Discriminative Stimulus Research Articles

Comparing the Effect of Echoic and Listener Responding in the Development of Complex Intraverbals.

This study aimed to compare the effects of echoic and listener responding in the emergence of complex intraverbal behavior in four children with autism spectrum disorder (ASD). Each participant was taught to provide an echoic response or a listener response for different discriminative stimuli for each condition. We used a nonconcurrent multiple probe design across participants and adapted an alternating treatment design to compare the effects between the two conditions. Pre- and posttests were used to evaluate the effects of the two different prompt types in the emergence of complex intraverbals. The results indicate that the echoic response was more effective than the listener response at increasing the emergence of complex intraverbal responses in three out of four participants.

Ventral Pallidal GABAergic Neuron Calcium Activity Encodes Cue-Driven Reward Seeking and Persists in the Absence of Reward Delivery.

Reward-seeking behavior is often initiated by environmental cues that signal reward availability. This is a necessary behavioral response; however, cue reactivity and reward-seeking behavior can become maladaptive. To better understand how cue-elicited reward seeking becomes maladaptive, it is important to understand the neural circuits involved in assigning appetitive value to rewarding cues and actions. Ventral pallidum (VP) neurons are known to contribute to cue-elicited reward-seeking behavior and have heterogeneous responses in a discriminative stimulus (DS) task. The VP neuronal subtypes and output pathways that encode distinct aspects of the DS task remain unknown. Here, we used an intersectional viral approach with fiber photometry to record bulk calcium activity in VP GABAergic (VP GABA) neurons in male and female rats as they learned and performed the DS task. We found that VP GABA neurons are excited by reward-predictive cues but not neutral cues and that this response develops over time. We also found that this cue-evoked response predicts reward-seeking behavior and that inhibiting this VP GABA activity during cue presentation decreases reward-seeking behavior. Additionally, we found increased VP GABA calcium activity at the time of expected reward delivery, which occurred even on trials when reward was omitted. Together, these findings suggest that VP GABA neurons encode reward expectation, and calcium activity in these neurons encodes the vigor of cue-elicited reward seeking.SIGNIFICANCE STATEMENT VP circuitry is a major driver of cue-evoked behaviors. Previous work has found that VP neurons have heterogenous responses and contributions to reward-seeking behavior. This functional heterogeneity is because of differences of neurochemical subtypes and projections of VP neurons. Understanding the heterogenous responses among and within VP neuronal cell types is a necessary step in further understanding how cue-evoked behavior becomes maladaptive. Our work explores the canonical GABAergic VP neuron and how the calcium activity of these cells encodes components of cue-evoked reward seeking, including the vigor and persistence of reward seeking.

The relationship between central and mid-peripheral motion perception and the hazard perception test in younger and older adults.

Vision standards for driving are typically based on visual acuity, despite evidence that it is a poor predictor of driving safety and performance. However, visual motion perception is potentially relevant for driving, as the vehicle and surroundings are in motion. This study explored whether tests of central and mid-peripheral motion perception better predict performance on a hazard perception test (HPT), which is related to driving performance and crash risk, than visual acuity. Additionally, we explored whether age influences these associations, as healthy ageing impairs performance on some motion sensitivity tests. Sixty-five visually healthy drivers (35 younger, mean age: 25.5; SD 4.3 years; 30 older adults, mean age: 71.0; SD 5.4 years) underwent a computer-based HPT, plus four different motion sensitivity tests both centrally and at 15° eccentricity. Motion tests included minimum displacement to identify motion direction (Dmin ), contrast detection threshold for a drifting Gabor (motion contrast), coherence threshold for a translational global motion stimulus and direction discrimination for a biological motion stimulus in the presence of noise. Overall, HPT reaction times were not significantly different between age groups (p = 0.40) nor were maximum HPT reaction times (p = 0.34). HPT response time was associated with motion contrast and Dmin centrally (r = 0.30, p = 0.02 and r = 0.28, p = 0.02, respectively) and with Dmin peripherally (r = 0.34, p = 0.005); these associations were not affected by age group. There was no significant association between binocular visual acuity and HPT response times (r = 0.02, p = 0.29). Some measures of motion sensitivity in central and mid-peripheral vision were associated with HPT response times, whereas binocular visual acuity was not. Peripheral testing did not show an advantage over central testing for visually healthy older drivers. Our findings add to the growing body of evidence that the ability to detect small motion changes may have potential to identify unsafe road users.

