from rats and non-human primates. Catecholamines were extracted and analyzed using HPLC with coulometric detection. A regional gradient of norepinephrine (NE) and DA was found throughout the cerebellum with NE levels always roughly 10-40-fold higher than DA in both rats and monkeys. In addition, in vivo microdialysis studies were performed in the rat posterior-inferior cerebellar vermis in anesthetized animals. Significant NE overflow was observed over baseline following reverse microdialysis induced release by potassium or d-amphetamine. DA overflow was not observed over baseline for potassium stimulation, but was significant for d-amphetamine stimulation. These studies refute the hypothesis that DA neurotransmission normally occurs in the rat cerebellar vermis, but highlight that vermal DA is released by d-amphetamine. The presence of DAT may therefore allow for enhanced regulation of NE and not regulation of released DA.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2006

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans.

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential.

Adolescent↗
PubMed2005

Methylphenidate increases cigarette smoking.

RATIONALE: Methylphenidate (Ritalin) and d-amphetamine (Dexedrine), stimulants commonly prescribed for behavioral problems associated with attention deficit hyperactivity disorder (ADHD), produce a similar constellation of behavioral effects. The results of previous studies suggest that d-amphetamine increases rates of smoking and the reinforcing effects of smoking. The effects of methylphenidate on smoking have not been assessed although it is the most commonly prescribed pharmacotherapy for ADHD and individuals with ADHD are at increased risk for smoking. OBJECTIVE: In this experiment the acute effects of a range of doses of methylphenidate (5, 10, 20, and 40 mg) and placebo were assessed in ten cigarette smokers who were not attempting to quit and were without ADHD or other Axis I psychiatric disorders. METHODS: Each dose of methylphenidate was tested once, whereas placebo was tested twice. One hour after ingesting drug, participants were allowed to smoke ad libitum for 4 h. Measures of smoking included total cigarettes smoked, total puffs, latency to the first cigarette, and carbon monoxide levels. Snacks and decaffeinated drinks were available ad libitum, and caloric intake during the 4-h smoking session was calculated. RESULTS: Methylphenidate dose dependently increased the total number of cigarettes smoked, number of puffs, and carbon monoxide levels. As expected, methylphenidate dose dependently decreased the number of food items consumed and caloric intake. CONCLUSIONS: The results of this experiment suggest that methylphenidate, like d-amphetamine, increases rates of cigarette smoking.

Adolescent↗
PubMed2005

Reinforcing effects of modafinil: influence of dose and behavioral demands following drug administration.

RATIONALE: The reinforcing effects of stimulant drugs are modulated by behavioral demands following drug administration. OBJECTIVE: The objective of this study was to assess the reinforcing effects of modafinil, a drug with purportedly low abuse potential, under different behavioral demands using a modified progressive-ratio procedure. METHODS: The reinforcing effects of oral modafinil (0, 100, 200, and 400 mg) were assessed in six healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session), and the order of performance and relaxation sessions was constant within a dose condition. RESULTS: Modafinil significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Modafinil produced comparable stimulant-like subjective ratings under both the performance and relaxation conditions. CONCLUSION: The findings of the present experiment demonstrate that modafinil can function as a reinforcer and that the reinforcing effects of modafinil are influenced by behavioral demands following drug administration, similar to those of other stimulant drugs.

Adult↗
PubMed2005

Oxazepam does not modulate the behavioral effects of d-amphetamine in humans.

