Abstract
Humans demonstrate significant behavioural advantages with particular perceptual dimensions (such as colour or shape) and when the relevant dimension is repeated in consecutive trials. These dimension-related behavioural modulations are significantly altered in neuropsychological and addiction disorders; however, their underlying mechanisms remain unclear. Here, we studied whether these behavioural modulations exist in other trichromatic primate species and whether repeated exposure to opioids influences them. In a target detection task where the target-defining dimension (colour or shape) changed trial by trial, humans exhibited shorter response time (RT) and smaller event-related electrodermal activity with colour dimension; however, macaque monkeys had shorter RT with shape dimension. Although the dimensional biases were in the opposite directions, both species were faster when the relevant dimension was repeated, compared with conditions when it changed, across consecutive trials. These indicate that both species formed dimensional sets and that resulted in a significant ‘switch cost’. Scheduled and repeated exposures to morphine, which is analogous to its clinical and recreational use, significantly augmented the dimensional bias in monkeys and also changed the switch cost depending on the relevant dimension. These cognitive effects occurred when monkeys were in abstinence periods (not under acute morphine effects) but expressing significant morphine-induced conditioned place preference. These findings indicate that significant dimensional biases and set formation are evolutionarily preserved in humans' and monkeys' cognition and that repeated exposure to morphine interacts with their manifestation. Shared neural mechanisms might be involved in the long-lasting effects of morphine and expression of dimensional biases and set formation in anthropoids.
| Original language | English |
|---|---|
| Article number | e13380 |
| Number of pages | 13 |
| Journal | Addiction Biology |
| Volume | 29 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Feb 2024 |
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This output contributes to the following UN Sustainable Development Goals (SDGs)
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SDG 3 Good Health and Well-being
Keywords
- conditioned place preference
- dimensional bias
- monkeys
- morphine
- switch cost
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In: Addiction Biology, Vol. 29, No. 2, e13380, 02.2024.
Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Morphine exposure modulates dimensional bias and set formation in anthropoids
AU - Ghasemian, Sadegh
AU - Pascoe, Alexander J.
AU - Vardanjani, Marzieh M.
AU - Haque, Zakia Z.
AU - Ignatavicius, Anna
AU - Fehring, Daniel J.
AU - Sheibani, Vahid
AU - Mansouri, Farshad A.
N1 - Funding Information: For human study, approval was given by the Human Research Ethics Committee at Monash University, and informed consent was collected from each participant. For animal study, all experimental procedures, including animal holding, training and testing were conducted following ethical guidelines of NIH and were approved by Animal Ethics Committee at Kerman University of Medical Sciences. We used six (four males and two females) adult rhesus monkeys (Macaca mulatta) with 8–11 kg weight at the beginning of study. All monkeys had experience with versions of stop-signal task47,48 and therefore were familiar with switch pressing and screen touching. All experimental procedures, including animal holding, training and testing, were conducted following ethical guidelines of NIH and were approved by Animal Ethics Committee at Kerman University of Medical Sciences. Monkeys were kept in primate home cages (Okazaki Co, Japan) but transferred to the experimental room using a wheeled transfer cage. A 12 h light–dark cycle and adjusted temperature (22 ± 2°C) were maintained at the holding room. For induction and examining morphine-associated CPP, we used a three-chamber apparatus within a sound-attenuated room. For this purpose, three steel cages with open vertical bars at their front were connected side-by-side through guillotine doors. This allowed monkeys' view of the room and made monitoring and recording of monkeys' behaviours possible. The middle chamber served as the entrance chamber and monkeys could freely enter the left and right chambers during the testing sessions. Inside each of the left/right chambers, specific visual cues were used to improve their discriminability. During conditioning, monkeys were guided to their assigned chamber and confined there by closing the doors between chambers. A CCD camera was used for video recording, and preference scores were calculated by offline analysis of videos. Training and testing sessions of the dimensional TDT were done in a sound-attenuated cubicle-room with dim light and controlled temperature. A 17″ touchscreen (Microtouch Touchscreen system, 3M) was used for presentation of stimuli and recording monkeys' responses. A computer-controlled liquid dispenser was used to deliver reward (juice) following correct responses. In each trial, presentation of test items instructed monkeys to press a switch at the middle bottom of the screen. During training and testing sessions, monkeys were positioned in a transfer-working cage with open bars, which allowed their access to the switch and touchscreen. Task events including stimulus presentation, recording animals' responses and delivering the reward were controlled in millisecond resolution by a program written in Matlab (MathWorks Inc) using Psychtoolbox-3 extension. In each trial, presentation of a start cue (a white circle with 6 cm diameter) at the centre of the touchscreen informed monkeys to initiate the trial by pressing the switch (Figure 1A). This immediately