Response-specific effects of punishment of a discriminated operant response

To determine whether the punishment of a discriminated operant behavior has effects that are specific to the punished response, rats were reinforced for performing two different instrumental responses (lever pressing and chain pulling) in the presence of a single discriminative stimulus (S). They were then either punished with mild footshock for performing one of the responses (R1) in S, or they received the same shocks in a noncontingent manner while performing R1 in S (i.e., a yoked control). In final tests of both R1 and R2 in S, the punished rats were more suppressed to R1 than R2, but the yoked rats were not. The results extend previous results with extinction rather than punishment learning (Bouton, Trask, & Carranza-Jasso, 2016) and support a larger parallel between extinction and punishment of both free-operant and discriminated-operant responding. Punishment is like extinction in creating a response-specific inhibition of either free or discriminated operant behavior.

Characterizing neural coding performance for populations of sensory neurons: comparing a weighted spike distance metrics to other analytical methods.

The identity of sensory stimuli is encoded in the spatio-temporal patterns of responses of the encoding neural population. For stimuli to be discriminated reliably, differences in population responses must be accurately decoded by downstream networks. Several methods to compare patterns of responses have been used by neurophysiologists to characterize the accuracy of the sensory responses studied. Among the most widely used analyses, we note methods based on Euclidean distances or on spike metric distances. Methods based on artificial neural networks and machine learning that recognize and/or classify specific input patterns have also gained popularity. Here, we first compare these three strategies using datasets from three different model systems: the moth olfactory system, the electrosensory system of gymnotids, and leaky-integrate-and-fire (LIF) model responses. We show that the input-weighting procedure inherent to artificial neural networks allows the efficient extraction of information relevant to stimulus discrimination. To combine the convenience of methods such as spike metric distances but leverage the advantages of weighting the inputs, we propose a measure based on geometric distances where each dimension is weighted proportionally to how informative it is. We show that the result of this Weighted Euclidian Distance (WED) analysis performs as well or better than the artificial neural network we tested and outperforms the more traditional spike distance metrics. We applied information theoretic analysis to LIF responses and compared their encoding accuracy with the discrimination accuracy quantified through this WED analysis. We show a high degree of correlation between discrimination accuracy and information content, and that our weighting procedure allowed the efficient use of information present to perform the discrimination task. We argue that our proposed measure provides the flexibility and ease of use sought by neurophysiologists while providing a more powerful way to extract relevant information than more traditional methods.

Metacontingency Terminology, Philosophical Assumptions, and the Scientific Dialogue: A Response to Ardila-Sánchez and Hayes (2023).

Ardila-Sánchez and Hayes (2023, this issue) discuss how differing philosophical assumptions might reflect on differing metacontingency terminology and debate some of the arguments presented by Sampaio and Haydu (2023). We respond by restating the urgent need to clarify the definition of cultural milieu, which is illustrated by an argument about discriminative stimuli as components of the cultural milieu. We clarify that the differences in metacontingency terminology that we did not emphasize were related to interlocking behavioral contingencies (IBCs) and cultural consequences, and not to cultural milieu and group-rule generation. We question any rigid separations of "Skinnerian" and "Kantorian views" of cultural phenomena, insisting that we focus on a unified culturo-behavior science. We elucidate that verbal responses and stimuli may participate in IBCs, cultural antecendents, or selecting environment variables; answer some questions about the latter two concepts; and clarify that the we presented a COVID-19 psychological support project not to empirically validate the concept, but to illustrate and test the conceptual coherence of the terms and theory.

Neurophysiological correlates of tactile width discrimination in humans.

Tactile information processing requires the integration of sensory, motor, and cognitive information. Width discrimination has been extensively studied in rodents, but not in humans. Here, we describe Electroencephalography (EEG) signals in humans performing a tactile width discrimination task. The first goal of this study was to describe changes in neural activity occurring during the discrimination and the response periods. The second goal was to relate specific changes in neural activity to the performance in the task. Comparison of changes in power between two different periods of the task, corresponding to the discrimination of the tactile stimulus and the motor response, revealed the engagement of an asymmetrical network associated with fronto-temporo-parieto-occipital electrodes and across multiple frequency bands. Analysis of ratios of higher [Ratio 1: (0.5-20 Hz)/(0.5-45 Hz)] or lower frequencies [Ratio 2: (0.5-4.5 Hz)/(0.5-9 Hz)], during the discrimination period revealed that activity recorded from frontal-parietal electrodes was correlated to tactile width discrimination performance between-subjects, independently of task difficulty. Meanwhile, the dynamics in parieto-occipital electrodes were correlated to the changes in performance within-subjects (i.e., between the first and the second blocks) independently of task difficulty. In addition, analysis of information transfer, using Granger causality, further demonstrated that improvements in performance between blocks were characterized by an overall reduction in information transfer to the ipsilateral parietal electrode (P4) and an increase in information transfer to the contralateral parietal electrode (P3). The main finding of this study is that fronto-parietal electrodes encoded between-subjects' performances while parieto-occipital electrodes encoded within-subjects' performances, supporting the notion that tactile width discrimination processing is associated with a complex asymmetrical network involving fronto-parieto-occipital electrodes.

