- Academic Editor
†These authors contributed equally.
Background: Early life social experience and the function of the
central serotonin (5-Hydroxytryptophan, 5-HT) system are involved in development of behavioral
impulsivity in which individuals act without forethought or before all necessary
information is available. However, most of the evidence has been obtained from
acute 5-HT manipulation, whereas, the present study aimed to investigate the
effects of subchronic regimen targeting of 5-HT
Impulsivity is an urge to perform a specific act following a stimulus caused by the physiological activation of a sense organ. Motoric impulsivity is a type of impulsivity in which individuals act without forethought or before all necessary information is available [1]. Increasing evidence reveals that disturbance of central serotonin (5-Hydroxytryptophan, 5-HT) functions leads to a variety of mental abnormalities, including behavioral impulsivity [2, 3, 4]. It is generally accepted that current evidence suggests a positive correlation between the neuronal activity of 5-HT and the ability to control impulsivity, at least in the domains of both cognitive impulsivity indexed by the preference toward large but delayed reward in the temporal discounting of reward task (TDRT) and motoric impulsivity indexed by the premature responding prior to information collection required in the 5-choice serial reaction time task (5-CSRTT) [5]. Most of the evidence supporting this proposition has been obtained from acute manipulation of 5-HT. Thus, it remains inconclusive as to the long-term or time-dependent effects of 5-HT on the behavioral phenotype of impulsivity, which is a role of great interest in its clinical use.
In clinical psychiatry, the time-dependent effect is crucial in the
interpretation of pharmacological intervention with 5-HT-related agents. The
current working hypothesis considers that the improvement of depressive mood is
time-dependently associated with reduced sensitivity of pre-synaptic 5-HT
Buspirone, a full agonist of presynaptic 5-HT
Among the factors that influence impulsivity, early life socialization is one that can be practically approached in rodent study. Rats underwent isolation rearing (IR) by experiencing social deprivation from weaning by being reared individually; allowed to see and smell others, but not physically contact them [11]. IR rats are less impulsive than their socially reared (SR) controls in both cognitive and motoric impulsiveness, as shown by TDRT and 5-CSRTT testing, respectively [12, 13]. For motoric waiting impulsivity, it has previously been demonstrated that in a time-dependent manner, a subchronic buspirone regimen increased the occurrence of premature activity, as opposed to its acute effect [10]. It is of interest to investigate whether IR may influence the buspirone effects in 5-CSRTT.
In the present study, adult IR rats were employed for the 5-CSRTT to obtain a
profile of their motoric impulsivity. A 15-days buspirone/desipramine regimen was
introduced in which both acute and subchronic effects of the drugs were examined.
The use of desipramine, a relatively selective norepinephrine reuptake inhibitor
(NRI) which is also used in treating impulsiveness [14, 15], was contrasted with
5-HT
A total 56 male and weaned Sprague-Dawley rats were randomly assigned into SR
group (2 rats/cage) and IR group (1 rat/cage) at 21 postnatal days (PD) and they
did the 5-CSRTT training at PD56. After 5-CSRTT training, the rats were further
assigned to saline, buspirone, or desipramine administrations. Therefore, there
were 6 groups in the present study: SR-Saline (n = 10), IR-Saline (n = 10),
SR-Buspirone (n = 9), IR-Buspirone (n = 9), SR-Desipramine (n = 9), and
IR-Desipramine (n = 9). Note the data of group of SR-Saline and SR-buspirone had
been used in our previous publication [10]. All rats were housed in the
laboratory animal center (National Defense Medical Center, Taipei, Taiwan) with
the humidity of (50%
The simplified experimental design. PD, postnatal days; IR, isolation rearing; 5-CSRTT, five-choice serial reaction time task.