led to substitution of the start cue by a fixation cross at the centre of the screen. Monkeys had to hold the switch down for a randomly selected delay period (200, 400 or 600 ms) until the fixation cross was replaced by two peripheral test items (a distractor and a target) on the left and right sides of the screen. The fixation cross acted as a cue to direct monkeys' gaze to the centre of screen while they waited for the target and distractor presentation. The left/right position of the target and distractor was counterbalanced across trials. Three colours (red [R:255, G:0, B:0], green [R:0, G:255, B:0] and blue [R:0, G:0, B:255]) and three shapes (triangles, circles and crosses) were used for making targets in the colour and shape dimension, respectively; the distractor was a white (R:255, G:255, B:255) rectangle. Within each trial, the target was distinguishable from the distractor in only one dimension, either colour (i.e., one of three coloured rectangles) or shape (i.e., one of three white shapes). The frequency of each possible target was counterbalanced across trials. For receiving a reward, monkeys had to release the switch after visual items (distractor and target) onset and touch the target within 2 s (response window). Correct responses led to black screen (1 s) and reward delivery. Touching the distractor or failing to touch either test item within the response window were considered as erroneous responses. Following an error, all items turned off, no reward was given and a white annulus (with an outer and inner diameter of 6 cm and 2 cm, respectively) was presented as the error signal for 700 ms at the centre of the screen. The ITI was 1.5 and 3 s after correct and error trials, respectively. Those trials in which the switch was released before the onset of test items (early release) were excluded from analyses. In this study, we primarily aimed to examine whether there was a dimensional bias and switch cost in monkeys performing a dimensional target selection task and whether exposure to morphine changed these dimension-related behavioural modulations. Therefore, cognitive testing was done before (as a baseline performance) and after morphine exposure. Monkeys' performance in dimensional TDT was tested in six pre-morphine and six post-morphine testing (daily) sessions. Figure 2 shows the time course of the longitudinal study with several phases of morphine administration and CPP testing. Rest periods indicate those days in which the animals did not receive any injection; however, their daily schedule remained consistent, and they performed other cognitive tasks (stop-signal task, but not the TDT).47,48 We administered morphine sulphate (Temad Co., Tehran, Iran) via intramuscular injection in six scheduled and intermittent phases. Each phase was composed of 2–12 days of alternating morphine and saline injections (see Figure 2 for more details). For the first phase, we used 1.5 and 3 mg/kg doses in the first and second injection/day, respectively. For the remaining injections, 4.5 mg/kg was used as the maintenance dose. In Phases 1–5, we also tested morphine-induced CPP to confirm morphine-induced behavioural changes in monkeys. A previously validated method was used for induction of morphine-induced CPP in monkeys.32 The details of induction and assessment of morphine-associated CPP have been described in our previous study.49 In the last (sixth) phase, only morphine was administered in six consecutive days (without conditioning and intervening saline days). At the end of the sixth phase, the cumulative dose of morphine reached 89 mg/kg, and monkeys were tested with dimensional TDT on Abstinence Days 21–25. Fifty-five undergraduate students (38 females) between the ages of 18–25 years old (20.75 ± 0.16, mean ± SEM) participated in the study. All participants had no history of neurological disorders, nor any medical conditions that may have interfered with their performance of the task. Approval was given by the Human Research Ethics Committee at Monash University, and informed consent was collected from each participant. While human participants performed the TDT, we recorded their event-related electrodermal activity (EDA), a measure of skin conductance in microsiemens (μS). Two surface electrodes were attached to participants' non-dominant ring and index fingers, which were connected to an electrodermal recording amplifier (ML116 GSR Amp, ADInstruments) sampling at a rate of 75 kHz. As EDA recording is sensitive to motion-related noise, we instructed participants to keep their non-dominant hand and arm still throughout their testing sessions. We calculated event-related EDA as the difference between the minimum and maximum values of phasic activity within a 3-s epoch following target selection.1,2,46 Due to several factors outside of experimental control, such as cold hands and low sweating levels, EDA could not be adequately recorded from two participants. Data from these two participants were chosen for exclusion based on the decision of an observer who was blinded to the data analysis. Consequently, we included EDA data from 53 human participants in total within our analysis. Each trial commenced by the presentation of a start cue (randomly chosen from a large set of multi-coloured images) in the centre of the screen, for which participants were instructed to subsequently press down the switch (Figure 1B). This immediately led to the substitution of the start cue with a fixation point at the centre of the screen. Participants had to hold the switch pressed for the duration of a randomly determined delay (450, 900 or 1350 ms) until the fixation point was replaced by two peripheral test items (a distractor and a target) positioned opposite to one another in one of 16 possible arrangements (forming a clock-like pattern). The frequency of