Psychological and physiological correlates of stimulus discrimination in adults.

The discrimination of cues in the environment that signal danger ("fear cue") is important for survival but depends critically on the discernment of such cues from ones that pose no threat ("safety cues"). In rodents, we previously demonstrated the underlying neurobiological mechanisms that support fear versus safety discrimination and documented that these mechanisms extend to the discrimination of reward as well. While learning about reward is equally important for survival, it remains an under-studied area of research, particularly in human studies of conditional discrimination. In the present study, we translated our rodent task of fear reward and neutral discrimination (fear, reward, and neutral discrimination [FRND]) for use in humans. Undergraduate students (N = 53) completed the FRND while electrodermal activity was recorded. Skin conductance response (SCR) amplitude, a marker of arousal response, was derived for fear, reward, and neutral cues that signaled no outcome; critical trials assessed conditional discrimination using combined fear + neutral and reward + neutral cues. Participants provided likeability ratings for each cue type. Results demonstrated that participants rated reward cues the best, fear cues the worst, and neutral cues in between, while SCR amplitude was largest for fear and reward cues and lowest for neutral cues. SCR amplitudes were reduced for fear + neutral (compared to fear) and reward + neutral cues (compared to reward). Results demonstrate that the FRND is a useful paradigm for the assessment of psychological and physiological discrimination of fear and reward. Implications and directions for future work are discussed.

SΔp: The Missing Discriminative Stimulus for Non-Punishment.

As the natural science of behavior evolves, the use of precise terminology is critical to maintain its conceptual and terminological integrity. The current state of terminology in stimulus control is well developed with respect to reinforcement and incomplete with respect to punishment. In this paper, we aim to make the case that the current conceptualization for discriminative stimulus control in relation to punishment would be enhanced by modifying the definition of the discriminative stimulus for punishment (SDp) and by adding a new term to the current taxonomy that denotes when a punishment contingency is inactive.

Low-Cost Virtual Reality to Support Imaginal Exposure Within PTSD Treatment: A Case Report Study Within a Community Mental Healthcare Setting

Revisiting what happened during (or after) a traumatic event is an important part of the treatment process in trauma-focused cognitive therapy (TF-CT). However, clinicians may have difficulty helping patients to intentionally retrieve these memories in order to engage with their content. As such, clinical tools to support the access and delivery of imaginal exposure content within treatment may prove to be particularly useful for therapists. This case report introduces work undertaken with Mr. A, a 38-year-old male, who 2 years prior had experienced a city centre assault. Initial assessment revealed a PCL-5 score of 64 and he met DSM-5 criteria for posttraumatic stress disorder (PTSD). Mr. A received 10 sessions of TF-CT wherein the traditional imaginal exposure components were implemented via a newly developed virtual reality (VR) development workflow called “VR Photoscan.” After 10 sessions, results showed PCL-5 scores decreased from 64 to 19 and Mr. A no longer met DSM-5 PTSD criteria. VR Photoscan was used during 4/10 sessions and included (1) reliving, (2) memory updating, and (3) stimulus discrimination activities. Mr. A also reported VR Photoscan as helpful regarding preparation for site visits. In conclusion, VR Photoscan technology provided a more visceral exposure experience which supported Mr. A to revisit the trauma memory. He reported high levels of satisfaction with the quality of the virtual environment and no issues using the VR technology. Produced with lower costs and shorter development times than typical computer-generated environments, VR Photoscan may be more easily implemented within routine care, although further research is required.

Aging effect of cross-modal interactions during audiovisual detection and discrimination by behavior and ERPs.

