Naltrexone-bupropion combinations do not affect cocaine self-administration in humans.

The FDA has not yet approved a pharmacotherapy for cocaine use disorder despite nearly four decades of research. This study determined the initial efficacy, safety, and tolerability of naltrexone-bupropion combinations as a putative pharmacotherapy for cocaine use disorder. Thirty-one (31) non-treatment seeking participants with cocaine use disorder completed a mixed-design human laboratory study. Participants were randomly assigned to the naltrexone conditions (i.e., 0, 50 mg/day; between-subject factor) and maintained on escalating doses of bupropion (i.e., 0, 100, 200, 400 mg/day; within-subject factor) for at least four days prior to the conduct of experimental sessions. Cocaine self-administration (IN, 0, 40, 80 mg) was then determined using a modified progressive ratio and relapse procedure. Subjective and cardiovascular effects were also measured. Cocaine produced prototypical dose-related increases in self-administration, subjective outcomes (e.g., "Like Drug"), and cardiovascular indices (e.g., heart rate, blood pressure) during placebo maintenance. Naltrexone and bupropion alone, or in combination, did not significantly decrease self-administration on either procedure. Low doses of bupropion (i.e., 100 mg) blunted the effects of the cocaine on subjective measures of "Like Drug" and "Stimulated". No unexpected adverse effects were observed with naltrexone and bupropion, alone and combined, in conjunction with cocaine. Together, these results do not support the use of these bupropion-naltrexone combinations for the treatment of cocaine use disorder. Future research should determine if novel drug combinations may decrease cocaine self-administration.

(Non-) impact of task experience on behavioral economic decision-making.

Behavioral economic research has been widely conducted via crowdsourcing resources to evaluate novel task designs or pilot interventions. One under recognized and yet-to-be tested concern is the impact of non-naïvety (i.e., prior task exposure) on behavioral economic task performance. We evaluated the influence of non-naïvety on task performance in two popular areas of behavioral economic research: behavioral economic demand and delay discounting. Participants (N = 485) recruited using Amazon Mechanical Turk (mTurk) completed alcohol and soda purchase tasks and delay discounting tasks for monetary and alcohol outcomes. Equivalence of responding and effect sizes with clinical variables were compared based on prior task experience. Over one quarter of participants reported demand task experience (26.9%) and nearly half endorsed delay discounting task experience (48.6%). Statistically equivalent responding was observed for alcohol purchase task data with less-than-small effect size differences based on task experience (d = 0.01-0.13). Similar results were observed for a soda purchase task thereby supporting generalization to a non-alcohol commodity. Measures of convergent and discriminant validity for behavioral economic demand indicated medium-to-large and stimulus-specific effect sizes with little variation based on prior task exposure. Delay discounting for money and alcohol showed some sensitivity to prior task experience (i.e., less steep discounting for non-naïve participants), however these effects were attenuated after accounting for group differences in alcohol use. These findings support the fidelity of behavioral economic task outcomes and emphasize that participant non-naïvety in crowdsourcing settings may minimally impact performance on behavioral economic assays commonly used in behavioral and addiction science. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Topiramate-phentermine combinations reduce cocaine self-administration in humans.

RATIONALE: Cocaine use disorder is an unrelenting public health concern. Despite nearly four decades of research, an FDA approved medication is not yet available. OBJECTIVES: The objective of this human laboratory study was to demonstrate the initial efficacy, safety and tolerability of topiramate-phentermine combinations for cocaine use disorder. METHODS: Thirty-one (31) participants with cocaine use disorder completed this mixed-model inpatient laboratory study. Participants were maintained on topiramate (0 [N = 11], 50 [N = 9] or 100 [N = 11] mg/day). Each topiramate group was concurrently maintained on phentermine (0, 15, 30 mg). Drug self-administration, subjective responses and cardiovascular effects following acute doses of intranasal cocaine (0, 40, 80 mg) were determined during separate experimental sessions after at least seven (7) days of maintenance on each condition. RESULTS: The three groups of participants were well matched demographically and generally did not differ significantly in their responses to a range of doses of intranasal cocaine (0, 10, 20, 40, 80 mg) during a medical safety session. Maintenance on topiramate and phentermine alone significantly decreased cocaine self-administration although these effects were modest in magnitude. Combining topiramate and phentermine robustly decreased cocaine self-administration. Topiramate and phentermine were well tolerated alone and combined, as well as in conjunction with cocaine. CONCLUSIONS: The results of the present study support advancing topiramate-phentermine combinations as a putative pharmacotherapeutic for cocaine use disorder.