each distractor/target arrangement was counterbalanced across trials. Six colours (green [R:0, G:255, B:0], red [R:255, G:0, B:0], blue [R:0, G:0, B:255], cyan [R:0, G:255, B:255], magenta [R:255, G:0, B:255] and yellow [R:255, G:255, B:0]) and six shapes (circles, triangles, crosses, ellipses, hexagons and rectangles) were used in making the targets in the colour and shape dimension, respectively; the distractor was a white (R:255, G:255, B:255) square. The position of the distractor and target changed trial by trial. The target item differed from the distractor in either the colour or shape dimensions, and the target-defining dimension in each trial was determined randomly without any notice to the participants. The size and spatial alignment of the target and distractor items remained consistent for both colour and shape dimensions, and therefore, requirements for spatial attention were kept uniform among both dimensions. Upon the presentation of the distractor and target items, subjects were supposed to immediately release the switch and then touch the target on a touchscreen within a limited (900 ms) response window. Correct responses were indicated by the target item flashing off (for 200 ms) and on (for 200 ms). Responses were considered erroneous if the participant touched the distractor, failed to touch the items within 900 ms (timeout errors) or released the switch before the onset of test items (early release). Erroneous responses were indicated by the disappearance of all test items and the onset of an error signal (pink annulus) for 500 ms at the centre of the screen. The inter-trial interval (ITI) was 2.3 s for both correct and erroneous trials. We used six (four males and two females) adult rhesus monkeys (Macaca mulatta) with 8–11 kg weight at the beginning of study. All monkeys had experience with versions of stop-signal task47,48 and therefore were familiar with switch pressing and screen touching. All experimental procedures, including animal holding, training and testing, were conducted following ethical guidelines of NIH and were approved by Animal Ethics Committee at Kerman University of Medical Sciences. Monkeys were kept in primate home cages (Okazaki Co, Japan) but transferred to the experimental room using a wheeled transfer cage. A 12 h light–dark cycle and adjusted temperature (22 ± 2°C) were maintained at the holding room. For induction and examining morphine-associated CPP, we used a three-chamber apparatus within a sound-attenuated room. For this purpose, three steel cages with open vertical bars at their front were connected side-by-side through guillotine doors. This allowed monkeys' view of the room and made monitoring and recording of monkeys' behaviours possible. The middle chamber served as the entrance chamber and monkeys could freely enter the left and right chambers during the testing sessions. Inside each of the left/right chambers, specific visual cues were used to improve their discriminability. During conditioning, monkeys were guided to their assigned chamber and confined there by closing the doors between chambers. A CCD camera was used for video recording, and preference scores were calculated by offline analysis of videos. Training and testing sessions of the dimensional TDT were done in a sound-attenuated cubicle-room with dim light and controlled temperature. A 17″ touchscreen (Microtouch Touchscreen system, 3M) was used for presentation of stimuli and recording monkeys' responses. A computer-controlled liquid dispenser was used to deliver reward (juice) following correct responses. In each trial, presentation of test items instructed monkeys to press a switch at the middle bottom of the screen. During training and testing sessions, monkeys were positioned in a transfer-working cage with open bars, which allowed their access to the switch and touchscreen. Task events including stimulus presentation, recording animals' responses and delivering the reward were controlled in millisecond resolution by a program written in Matlab (MathWorks Inc) using Psychtoolbox-3 extension. In each trial, presentation of a start cue (a white circle with 6 cm diameter) at the centre of the touchscreen informed monkeys to initiate the trial by pressing the switch (Figure 1A). This immediately led to substitution of the start cue by a fixation cross at the centre of the screen. Monkeys had to hold the switch down for a randomly selected delay period (200, 400 or 600 ms) until the fixation cross was replaced by two peripheral test items (a distractor and a target) on the left and right sides of the screen. The fixation cross acted as a cue to direct monkeys' gaze to the centre of screen while they waited for the target and distractor presentation. The left/right position of the target and distractor was counterbalanced across trials. Three colours (red [R:255, G:0, B:0], green [R:0, G:255, B:0] and blue [R:0, G:0, B:255]) and three shapes (triangles, circles and crosses) were used for making targets in the colour and shape dimension, respectively; the distractor was a white (R:255, G:255, B:255) rectangle. Within each trial, the target was distinguishable from the distractor in only one dimension, either colour (i.e., one of three coloured rectangles) or shape (i.e., one of three white shapes). The frequency of each possible target was counterbalanced across trials. For receiving a reward, monkeys had to release the switch after visual items (distractor and target) onset and touch the target within 2 s (response window). Correct responses led to black screen (1 s) and reward delivery. Touching the distractor or failing to touch either test item within the response window were considered as erroneous responses. Following an error, all items turned off, no reward was given and a white annulus (with an outer and inner diameter of 6 cm