Benzodiazepines, which are gamma-aminobutyric acid-A (GABA(A)) receptor positive modulators, can block the behavioral effects of psychomotor stimulants. In the present study, the ability of oxazepam, which may have less abuse potential compared to some other benzodiazepines, to attenuate the discriminative-stimulus, subject-rated and psychomotor performance effects of d-amphetamine in humans was determined. Six healthy participants (2 female, 4 male) learned to discriminate 15 mg oral d-amphetamine. After acquiring the discrimination (i.e., > or = 80% correct responding on 4 consecutive days), the effects of d-amphetamine (0, 2.5, 5, 10 and 15 mg), alone and in combination with acutely administered oxazepam (0 and 20 mg) were assessed. d-Amphetamine alone functioned as a discriminative stimulus, produced stimulant-like subject-rated effects (e.g., increased ratings of Stimulated on a Drug-Effect Questionnaire) and enhanced psychomotor performance. Oxazepam alone increased subject ratings of sedation (e.g., increased ratings of Sluggish, Fatigued and Lazy on a Drug-Effect Questionnaire) and impaired psychomotor performance. Oxazepam alone did not occasion d-amphetamine-like discriminative-stimulus effects, and had no effect on the discriminative-stimulus or subject-rated effects of d-amphetamine when given in combination. The results of this experiment are discordant with previous research and suggest that benzodiazepines differ in their ability to modulate the behavioral effects of d-amphetamine.

Adult↗
PubMed2005

Discriminative stimulus and self-reported effects of methylphenidate, d-amphetamine, and triazolam in methylphenidate-trained humans.

Asymmetrical generalization between drugs on drug-discrimination procedures has been demonstrated for sedative and stimulant drugs in animals and to some extent with sedative drugs in humans. The aim of this experiment was to examine the discriminative-stimulus effects of d-amphetamine in methylphenidate-trained humans. A previous study demonstrated that methylphenidate substitutes for d-amphetamine in d-amphetamine-trained humans. Six healthy human participants first learned to discriminate 30 mg oral methylphenidate. Doses of oral methylphenidate, d-amphetamine, triazolam, and placebo were then tested to determine whether they share discriminative-stimulus and self-reported effects with 30 mg methylphenidate. Methylphenidate and d-amphetamine dose-dependently increased methylphenidate-appropriate responding and produced prototypical stimulant-like effects. Triazolam produced low levels of methylphenidate-appropriate responding and prototypical sedative-like effects. The results of this experiment are concordant with previous studies and suggest that the behavioral effects of oral methylphenidate and d-amphetamine overlap extensively and that the discriminative-stimulus effects of methylphenidate and d-amphetamine are symmetrical.

Adult↗
PubMed2005

Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of D-amphetamine in humans.

The results of animal research suggest that the use of partial agonists at dopamine (DA) D2 receptors may be an effective strategy for the treatment of stimulant dependence. Aripiprazole is an atypical antipsychotic that has partial agonist activity at D2 receptors. In this experiment, seven human participants with a history of nontherapeutic stimulant use learned to discriminate 15 mg oral D-amphetamine. After acquiring the discrimination (ie > or =80% correct responding on four consecutive sessions), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and in combination with aripiprazole (0 and 20 mg), were assessed. D-Amphetamine alone functioned as a discriminative stimulus, produced prototypical subject-rated drug effects (eg increased ratings of Active, Alert, Energetic) and elevated cardiovascular indices. These effects were generally a function of dose. Aripiprazole alone did not occasion D-amphetamine-appropriate responding or produce subject-rated effects, but modestly impaired performance. Administration of aripiprazole significantly attenuated the discriminative-stimulus and cardiovascular effects of D-amphetamine, as well as some of the subject-rated drug effects. These data are consistent with previous preclinical findings and suggest that DA partial agonists deserve further evaluation as potential pharmacotherapies in the management of stimulant dependence. Future studies should investigate the ability of aripiprazole or related compounds to attenuate the behavioral effects of stimulants associated with a greater degree of dependence, such as methamphetamine or cocaine, in dependent individuals.

Adult↗
PubMed2004

Acute administration of the GABA reuptake inhibitor tiagabine does not alter the effects of oral cocaine in humans.