Buspirone (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in saline and the rats were intraperitoneally (i.p.) injected buspirone with 0.5 mg/kg. Desipramine (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in deionised water and the rats were received 2.5 mg/kg desipramine by subcutaneous injection. The rats were received buspirone or desipramine once per day during the 15-day 5-CSRTT paradigm. The acute administration was be arranged on the Day 1 and Day 15, in which the buspirone, desipramine, and saline were administrated 60, 30, 30 min before the 5-CSRTT, respectively. The subchronic regimen was be arranged daily from Day 2 to Day 14, and all drugs were be administrated 30 min after 5-CSRTT. The doses chosen for buspirone (0.5 mg/kg) and desipramine (2.5 mg/kg) were based on the literatures that the drugs at these doses showed high sensitive to exert effects on the premature responding of the 5-CSRTT [10, 16, 17].
Locomotor activity was measured when the rats 8 weeks old. The distance
travelled was summed up every 5 min within a total 60 min test by the software of
Activity Monitor® 5 (Med Associates, Inc., Fairfax, VT, USA). The apparatus
of locomotor activity (Med Associates, Inc., Fairfax, VT, USA) was a Plexiglass chambers
(43
The 5-CSRTT training procedure was similar to our previously studies [13, 18, 19]. The size of 5-CSRTT chamber (TSE Systems GmbH, Bad Homburg, Germany) was 25
A correct response was recorded when rats responded to the illumination aperture within a limited illumination period of the hole, then the reward of a food pellet was delivered to the magazine. An incorrect response was recorded when rats responded to a non-illuminated aperture, and it was punished by a 5 s timeout period accompanied by the chamber light extinguished. A session was stopped after 30 min or 100 completed trials, it depended on which came first.
The percentage of accuracy was collected by the following formula: [correct responses/(correct responses + incorrect responses)]. The percentage of omission was collected by the following formula: (the trials of no response during an ITI/total trial). Premature was recorded when rats “first” responded to any one of the apertures prior to any apertures illumination. Correct latency was means the time duration from an aperture illumination to the rats responded to the correct hole. Collect latency was means the time duration from the rats responded to the correct hole to they take the reward food pellet.
In the present study, three-way Analysis of Variance (ANOVA) was employed in the data of subchronic
treatment with two between-subjects factors of rearing (SR and IR) and treatment
(saline and buspirone or saline and desipramine), and a within-subjects factor of
time. Two-way ANOVA was used in the data of locomotor activity and acute
treatment with between-subjects factor of rearing (SR and IR) or treatment
(saline and buspirone or saline and desipramine), or within-subjects factor of
time. p-values of
The effect of early life social deprivation was validated by characteristically
hyperactivity of IR rats in the locomotion test (F
The locomotor activity after IR and SR. Two-way ANOVA was
employed for statistical analysis with a between-subjects factor of rearing (SR
and IR) and a within-subjects factor of time. The data represent the
mean
For the percentage of accuracy, there were no significant effects (Fig. 3A). For
the percentage of omission, the data showed a significant interaction between
time and treatment (F
The performances of IR and subchronic buspirone administration
on the 5-CSRTT. (A) The percentage of accuracy. (B) The percentage of omission.
(C) The premature response. (D) The correct latency. (E) The collect
latency. Three-way ANOVA was employed for statistical analysis with
between-subjects factors of rearing (SR and IR) and treatment (saline and
buspirone), and a within-subjects factor of time. The data represent the mean
For the percentage of accuracy, there were no significant effects (Fig. 4A). For
the percentage of omission, ANOVA showed significant interactions between time
and treatment (F
The performances of IR and subchronic desipramine administration
on the 5-CSRTT. (A) The percentage of accuracy. (B) The percentage of omission.
(C) The premature response. (D) The correct latency. (E) The collect latency.