and 2 cm, respectively) was presented as the error signal for 700 ms at the centre of the screen. The ITI was 1.5 and 3 s after correct and error trials, respectively. Those trials in which the switch was released before the onset of test items (early release) were excluded from analyses. In this study, we primarily aimed to examine whether there was a dimensional bias and switch cost in monkeys performing a dimensional target selection task and whether exposure to morphine changed these dimension-related behavioural modulations. Therefore, cognitive testing was done before (as a baseline performance) and after morphine exposure. Monkeys' performance in dimensional TDT was tested in six pre-morphine and six post-morphine testing (daily) sessions. Figure 2 shows the time course of the longitudinal study with several phases of morphine administration and CPP testing. Rest periods indicate those days in which the animals did not receive any injection; however, their daily schedule remained consistent, and they performed other cognitive tasks (stop-signal task, but not the TDT).47,48 We administered morphine sulphate (Temad Co., Tehran, Iran) via intramuscular injection in six scheduled and intermittent phases. Each phase was composed of 2–12 days of alternating morphine and saline injections (see Figure 2 for more details). For the first phase, we used 1.5 and 3 mg/kg doses in the first and second injection/day, respectively. For the remaining injections, 4.5 mg/kg was used as the maintenance dose. In Phases 1–5, we also tested morphine-induced CPP to confirm morphine-induced behavioural changes in monkeys. A previously validated method was used for induction of morphine-induced CPP in monkeys.32 The details of induction and assessment of morphine-associated CPP have been described in our previous study.49 In the last (sixth) phase, only morphine was administered in six consecutive days (without conditioning and intervening saline days). At the end of the sixth phase, the cumulative dose of morphine reached 89 mg/kg, and monkeys were tested with dimensional TDT on Abstinence Days 21–25. For statistical comparisons, we used IBM SPSS statistical package. To examine morphine-associated place preference in CPP tests, a one-way repeated-measure ANOVA was applied to the mean preference scores. The preference score was calculated as the relative duration of visits to the morphine-associated chamber. To this aim, for each monkey, the time spent in the morphine chamber was divided by total time that monkey spent in both morphine- and saline-associated chambers. Preference scores were calculated for pre-conditioning and five post-conditioning tests; then, we included a Morphine factor with six levels corresponding to the cumulative doses of morphine (0, 22.5, 40.5, 49.5, 54 and 58.5 mg/kg). For each post-conditioning test, the mean values across sessions were used for the analyses. For examination of dimensional bias and switch cost, we used only RT values because humans' and monkeys' accuracy rates were near the ceiling (see Section 3). We calculated RT as the time between target onset until the release of the switch (but not touching the target on the screen) in correct trials. Normalized values were calculated for each condition by dividing the actual RT value of that condition by the average of all conditions for each participant/monkey. We used normalized RT values in the analyses because it controls for the differences in overall RT between subjects, which might result from individual differences in motivation or relative position within the testing cage. EDA data collected from humans were also subject to the same normalization procedure in order to control for individual variations in sweating levels.1,2 A response window (2 s for monkeys and 900 ms for humans) was implemented in each trial to encourage speeded response and prevent extremely slow or unattended responses (i.e., all responses longer than the response window were considered as errors), and therefore, all analysed RT values remained within the response window. Because arbitrary procedures are used in the selection of the outliers, we did not exclude any data (RT values) as outliers, and therefore, all RT values from correct trials were included in the analyses. A randomized delay (200, 400 or 600 ms) was applied before target onset to prevent anticipatory responses. In humans, data were collected in two stages within a daily session, where the first and the second stage were separated by a 5-min rest period. Humans performed 200 trials of the TDT in each stage. Therefore, a Stage factor (first/second stage, within subject) was included in the repeated-measure ANOVA for humans, which also allowed us to assess within-session learning among participants. In monkeys, data were collected across six sessions before and after morphine exposure. For each monkey, we used the session means in pre-morphine and post-morphine testing sessions, and therefore, both a Morphine factor (pre-morphine/post-morphine, within subject) and a Monkey factor (six monkeys, between subject) were included in the repeated-measure ANOVA. In both species, trials were classified based on the dimension by which the target differed to the distractor (colour or shape) and by the repetition (colour–colour or shape–shape) or switch (shape–colour or colour–shape) sequences of the target-defining dimension across two consecutive trials. Accordingly, a Dimension factor (colour/shape, within subject) and a Sequence factor (repeat/switch, within subject) were included in the repeated-measure ANOVA. For reporting the results of repeated-measure ANOVA, Mauchly's sphericity test was considered, and where it was violated, the Greenhouse–Geisser correction was applied. Publisher Copyright: © 2024 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.