Numerous studies have shown that aging greatly affects audiovisual integration; however, it is still unclear when the aging effect occurs, and its neural mechanism has yet to be fully elucidated. We assessed the audiovisual integration (AVI) of older (n = 40) and younger (n = 45) adults using simple meaningless stimulus detection and discrimination tasks. The results showed that the response was significantly faster and more accurate for younger adults than for older adults in both the detection and discrimination tasks. The AVI was comparable for older and younger adults during stimulus detection (9.37% vs. 9.43%); however, the AVI was lower for older than for younger adults during stimulus discrimination (9.48% vs. 13.08%) behaviorally. The electroencephalography (EEG) analysis showed that comparable AVI amplitude was found at 220-240 ms for both groups during stimulus detection and discrimination, but there was no significant difference between brain regions for older adults but a higher AVI amplitude in the right posterior for younger adults. Additionally, a significant AVI was found for younger adults in 290-310 ms but was absent for older adults during stimulus discrimination. Furthermore, significant AVI was found in the left anterior and right anterior at 290-310 ms for older adults but in the central, right posterior and left posterior for younger adults. These results suggested that the aging effect of AVI occurred in multiple stages, but the attenuated AVI mainly occurred in the later discriminating stage attributed to attention deficit.

Pharmacokinetic and Pharmacodynamic Consequences of Cytochrome P450 3A Inhibition on Mitragynine Metabolism in Rats.

Mitragynine, an opioidergic alkaloid present in Mitragyna speciosa (kratom), is metabolized by cytochrome P450 3A (CYP3A) to 7-hydroxymitragynine, a more potent opioid receptor agonist. The extent to which conversion to 7-hydroxymitragynine mediates the in vivo effects of mitragynine is unclear. The current study examined how CYP3A inhibition (ketoconazole) modifies the pharmacokinetics of mitragynine in rat liver microsomes in vitro. The study further examined how ketoconazole modifies the discriminative stimulus and antinociceptive effects of mitragynine in rats. Ketoconazole [30 mg/kg, oral gavage (o.g.)] increased systemic exposure to mitragynine (13.3 mg/kg, o.g.) by 120% and 7-hydroxymitragynine exposure by 130%. The unexpected increase in exposure to 7-hydroxymitragynine suggested that ketoconazole inhibits metabolism of both mitragynine and 7-hydroxymitragynine, a finding confirmed in rat liver microsomes. In rats discriminating 3.2 mg/kg morphine from vehicle under a fixed-ratio schedule of food delivery, ketoconazole pretreatment increased the potency of both mitragynine (4.7-fold) and 7-hydroxymitragynine (9.7-fold). Ketoconazole did not affect morphine's potency. Ketoconazole increased the antinociceptive potency of 7-hydroxymitragynine by 4.1-fold. Mitragynine (up to 56 mg/kg, i.p.) lacked antinociceptive effects both in the presence and absence of ketoconazole. These results suggest that both mitragynine and 7-hydroxymitragynine are cleared via CYP3A and that 7-hydroxymitragynine is formed as a metabolite of mitragynine by other routes. These results have implications for kratom use in combination with numerous medications and citrus juices that inhibit CYP3A. SIGNIFICANCE STATEMENT: Mitragynine is an abundant kratom alkaloid that exhibits low efficacy at the μ-opioid receptor (MOR). Its metabolite, 7-hydroxymitragynine, is also an MOR agonist but with higher affinity and efficacy than mitragynine. Our results in rats demonstrate that cytochrome P450 3A (CYP3A) inhibition can increase the systematic exposure of both mitragynine and 7-hydroxymitragynine and their potency to produce MOR-mediated behavioral effects. These data highlight potential interactions between kratom and CYP3A inhibitors, which include numerous medications and citrus juices.

Cortical visual impairment at birth can be improved rapidly by vision training in adulthood: A case study.