The condom purchase task: A hypothetical demand method for evaluating sexual health decision-making.

Behavioral economic theory has proved useful for understanding the influence of delay and probability on sexual health decision-making. Demand is another principle at the intersection of microeconomics and psychology that has helped advance research relevant to health behaviors. The purpose of the present study was to develop and test a demand measure related to sexual health decision-making and the influence of sexually transmitted infection (STI) risk. Participants (N = 438) recruited using Amazon Mechanical Turk completed a commodity purchase task assessing hypothetical condom demand. Condom demand was evaluated at varied prices for use with hypothetical sexual partners that varied in STI risk. Demand was characterized by prototypic decreases in consumption with increases in cost. Higher partner STI risk was associated with greater intentions for condom-protected sex at no cost and smaller decreases in condom demand with increases in cost. Price sensitivity was also related to individual difference factors relevant to sexual health (e.g., alcohol use severity, lower STI knowledge). This study supports the utility of a condom purchase task for indexing condom valuation and capturing individual difference and contextual risk factors relevant to STI transmission. Future studies may leverage this methodology as a means to study sexual health decision-making.

Human Drug Discrimination: Elucidating the Neuropharmacology of Commonly Abused Illicit Drugs.

Drug-discrimination procedures empirically evaluate the control that internal drug states have over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs in vivo. As a result, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This chapter provides a basic overview of human drug-discrimination procedures and reviews the extant literature concerning the use of these procedures to elucidate the underlying neuropharmacological mechanisms of commonly abused illicit drugs (i.e., stimulants, opioids, and cannabis) in humans. This chapter is not intended to review every available study that used drug-discrimination procedures in humans. Instead, when possible, exemplary studies that used a stimulant, opioid, or Δ9-tetrahydrocannabinol (the primary psychoactive constituent of cannabis) to assess the discriminative-stimulus effects of drugs in humans are reviewed for illustrative purposes. We conclude by commenting on the current state and future of human drug-discrimination research.

N-Acetylcysteine reduces cocaine-cue attentional bias and differentially alters cocaine self-administration based on dosing order.

BACKGROUND: Disrupted glutamate homeostasis is thought to contribute to cocaine-use disorder, in particular, by enhancing the incentive salience of cocaine stimuli. n-Acetylcysteine might be useful in cocaine-use disorder by normalizing glutamate function. In prior studies, n-acetylcysteine blocked the reinstatement of cocaine seeking in laboratory animals and reduced the salience of cocaine stimuli and delayed relapse in humans. METHODS: The present study determined the ability of maintenance on n-acetylcysteine (0 or 2400mg/day, counterbalanced) to reduce the incentive salience of cocaine stimuli, as measured by an attentional bias task, and attenuate intranasal cocaine self-administration (0, 30, and 60mg). Fourteen individuals (N=14) who met criteria for cocaine abuse or dependence completed this within-subjects, double-blind, crossover-design study. RESULTS: Cocaine-cue attentional bias was greatest following administration of 0mg cocaine during placebo maintenance, and was attenuated by n-acetylcysteine. Cocaine maintained responding during placebo and n-acetylcysteine maintenance, but the reinforcing effects of cocaine were significantly attenuated across both maintenance conditions in participants maintained on n-acetylcysteine first compared to participants maintained on placebo first. CONCLUSIONS: These results collectively suggest that a reduction in the incentive salience of cocaine-related stimuli during n-acetylcysteine maintenance may be accompanied by reductions in cocaine self-administration. These results are in agreement with, and link, prior preclinical and clinical trial results suggesting that n-acetylcysteine might be useful for preventing cocaine relapse by attenuating the incentive salience of cocaine cues.

Cocaine preexposure enhances sexual conditioning and increases resistance to extinction in male Japanese quail.