Drugs affecting central gamma-aminobutyric acid (GABA) systems may have promise as treatments for cocaine addiction. In the present study, tiagabine (Gabatril), a GABA reuptake inhibitor, was investigated for its ability to modify the discriminative-stimulus, reinforcing, subject-rated, performance and cardiovascular effects of oral cocaine in non-treatment seeking cocaine users. Initially, acute doses of 4 mg tiagabine were tested alone and in combination with oral cocaine in four participants to establish the safety of cocaine-tiagabine combinations. A higher dose of tiagabine (8 mg) was then tested in a larger group (n = 6). Participants learned to discriminate 150 mg of oral cocaine. The effects of cocaine (0-150 mg, p.o.) administered alone and in combination with tiagabine were then determined. Subject-rated, performance and cardiovascular measures were obtained at regular intervals. The reinforcing effects of cocaine, tiagabine and cocaine-tiagabine combinations were assessed using the Multiple-Choice Procedure. Cocaine alone produced prototypical behavioral and physiological effects (i.e., functioned as a discriminative and reinforcing stimulus, produced stimulant-like subject-rated effects, improved performance and increased heart rate). In general, acute administration of tiagabine did not alter the effects of oral cocaine. These findings suggest that tiagabine would not be effective at preventing continued cocaine use by blocking its acute, abuse-related effects.

Administration, Oral↗
PubMed2004

Differential effects of amphetamine isomers on dopamine release in the rat striatum and nucleus accumbens core.

RATIONALE: Current medications for attention-deficit/hyperactivity disorder (ADHD) include some single isomer compounds [dextroamphetamine (D: -amphetamine, dexedrine) and dexmethylphenidate (Focalin)] and some racemic compounds [methylphenidate and mixed-salts amphetamine (Adderall)]. Adderall, which contains approximately 25% L: -amphetamine, has been successfully marketed as a first-line medication for ADHD. Although different clinical effects have been observed for D: -amphetamine, Adderall, and benzedrine; potential psychopharmacological differences on the level of neurotransmission between D: -amphetamine and L: -amphetamine have not been well characterized. OBJECTIVES: To evaluate potential differences in the isomers, we used the technique of high-speed chronoamperometry with Nafion-coated single carbon-fiber microelectrodes to measure amphetamine-induced release of dopamine (DA) in the striatum and nucleus accumbens core of anesthetized male Fischer 344 rats. Amphetamine solutions were locally applied by pressure ejection using micropipettes. RESULTS: The presence of L: -amphetamine in the D: ,L: -amphetamine solutions did not cause increased release of DA but did change DA release kinetics. The D: ,L: -amphetamine-evoked signals exhibited significantly faster rise times and shorter signal decay times. This difference was also observed in the nucleus accumbens core. When L: -amphetamine was locally applied, DA release was not significantly different in amplitude, and it exhibited the same rapid kinetics of D: ,L: -amphetamine. CONCLUSIONS: These data support the hypothesis that amphetamine isomers have different effects on release of DA from nerve endings. It is possible that L: -amphetamine may have unique actions on the DA transporter, which is required for the effects of amphetamine on DA release from nerve terminals.

Amphetamines↗
PubMed2004

Reinforcing effects of methylphenidate: influence of dose and behavioral demands following drug administration.

RATIONALE: The reinforcing effects of stimulant drugs such as D-amphetamine, caffeine, and cocaine are modulated by behavioral demands following drug administration. OBJECTIVE: The objective of this study was to assess the reinforcing effects of methylphenidate under different behavioral demands using a modified progressive-ratio procedure. METHODS: The reinforcing effects of oral methylphenidate (0, 10, 20, and 40 mg) were assessed in seven healthy adult volunteers under both performance and relaxation conditions. Performance sessions required volunteers to complete simple arithmetic problems for three 50-min blocks. Relaxation sessions required volunteers to sit quietly in a semi-reclined position in a darkened room for three 50-min blocks. Two sampling sessions (one performance and one relaxation session) always preceded two self-administration sessions (one performance and one relaxation session) and the order of relaxation and performance sessions was constant within a dose condition. RESULTS: Methylphenidate significantly increased break point and number of capsules earned on the modified progressive-ratio procedure as an increasing function of dose under the performance, but not the relaxation, condition. Methylphenidate produced comparable stimulant-like subject ratings under both the performance and relaxation conditions. CONCLUSION: The findings of the present experiment suggest that the reinforcing effects of methylphenidate, like D-amphetamine and cocaine, are influenced by behavioral demands following drug administration.