PY - 2024/2
Y1 - 2024/2
N2 - Humans demonstrate significant behavioural advantages with particular perceptual dimensions (such as colour or shape) and when the relevant dimension is repeated in consecutive trials. These dimension-related behavioural modulations are significantly altered in neuropsychological and addiction disorders; however, their underlying mechanisms remain unclear. Here, we studied whether these behavioural modulations exist in other trichromatic primate species and whether repeated exposure to opioids influences them. In a target detection task where the target-defining dimension (colour or shape) changed trial by trial, humans exhibited shorter response time (RT) and smaller event-related electrodermal activity with colour dimension; however, macaque monkeys had shorter RT with shape dimension. Although the dimensional biases were in the opposite directions, both species were faster when the relevant dimension was repeated, compared with conditions when it changed, across consecutive trials. These indicate that both species formed dimensional sets and that resulted in a significant ‘switch cost’. Scheduled and repeated exposures to morphine, which is analogous to its clinical and recreational use, significantly augmented the dimensional bias in monkeys and also changed the switch cost depending on the relevant dimension. These cognitive effects occurred when monkeys were in abstinence periods (not under acute morphine effects) but expressing significant morphine-induced conditioned place preference. These findings indicate that significant dimensional biases and set formation are evolutionarily preserved in humans' and monkeys' cognition and that repeated exposure to morphine interacts with their manifestation. Shared neural mechanisms might be involved in the long-lasting effects of morphine and expression of dimensional biases and set formation in anthropoids.
AB - Humans demonstrate significant behavioural advantages with particular perceptual dimensions (such as colour or shape) and when the relevant dimension is repeated in consecutive trials. These dimension-related behavioural modulations are significantly altered in neuropsychological and addiction disorders; however, their underlying mechanisms remain unclear. Here, we studied whether these behavioural modulations exist in other trichromatic primate species and whether repeated exposure to opioids influences them. In a target detection task where the target-defining dimension (colour or shape) changed trial by trial, humans exhibited shorter response time (RT) and smaller event-related electrodermal activity with colour dimension; however, macaque monkeys had shorter RT with shape dimension. Although the dimensional biases were in the opposite directions, both species were faster when the relevant dimension was repeated, compared with conditions when it changed, across consecutive trials. These indicate that both species formed dimensional sets and that resulted in a significant ‘switch cost’. Scheduled and repeated exposures to morphine, which is analogous to its clinical and recreational use, significantly augmented the dimensional bias in monkeys and also changed the switch cost depending on the relevant dimension. These cognitive effects occurred when monkeys were in abstinence periods (not under acute morphine effects) but expressing significant morphine-induced conditioned place preference. These findings indicate that significant dimensional biases and set formation are evolutionarily preserved in humans' and monkeys' cognition and that repeated exposure to morphine interacts with their manifestation. Shared neural mechanisms might be involved in the long-lasting effects of morphine and expression of dimensional biases and set formation in anthropoids.
KW - conditioned place preference
KW - dimensional bias
KW - monkeys
KW - morphine
KW - switch cost
UR - https://www.scopus.com/pages/publications/85184713139
U2 - 10.1111/adb.13380
DO - 10.1111/adb.13380
M3 - Article
C2 - 38333998
AN - SCOPUS:85184713139
SN - 1355-6215
VL - 29
JO - Addiction Biology
JF - Addiction Biology
IS - 2
M1 - e13380
ER -