The incentive-sensitization theory posits that drug addiction results from altered learning and motivational processes that stem from drug-induced changes in the brain's reward circuitry. Although it is generally accepted that problematic drug use results from these neuroadaptations, less research has focused on how these neural changes affect the incentive-motivational properties of naturally rewarding stimuli such as sex. The present set of experiments was conducted to investigate (1) dose-dependent effects of preexposure to chronic cocaine on sexual conditioning and (2) how prior cocaine exposure affects the extinction of sexually conditioned behavior in male Japanese quail. In Experiment 1, male quail were exposed to saline or to cocaine (5, 10, or 20 mg/kg ip) for 10 days, and their locomotor activity was measured. After a washout period, ten sexual-conditioning trials were conducted in which a light (CS) was presented prior to the presentation of a female quail (US) and approach to the light was measured. The results showed that cocaine dose-dependently enhanced sexually conditioned approach behavior and copulation. Experiment 2 was procedurally similar to Experiment 1, except that the quail received either saline or 10 mg/kg cocaine (ip) and 24 extinction trials were conducted. During extinction, no female was presented after the CS. The results showed that preexposure to cocaine delayed extinction. Therefore, cocaine may dose-dependently increase the strength of sexual conditioning, and this may subsequently increase resistance to extinction. These findings and their possible mechanisms are explored.

Effects of acute buspirone administration on inhibitory control and sexual discounting in cocaine users.

OBJECTIVE: Cocaine users display deficits in inhibitory control and make impulsive choices that may increase risky behavior. Buspirone is an anxiolytic that activates dopaminergic and serotonergic systems and improves impulsive choice (i.e., reduces sexual risk-taking intent) in cocaine users when administered chronically. We evaluated the effects of acutely administered buspirone on inhibitory control and impulsive choice. METHODS: Eleven subjects with a recent history of cocaine use completed this within-subject, placebo-controlled study. Subjects performed two cued go/no-go and a sexual risk delay-discounting task following oral administration of buspirone (10 and 30 mg), triazolam (0.375 mg; positive control), and placebo (negative control). Physiological and psychomotor performance and subject-rated data were also collected. RESULTS: Buspirone failed to change inhibitory control or impulsive choice; however, slower reaction times were observed at the highest dose tested. Buspirone did not produce subject-rated drug effects but dose-dependently decreased diastolic blood pressure. Triazolam impaired psychomotor performance and increased ratings of positive subject-rated effects (e.g., Like Drug). CONCLUSIONS: These findings indicate that acutely administered buspirone has little impact on behavioral measures of inhibitory control and impulsive sexual decision-making. Considering previous findings with chronic dosing, these findings highlight that the behavioral effects of buspirone differ as a function of dosing conditions.

Human drug discrimination: A primer and methodological review.

Drug-discrimination procedures empirically evaluate the control that internal drug states exert over behavior. They provide a highly selective method to investigate the neuropharmacological underpinnings of the interoceptive effects of drugs. Historically, drug discrimination has been one of the most widely used assays in the field of behavioral pharmacology. Drug-discrimination procedures have also been adapted for use with humans and are conceptually similar to preclinical drug-discrimination techniques in that a behavior is differentially reinforced contingent on the presence or absence of a specific interoceptive drug stimulus. This review gives some general history and background concerning the major theoretical concepts and principles of drug-discrimination research as well as its relevance to substance-use disorders. This article also provides a procedural overview and discusses key methodological issues that must be considered when designing and conducting a human drug-discrimination study. Although drug discrimination is unequivocally one of the most sophisticated and useful behavioral assays to investigate the underlying neuropharmacology of drugs in vivo, enthusiasm for its use has steadily declined in the last decade and a half. We conclude by commenting on the current state of drug-discrimination research and suggest potential avenues for future drug-discrimination research. (PsycINFO Database Record

Differential sensitivity to learning from positive and negative outcomes in cocaine users.