Cortical visual impairment (CVI) is a severe loss of visual function caused by damage to the visual cortex or its afferents, often as a consequence of hypoxic insults during birth. It is one of the leading causes of vision loss in children, and it is most often permanent. Several studies have demonstrated limited vision restoration in adults who trained on well-controlled psychophysical tasks, after acquiring CVI late in life. Other studies have shown improvements in children who underwent vision training. However, little is known about the prospects for the large number of patients who acquired CVI at birth but received no formal therapy as children. We, therefore, conducted a proof-of-principle study in one CVI patient long after the onset of cortical damage (age 18), to test the training speed, efficacy and generalizability of vision rehabilitation using protocols that had previously proven successful in adults. The patient trained at home and in the laboratory, on a psychophysical task that required discrimination of complex motion stimuli presented in the blind field. Visual function was assessed before and after training, using perimetric measures, as well as a battery of psychophysical tests. The patient showed remarkably rapid improvements on the training task, with performance going from chance to 80% correct over the span of 11 sessions. With further training, improved vision was found for untrained stimuli and for perimetric measures of visual sensitivity. Some, but not all, of these performance gains were retained upon retesting after one year. These results suggest that existing vision rehabilitation programs can be highly effective in adult patients who acquired CVI at a young age. Validation with a large sample size is critical, and future work should also focus on improving the usability and accessibility of these programs for younger patients.

Auditory and Somatosensory Development for Speech in Later Childhood.

This study collected measures of auditory-perceptual and oral somatosensory acuity in typically developing children and adolescents aged 9-15 years. We aimed to establish reference data that can be used as a point of comparison for individuals with residual speech sound disorder (RSSD), especially for RSSD affecting American English rhotics. We examined concurrent validity between tasks and hypothesized that performance on at least some tasks would show a significant association with age, reflecting ongoing refinement of sensory function in later childhood. We also tested for an inverse relationship between performance on auditory and somatosensory tasks, which would support the hypothesis of a trade-off between sensory domains. Ninety-eight children completed three auditory-perceptual tasks (identification and discrimination of stimuli from a "rake"-"wake" continuum and category goodness judgment for naturally produced words containing rhotics) and three oral somatosensory tasks (bite block with auditory masking, oral stereognosis, and articulatory awareness, which involved explicit judgments of relative tongue position for different speech sounds). Pairwise associations were examined between tasks within each domain and between task performance and age. Composite measures of auditory-perceptual and somatosensory functions were used to investigate the possibility of a sensory trade-off. Statistically significant associations were observed between the identification and discrimination tasks and the bite block and articulatory awareness tasks. In addition, significant associations with age were found for the category goodness and bite block tasks. There was no statistically significant evidence of a trade-off between auditory-perceptual and somatosensory domains. This study provided a multidimensional characterization of speech-related sensory function in older children/adolescents. Complete materials to administer all experimental tasks have been shared, along with measures of central tendency and dispersion for scores in two subgroups of age. Ultimately, we hope to apply this information to make customized treatment recommendations for children with RSSD based on sensory profiles.

Assessment of Abuse-Related Discriminative Stimulus Effects of Nicotine Aerosol in Rodents.

The rapid increase in e-cigarette use highlights the importance of developing relevant, predictive animal models exploring their potential health implications. The goal of the present study was to examine the abuse-related effects of brief, repeated e-cigarette aerosol exposures in rodents modeling human e-cigarette user behavior. We evaluated the discriminative stimulus effects of brief, repeated puffs of inhaled nicotine in rats that had been trained to discriminate injected nicotine from saline. Locomotor activity measurement following exposure to injected and aerosolized nicotine was also assessed as an additional behavioral outcome. We hypothesized that the stimulus effects of nicotine aerosol were central nervous system (CNS)-mediated and comparable to that produced by an injected nicotine training stimulus. We further hypothesized that number of aerosol puffs and the e-liquid nicotine concentration which was aerosolized would impact the substitution of nicotine aerosol for injected nicotine. Both nicotine injections and exposures to nicotine aerosol produced a dose-dependent effect on locomotor activity. Nicotine aerosol under our puffing conditions produced e-liquid nicotine concentration-dependent and puff-number-dependent complete substitution for the injected nicotine training condition. The nicotinic antagonist, mecamylamine, completely blocked nicotine-appropriate responding produce by the training dose of 0.3 mg/kg injected nicotine as well as that resulting from exposure to aerosol puffs generated by e-liquid containing 3 mg/ml nicotine, demonstrating that the stimulus of inhaled nicotine was most likely CNS-mediated and not due to olfactory stimulus properties. Overall, the results support the hypothesis that an aerosol exposure drug discrimination model in rodents has applicability to studying the abuse-related effects of e-cigarettes. SIGNIFICANCE STATEMENT: Animal models of nicotine aerosol exposure using testing conditions resembling human e-cigarette use are lacking. In this study, we test a novel preclinical model of nicotine vaping in rodents which allows for the exploration of the abuse-related effects of e-cigarettes. This model has the potential to contribute both to our understanding of the abuse-related pharmacological effects of e-cigarettes as well as aid in the development of rationale, evidence-based e-cigarette regulatory policies.