Administration, Oral↗
PubMed2004

Alprazolam attenuates the behavioral effects of d-amphetamine in humans.

The results of preclinical behavioral pharmacology studies suggest that gamma-aminobutyric acidA (GABAA) receptor modulators attenuate the behavioral effects of commonly abused stimulants such as amphetamines and cocaine under a variety of behavioral arrangements including drug discrimination and self-administration. In the present experiment, 6 healthy humans learned to discriminate 15-mg oral D-amphetamine. After acquiring the discrimination (ie, . > or = 80% correct responding on 4 consecutive days), the effects of a range of doses of D-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and following pretreatment with alprazolam (0 and 0.5 mg), a GABAA receptor modulator, were assessed. D-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects (eg, increased scores on a Stimulant-Sensitive Adjective-Rating Scale). These effects were generally a function of dose. Alprazolam alone did not occasion D-amphetamine-like discriminative stimulus effects, nor did it increase ratings of sedation or impair performance. Alprazolam pretreatment significantly attenuated the discriminative stimulus effects of D-amphetamine, and some of the self-reported drug effects. Future human laboratory experiments should compare the behavioral effects of D-amphetamine alone and following pretreatment with alprazolam using other behavioral arrangements such as drug self-administration. Future laboratory experiments with humans should also determine if benzodiazepines with lower abuse potential (eg, oxazepam) might also attenuate the behavioral effects of D-amphetamine.

Adolescent↗
PubMed2004

Reinforcing, subject-rated, performance and physiological effects of methylphenidate and d-amphetamine in stimulant abusing humans.

Methylphenidate has potential for abuse because it produces behavioural effects similar to those observed with other abused stimulants, such as d-amphetamine and cocaine. The aim of this study was to further characterize the abuse potential of oral methylphenidate relative to oral d-amphetamine. Ten drug-abusing volunteers were recruited to participate in this study, which consisted of seven dose conditions: methylphenidate (16, 32 and 48 mg), d-amphetamine (8, 16 and 24 mg) and placebo. The reinforcing effects of these drugs were assessed during a self-administration session (preceded by a sampling session for each condition) with a modified progressive-ratio procedure. Subject-rated, performance and physiological effects were assessed concurrently during both the sampling and self-administration sessions. The intermediate dose of methylphenidate and d-amphetamine increased responding significantly above placebo levels. Both methylphenidate and d-amphetamine produced dose-dependent increases in stimulant-like subject ratings (e.g. Active, Alert, or Energetic and High), but the effects of these drugs were not isomorphic. These findings are consistent with epidemiological data and previous findings from laboratory studies that suggest methylphenidate has at least some abuse potential.

Adult↗
PubMed2003

Baclofen does not alter the reinforcing, subject-rated or cardiovascular effects of intranasal cocaine in humans.

RATIONALE: There is evidence from research in animals and humans that the gamma-aminobutyric acid B receptor subtype (GABA(B)) agonist baclofen may have promise as a pharmacotherapy for cocaine addiction. OBJECTIVES: In the present study, the ability of baclofen to modify the reinforcing, subject-rated and cardiovascular effects of intranasal cocaine in humans was determined. METHODS: Non-treatment-seeking volunteers ( n=7) with recent histories of cocaine use were recruited to participate in this placebo-controlled, double-blind study. Baclofen (0, 10, 20 and 30 mg) was administered orally, followed approximately 1.5 h later by intranasal cocaine (4 mg [placebo] and 45 mg). Subject-rated and cardiovascular measures were taken prior to baclofen administration and then at regular intervals after cocaine was administered. The reinforcing effects of cocaine and cocaine-baclofen combinations were assessed using the Multiple-Choice Procedure. RESULTS: Intranasal cocaine significantly increased the crossover point on the Multiple-Choice Procedure relative to placebo, suggesting that this cocaine dose functioned as a reinforcer. This dose of intranasal cocaine also produced increases in subject-rated effects typical of psychostimulants and elevated cardiovascular measures. The time course for the effects of cocaine was consistent with its pharmacokinetic profile following intranasal administration; increases in subject-rated and cardiovascular effects were observed almost immediately following administration and peaked at approximately 30 min. Pretreatment with baclofen had no significant effect alone, nor in combination with cocaine, on any outcome. CONCLUSIONS: These data demonstrated that acute administration of three clinically relevant baclofen doses did not influence the acute behavioral effects of intranasal cocaine in humans.