BACKGROUND: Altered sensitivity to positive and negative outcomes may be linked to the maladaptive choices characteristic of substance use disorders. Few studies have determined the distinct roles that positive and negative outcomes play in stimulus-response learning in cocaine users. The purpose of the present study was to investigate sensitivity to learning from positive and negative outcomes on a probabilistic learning task in cocaine users employing human laboratory and crowdsourcing techniques. METHODS: Individuals who reported cocaine use were recruited for a laboratory study (Experiment 1) or an online study on Amazon.com's Mechanical Turk (mTurk) (Experiment 2). All participants completed a feedback-based probabilistic learning task in which images were classified into categories (A versus B). Positive and negative outcomes were provided in a probabilistic manner on separate trials. Proportion of optimal responses and response times were recorded. RESULTS: Active cocaine users were less sensitive to learning from positive relative to negative outcomes. These effects were consistent across image type and session in the laboratory sample. Similarly, reduced sensitivity to learning from positive outcomes was observed in cocaine users on mTurk. Control participants did not show suboptimal performance following positive or negative outcomes. CONCLUSIONS: This study extends the limited research on feedback-based learning in drug users by demonstrating reduced sensitivity to positive outcomes in cocaine users recruited in the human laboratory and online. Future studies on the clinical significance and mechanisms underlying this bias are needed to understand its relevance as a target for intervention development.

Buspirone reduces sexual risk-taking intent but not cocaine self-administration.

Impulsive sexual decision-making may underlie sexual risk-taking behavior that contributes to the disproportionately high prevalence of HIV infection among cocaine users. Delay-discounting procedures measure impulsive decision-making and may provide insight into the underlying mechanisms of sexual risk-taking behavior. The anxiolytic drug buspirone reduces delay discounting in rats and blunts the reinforcing effects of cocaine in some preclinical studies suggesting that it might have utility in the treatment of cocaine-use disorders. This study determined whether buspirone mitigates impulsive risky sexual decision-making in cocaine users on a sexual delay-discounting procedure. The effects of buspirone maintenance on the abuse-related and physiological effects of cocaine were also tested. Nine (N = 9) current cocaine users completed a repeated-measures, inpatient protocol in which sexual delay discounting was assessed after 3 days of maintenance on placebo and buspirone (30 mg/day) in counterbalanced order. The reinforcing, subject-rated, and physiological effects of placebo and intranasal cocaine (15 and 45 mg) were also assessed during buspirone and placebo maintenance. Buspirone increased the likelihood of condom use for hypothetical sexual partners that were categorized as most likely to have a sexually transmitted infection and least sexually desirable. Cocaine functioned as a reinforcer and increased positive subjective effects ratings, but buspirone maintenance did not impact these effects of cocaine. Buspirone was also safe and tolerable when combined with cocaine and may have blunted some its cardiovascular effects. The results from the sexual delay-discounting procedure indicate that buspirone may reduce preference for riskier sex in cocaine users. (PsycINFO Database Record

Abuse Potential of Oral Phendimetrazine in Cocaine-dependent Individuals: Implications for Agonist-like Replacement Therapy.

OBJECTIVES: Phendimetrazine is a prodrug for the monoamine releaser phenmetrazine-a drug with known abuse potential. Preclinical studies suggest that phendimetrazine has limited abuse potential and may have promise as an agonist-like replacement therapy for cocaine dependence. This study evaluated the abuse potential of phendimetrazine in humans. METHODS: Nine cocaine-dependent individuals (N = 9) were enrolled to investigate the abuse potential of phendimetrazine and d-amphetamine, using a double-blind, placebo-controlled, within-subject design. Subjective and cardiovascular effects of oral phendimetrazine (35, 70, and 105 mg), d-amphetamine (10, 20, and 30 mg), and placebo were assessed in quasi-random order across 8 sessions lasting for approximately 8 hours each. RESULTS: d-Amphetamine (20 and 30 mg) significantly increased cardiovascular measures in a time and dose-related manner, but phendimetrazine did not systematically alter cardiovascular measures. Although d-amphetamine and phendimetrazine significantly increased ratings indicative of abuse potential (eg, drug liking) and stimulant-like effects relative to placebo, these increases were generally small in magnitude, with phendimetrazine producing significant effects on fewer abuse-related measures and at fewer time points than d-amphetamine. CONCLUSIONS: These preliminary findings suggest that oral phendimetrazine and d-amphetamine may have limited abuse potential in cocaine-dependent individuals. These findings collectively emphasize that the clinical utility of medications to treat cocaine-use disorders should be weighed carefully against their potential for abuse and diversion, with careful attention paid to evaluating abuse potential in a clinically relevant population of interest. Future studies are needed to further elucidate the potential utility of phendimetrazine as an agonist-like replacement therapy for cocaine dependence.