Effects of phase synchronization and frequency specificity in the encoding of conditioned fear-a web-based fear conditioning study.

Oscillatory synchronization in the theta-frequency band was found to play a causal role in binding information of different modalities in declarative memory. Moreover, there is first evidence from a laboratory study that theta-synchronized (vs. asynchronized) multimodal input in a classical fear conditioning paradigm resulted in better discrimination of a threat-associated stimulus when compared to perceptually similar stimuli never associated with the aversive unconditioned stimulus (US). Effects manifested in affective ratings and ratings of contingency knowledge. However, theta-specificity was not addressed so far. Thus, in the present pre-registered web-based fear conditioning study, we compared synchronized (vs. asynchronized) input in a theta-frequency band vs. the same synchronization manipulation in a delta frequency. Based on our previous laboratory design, five visual gratings of different orientations (25°, 35°, 45°, 55°, 65°) served as conditioned stimuli (CS) with only one (CS+) paired with the auditory aversive US. Both CS and US were luminance or amplitude modulated, respectively, in a theta (4 Hz) or delta (1.7 Hz) frequency. In both frequencies, CS-US pairings were presented either in-phase (0° phase lag) or out-of-phase (90°, 180°, 270°), resulting in four independent groups (each group N = 40). Phase synchronization augmented the discrimination of CSs in CS-US contingency knowledge but did not affect valence and arousal ratings. Interestingly, this effect occurred independent of frequency. In sum, the current study proves the ability to successfully conduct complex generalization fear conditioning in an online setting. Based on this prerequisite, our data supports a causal role of phase synchronization in the declarative CS-US associations for low frequencies rather than in the specific theta-frequency band.

Auditory cortex plasticity supports social learning

The acquisition of new auditory skills can be facilitated by experiencing a conspecific performing a well-defined behavior (i.e., social learning). Although the neural bases for auditory social learning remain uncertain, one plausible hypothesis is that social experience induces long-term changes to auditory cortex, thereby facilitating the subsequent acquisition of an auditory skill. To explore this idea, we developed a social learning paradigm in which naïve observer gerbils are exposed to a demonstrator that performs an amplitude modulation (AM) rate discrimination task on the other side of an opaque divider. Thus, observers have no access to visual cues. When exposed to a demonstrator for five successive days, observers subsequently acquire the AM task more rapidly than controls. Two experiments suggest that auditory cortex is necessary and sufficient for social learning. First, inactivating the observer’s auditory cortex during each social exposure session significantly delayed task acquisition. Second, recordings from the observer’s auditory cortex revealed that individual neurons displayed a significant improvement in AM stimulus discrimination across the five exposure sessions, and the magnitude of neural improvement correlated with an animal’s subsequent rate of task acquisition. Together, these findings suggest that auditory cortex plasticity plays a pivotal role in social learning.

Comparison of locomotor stimulant and drug discrimination effects of four synthetic cathinones to commonly abused psychostimulants.

The underground market is constantly flooded with newer synthetic as alternatives to the older cathinones. Drug Enforcement Administration (DEA) has identified four cathinone compounds of particular concern: 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (3,4-MD-α-PHP), 4-chloro-α-pyrrolidinopropiophenone (4-Cl-α-PPP), alpha-pyrrolidinoisohexiophenone (α-PiHP) and 4-chloro-pentedrone (4-Cl-pentedrone). The current study aimed to evaluate the behavioral pharmacology of four synthetic cathinones. 3,4-MD-α-PHP, 4-Cl-α-PPP, α-PiHP, and 4-CPD were tested for locomotor activity in mice and in a drug discrimination assay with rats trained to discriminate either methamphetamine or cocaine. Locomotor stimulant effects of 3,4-MD-α-PHP ((effective dose) ED50 = 1.98 mg/kg), α-PiHP (ED50 = 2.46 mg/kg), and 4-Cl-α-PPP (ED50 = 7.18 mg/kg) were observed within 10 min following injection and lasted from 2 to 3.5 h. The stimulant action of 4-CPD (ED50 = 17.24 mg/kg) was delayed, occurring 40-70 min following injection. The maximal motor stimulant actions of 3,4-MD-α-PHP and α-PiHP 1 were equivalent to that of cocaine and methamphetamine, whereas 4-CPD (50% of cocaine) and 4-Cl-α-PPP (73% of cocaine) were less efficacious. All of the test compounds fully substituted for the discriminative stimulus effects of cocaine, 3,4-MD-α-PHP (ED50 = 2.28 mg/kg), α-PiHP (ED50 = 3.84 mg/kg), and 4-Cl-α-PPP (ED50 = 15.56 mg/kg). Only 3,4-MD-α-PHP (ED50 = 1.65 mg/kg), α-PiHP (ED50 = 1.87 mg/kg), and 4-Cl-α-PPP (ED50 = 9.79 mg/kg) fully substituted for the discriminative stimulus effects of methamphetamine. 4-Cl-pentedrone caused 55-70% methamphetamine-appropriate responding at doses that also suppressed responding and produced convulsions. These data indicate that 3,4-MD-α-PHP, α-PiHP, and 4-Cl-α-PPP have a potential for abuse similar to that of methamphetamine and cocaine. In contrast, 4-Cl-pentedrone may not be popular for recreational use due to its convulsant effects.