Administration, Intranasal↗
PubMed2003

Reinforcing, subject-rated, and physiological effects of intranasal methylphenidate in humans: a dose-response analysis.

The results of previously published reports suggest that oral methylphenidate has potential for abuse. An increase in insufflation of methylphenidate has been reported recently. To our knowledge, however, there are no published reports that examined the effects of intranasal methylphenidate. The purpose of this experiment was to characterize the reinforcing, subject-rated, and physiological effects of intranasal methylphenidate (0, 10, 20, and 30 mg). Eight volunteers (five males and three females) with recent histories of recreational stimulant use were recruited to participate in this experiment. Drug doses were administered in a double-blind fashion under medical supervision, but for safety purposes they were administered in ascending order. Intranasal methylphenidate increased the crossover point on the Multiple-Choice Questionnaire in a linear fashion, which suggests that intranasal methylphenidate functioned as a reinforcer. Intranasal methylphenidate also produced linear dose-dependent prototypical stimulant-like subjective effects (e.g. increases in ratings of Good Effects and High). Intranasal methylphenidate increased heart rate as a function of dose, but the magnitude of this effect was not clinically significant (i.e. average peak heart rate following administration of the highest dose was less than 82 beats per min). The results of this study suggest that across a range of doses, intranasal methylphenidate produces behavioral effects that are characteristic of abused stimulants. Future studies should test higher doses and directly compare the behavioral effects of intranasal methylphenidate to those of a prototypical abused stimulant (e.g. cocaine).

Administration, Intranasal↗
PubMed2003

Risperidone attenuates the discriminative-stimulus effects of d-amphetamine in humans.

Studies conducted with nonhuman laboratory animals have consistently shown that atypical antipsychotics that are mixed dopamine and serotonin antagonists attenuate the discriminative-stimulus effects of amphetamine. In the present experiment, eight healthy humans learned to discriminate 15 mg of oral d-amphetamine. After acquiring the discrimination (i.e., > or = 80% correct responding on four consecutive days), the effects of a range of doses of d-amphetamine (0, 2.5, 5, 10, and 15 mg), alone and after pretreatment with risperidone (0 and 1 mg), a D2 dopamine and 5-hydroxytryptamine (5-HT)2 serotonin antagonist, were assessed. d-Amphetamine alone functioned as a discriminative stimulus and produced stimulant-like self-reported drug effects (e.g., increased ratings of "like drug"). These effects were generally a function of dose. Risperidone alone did not occasion d-amphetamine-appropriate responding, but impaired performance. Risperidone pretreatment significantly attenuated the discriminative-stimulus effects of d-amphetamine, and some of the self-reported drug effects. The results of the present experiment suggest that combining drug-discrimination and self-reported drug-effect questionnaires may be an effective strategy for assessing the behavioral effects of agonist-antagonist interactions. Future studies should compare the behavioral effects of d-amphetamine after pretreatment with a selective D2 dopamine (e.g., haloperidol) or 5-HT2 serotonin (e.g., ritanserin) antagonist to determine the relative contribution of dopamine and serotonin systems in mediating the behavioral effects of stimulants in humans. The results of these studies might guide the development of a pharmacotherapy for the treatment of amphetamine abuse/dependence.

Adolescent↗