Pavlovian discriminative stimulus effects of methamphetamine in male Japanese quail (Coturnix japonica).

Pavlovian drug discrimination (DD) procedures demonstrate that interoceptive drug stimuli may come to control behavior by informing the status of conditional relationships between stimuli and outcomes. This technique may provide insight into processes that contribute to drug-seeking, relapse, and other maladaptive behaviors associated with drug abuse. The purpose of the current research was to establish a model of Pavlovian DD in male Japanese quail. A Pavlovian conditioning procedure was used such that 3.0 mg/kg methamphetamine served as a feature positive stimulus for brief periods of visual access to a female quail and approach behavior was measured. After acquisition training, generalization tests were conducted with cocaine, nicotine, and haloperidol under extinction conditions. SCH 23390 was used to investigate the involvement of the dopamine D1 receptor subtype in the methamphetamine discriminative stimulus. Results showed that cocaine fully substituted for methamphetamine but nicotine only partially substituted for methamphetamine in quail. Haloperidol dose-dependently decreased approach behavior. Pretreatment with SCH 23390 modestly attenuated the methamphetamine discrimination suggesting that the D1 receptor subtype may be involved in the discriminative stimulus effects of methamphetamine. The findings are discussed in relation to drug abuse and associated negative health consequences.

Relationship between drug discrimination and ratings of subjective effects: implications for assessing and understanding the abuse potential of D-amphetamine in humans.

The discriminative and subjective effects of drugs in humans are related, but the full extent of this relationship remains to be determined. To further explore this relationship, a retrospective analysis was conducted on data from six studies completed in our laboratory that used identical procedures. The relationship between the discriminative and subjective effects of a range of doses of D-amphetamine (i.e. 2.5-15 mg) was examined using correlational analyses. Significant correlations with discrimination performance were observed on 15 of 20 items from the Drug-Effect Questionnaire across a range of qualities [e.g. Pay For (a positive effect indicative of abuse potential) and Active (a stimulant-like effect)], but the magnitude of these relationships was modest (r<0.52). The current findings demonstrate that diverse subjective effects contribute to the discriminative effects of D-amphetamine and indicate that the former are a more practical means to assess the abuse potential of drugs. Although these procedures are fundamentally related in that they rely on the presence of an interoceptive drug state, they differ in the dimension(s) of the interoceptive effects that participants must quantify. The simultaneous use of drug discrimination and subjective effects may, therefore, reveal complimentary aspects of drug effects that underlie their potential for abuse.

Relationship between oral D-amphetamine self-administration and ratings of subjective effects: do subjective-effects ratings correspond with a progressive-ratio measure of drug-taking behavior?

The abuse potential of drugs has traditionally been determined in humans using subjective ratings of drug effects. However, drug self-administration procedures also provide valuable information about the reinforcing effects of drugs that may contribute to their potential for abuse. Although ratings of subjective effects and drug self-administration data are generally concordant, some divergent findings have been reported. Therefore, the aim of the present analysis was to directly investigate the relationship between the subjective-effects profile and self-administration of oral D-amphetamine in healthy volunteers with a history of stimulant use or abuse, using Pearson's correlational analyses. The results indicated that positive subjective and reinforcing effects significantly increased as a function of D-amphetamine dose. Further, significant, but modest, correlations were observed between ratings of six of 17 total items (Any Effect, High, Like Drug, Good Effects, Willing to Pay For, and Willing to Take Again) and D-amphetamine self-administration under a progressive-ratio schedule of reinforcement. The current findings suggest that, at least under the current set of conditions with oral D-amphetamine, subjective-effects measures and drug self-administration data likely provide different but complimentary information about abuse potential. The most informative findings will thus be obtained from studies that use ratings of subjective effects and drug self-administration methods.

Nicotine induces a conditioned place preference in male Japanese quail (Coturnix japonica).