The piperazine analogue para-fluorophenylpiperazine alters timing of the physiological effects of the synthetic cannabinoid receptor agonist AMB-FUBINACA, without changing its discriminative stimulus, signalling effects, or metabolism

AMB-FUBINACA is a synthetic cannabinoid receptor agonist (SCRA), which has been associated with substantial abuse and health harm since 2016 in many countries including New Zealand. A characteristic of AMB-FUBINACA use in New Zealand has included the observation that forensic samples (from autopsies) and drugs seized by police have often been found to contain para-fluorophenylpiperazine (pFPP), a relatively little-characterised piperazine analogue that has been suggested to act through 5HT1a serotonin receptors. In the current study, we aimed to characterise the interactions of these two agents in rat physiological endpoints using plethysmography and telemetry, and to examine whether pFPP altered the subjective effects of AMB-FUBINACA in mice trained to differentiate a cannabinoid (THC) from vehicle. Though pFPP did not alter the ability of AMB-FUBINACA to substitute for THC, it did appear to abate some of the physiological effects of AMB-FUBINACA in rats by delaying the onset of AMB-FUBINACA-mediated hypothermia and shortening duration of bradycardia. In HEK cells stably expressing the CB1 cannabinoid receptor, 5HT1a, or both CB1 and 5HT1a, cAMP signalling was recorded using a BRET biosensor (CAMYEL) to assess possible direct receptor interactions. Although low potency pFPP agonism at 5HT1a was confirmed, little evidence for signalling interactions was detected in these assays: additive or synergistic effects on potency or efficacy were not detected between pFPP and AMB-FUBINACA-mediated cAMP inhibition. Experiments utilising higher potency, classical 5HT1a ligands (agonist 8OH-DPAT and antagonist WAY100635) also failed to reveal evidence for mutual CB1/5HT1a interactions or cross-antagonism. Finally, the ability of pFPP to alter the metabolism of AMB-FUBINACA in rat and human liver microsomes into its primary carboxylic acid metabolite via carboxylesterase-1 was assessed by HPLC; no inhibition was detected. Overall, the effects we have observed do not suggest that increased harm/toxicity would result from the combination of pFPP and AMB-FUBINACA.

An evaluation of methods for studying the effects of conditioned reinforcement on human choice.

Shahan et al. (2006) found that the relative rate of pigeons' pecking on two observing responses (i.e., responses that only produced an S+ or stimulus correlated with primary reinforcement) was well described by the relative rate of S+ delivery. Researchers have not evaluated the effects of S+ delivery rate in a concurrent observing response procedure with human subjects, so the necessary procedural modifications for studying the effects of conditioned reinforcement on human choice remain unclear. The purpose of the current study was to conduct an additive component analysis of modifications to the procedures of Shahan et al. (2006). We evaluated the additive effects of introducing response cost, a changeover response, and ordinal discriminative stimuli on correspondence with the results of Shahan et al. and the quality of fits of the generalized matching equation. When our procedures were most similar to those of Shahan et al., we observed low rates of observing and indifference between the two observing responses. For the group of subjects with whom all three additive components were included, we obtained the highest level of sensitivity to relative rate of S+ delivery, but the slope and R2 of our fits of the generalized matching equation were still much lower than those obtained by Shahan et al. Potential reasons for these discrepancies, methods of resolving them, and implications for future research are discussed.