Visual stimuli may play an important role in the development and maintenance of addiction in humans. Research with a visually-oriented animal model such as Japanese quail (Coturnix japonica) may provide insight into how visual cues contribute to the addiction process. The aim of the current study was to investigate the rewarding properties of nicotine in male Japanese quail using a biased conditioned place preference (CPP) procedure. Adult male quail (N=30) were allowed to freely explore the entire CPP apparatus during a place preference pre-test and time spent in each chamber was measured. During nicotine conditioning sessions, quail were administered nicotine (0.5, 1.0, or 2.0mg/kg) or saline and were then confined to their initially least preferred chamber. On alternating days, all quail received saline and were confined to their initially preferred chamber. Locomotor activity was assessed in both chambers. The conditioning chambers had yellow or green walls to enhance the visual salience of each context. Following 8 conditioning sessions (4 nicotine; 4 saline), quail were allowed to explore the entire apparatus during a CPP post-test and time spent in each chamber was measured. The results indicated that quail treated with 0.5 and 1.0mg/kg nicotine significantly increased the amount of time they spent in the nicotine-paired chamber compared to saline controls, suggesting that nicotine produced a CPP. Furthermore, quail treated with 0.5mg/kg nicotine showed a significant increase in locomotor activity with repeated treatments. The current findings suggest that nicotine may have a rewarding effect in quail and may tentatively suggest that the neuropharmacological mechanisms that mediate CPP for nicotine are conserved in birds.

Chronic pre-exposure to methamphetamine following 31 days of withdrawal impairs sexual performance but not sexual conditioning in male Japanese quail.

In the current study, male quail were administered methamphetamine (3.0 or 5.6 mg/kg IP) or saline once daily for 10 days and locomotor activity was assessed. Following a 31-day withdrawal period, sexual conditioning trials were conducted such that a conditioned stimulus (CS) was presented prior to a copulatory opportunity with a female quail. Male quail treated with methamphetamine (5.6 mg/kg) showed a decrease in locomotor activity from Trial 1 to Trial 10 suggesting a potential tolerance effect. Following the 31-day withdrawal period, all male quail that received the CS paired with a copulatory opportunity showed enhanced approach to the CS, regardless of treatment history. Thus, chronic pre-exposure to methamphetamine did not alter sexual conditioning. In contrast, chronic pre-exposure to methamphetamine (3.0 mg/kg) decreased the frequency of successful copulations suggesting that it impaired sexual performance. The findings suggest that methamphetamine may differentially affect the neural circuitry involved in motivational systems compared with those involved in consummatory aspects of sexual behavior. These effects may last long after drug cessation.

Chronic preexposure to methylphenidate cross-sensitizes methamphetamine in male Japanese quail.

An increasing debate exists about the potential of exposure to methylphenidate increasing later risk of drug abuse. The objective of this study was to investigate whether chronic preexposure to methylphenidate would induce cross-sensitization to a subsequent methamphetamine challenge in male Japanese quail. Male quail were treated intraperitoneally with either 5, 10, or 20 mg/kg methylphenidate or saline for 14 days. After a 14-day washout period, birds were challenged with 5.6 mg/kg of methamphetamine. Methylphenidate-induced behavioral sensitization was not evident after 14 days of preexposure. However, locomotor activity was greater during the methamphetamine challenge in birds that were preexposed to a high dose of methylphenidate. The findings suggest that chronic preexposure to methylphenidate may be sufficient to alter later responding to methamphetamine, regardless of whether preexposure resulted in behavioral sensitization.

Methamphetamine impairs sexual motivation but not sexual performance in male Japanese quail.

The present study investigated the effects of chronic pre-exposure to methamphetamine on sexual motivation and performance in male Japanese quail. Quail were pre-exposed to methamphetamine (1.0 or 3.0 mg/kg ip) or saline (ip) once daily for 10 days and locomotor activity was measured. After a 10 day washout period, sexual motivation was measured in a straight-arm runway with visual access to a female at one end. Three to 5 hr after sexual motivation tests, males were allowed to copulate with a receptive female quail and copulatory behavior was assessed. Tests were conducted once per day for 10 days. Results showed that males pre-exposed to methamphetamine had decreased locomotor activity compared to saline controls. Males pre-exposed to METH later ran slower toward a female in the runway and spent less time near her. In contrast, methamphetamine pre-exposed males showed similar copulatory behavior as saline pre-exposed males. The findings suggest that chronic pre-exposure to methamphetamine may impair sexual motivation but not sexual performance. The findings are discussed from a comparative perspective and with regard to their clinical relevance.