Three-way ANOVA was employed for statistical analysis with between-subjects
factors of rearing (SR and IR) and treatment (saline and desipramine), and a
within-subjects factor of time. The data represent the mean
For the percentage of accuracy, ANOVA exhibited a significant effect of time
(F
The acute effects of buspirone before (i.e., Day 1) and after
(i.e., Day 15) the subchronic regimen on the 5-CSRTT performances in IR and SR
rats. (A) The percentage of accuracy. (B) The percentage of omission. (C) The
premature response. (D) The correct latency. (E) The collect latency. Two-way
ANOVA was employed for statistical analysis with a between-subjects factor of
rearing (SR and IR) and a within-subjects factor of time. The data represent the
mean
For the percentage of accuracy, ANOVA exhibited a significant effect of time
(F
The acute effects of desipramine before (i.e., day 1) and after
(i.e., day 15) the subchronic regimen on the 5-CSRTT performances after IR and
SR. (A) The percentage of accuracy. (B) The percentage of omission. (C) The
premature response. (D) The correct latency. (E) The collect latency. Two-way
ANOVA was employed for statistical analysis with a between-subjects factor of
rearing (SR and IR) and a within-subjects factor of time. The data represent the
mean
The present study examined the behavioral effects of buspirone/desipramine on
the performance of the 5-CSRTT test in IR rats. Three major findings were
obtained: (i) IR rats exhibited more locomotor activity than SR rats. (ii) IR
rats behaved differently when compared with their SR controls. It was found that
buspirone progressively increased the baseline level of premature responding in a
time dependent manner in SR but not IR rats. (iii) Both IR and SR rats exhibited
less premature responding following acute buspirone challenge. (iv) During the
subchronic desipramine regimen, IR rats exhibited the same trend of SR controls
to increase their baseline premature responding. These results suggest that early
life social experience is involved in the functions of 5-HT
Compared with SR rats, IR rats presented more locomotor activity but less premature responding, demonstrating the different natures of these two conditions. Although hyperactive locomotion and premature responding are both considered behavioral output, each has its own working mechanism. Locomotor activity is a non-specific behavioral output and the hyperactive characteristic of IR rats can be used to validate the success of the IR paradigm [20], whereas premature responding is a specific index that reflects the ability to control motoric impulsiveness.
Rats subject to repeated buspirone treatment exhibited greater baseline
premature responding in the 5-CSRTT case, indicating they were more motorically
impulsive, a different response to that of the acute effect of the drug [10].
Concordant with this behavioral finding, Newman and colleagues [21] demonstrated
at a cellular level that long-term administration of buspirone reduced the 5-HT
inhibition of forskolin-stimulated adenylate cyclase activity in rat hippocampal
membranes, similar to the chronic effect of fluoxetine, a well-documented SSRI.
It should be noted that in clinical application, although SSRIs have been used
for their anti-impulsivity effect, the contribution of 5-HT
The most important finding in the present study is that the above subchronic buspirone effects disappeared in rats during the ongoing IR paradigm as revealed by significant statistical interactions between rearing condition and treatment. IR rats exhibited greater impulsiveness than SR rats during the subchronic buspirone treatment. The underlying mechanism can be complicated, but it at least relates to (i) the IR-induced greater ability to inhibit the ‘waiting impulsivity’ not only in motoric impulsivity as shown in the present study but also the cognitive impulsivity of TDRT as well [13], (ii) a developmentally specific phenomenon because it did not occur in the IR case but only with the re-socialization protocol [24]. In other words, the ongoing/continuous social isolation following the critical period of rats, as it influences the IR-impaired ability of prepulse inhibition of the startle reflex [20], and is crucial as well to ensure the IR effect of inhibiting impulsiveness. The experience of long-term, ongoing social isolation has been usually considered adverse or negative. Why IR rats exhibit a greater ability to control their impulsiveness is paradoxically intriguing. What is ‘lacking’ following IR across the adolescent period is crucial, in which play-fighting (also known as ‘social play’) and activities including pouncing and pinning are critical to the development of motoric/cognitive functions [25, 26]. Lack of these activities may develop a behavioral strategy of less risk-taking or impulsiveness.
The data also revealed that the premature responding of the buspirone treated
rats gradually increased to reach its maximal level on Day 7. This time-dependent
effect fits the desensitization hypothesis of the somatodendritic 5HT
In contrast to its long-term effect to increase baseline premature responding, acute buspirone, whether administered either before or after the subchronic regimen, tended to reduce the reactivity of responding. Note that in neurochemical terms, the acute effect of buspirone did not alter synaptic 5-HT efflux, it was decreased in ventral hippocampus but increased in medial prefrontal cortex [9]. As reduced 5-HT function is in general considered to disrupt impulse control, this discrepancy needs to be solved by mechanisms other than area-based neurochemical change. Alternatively, it is possible that this is because of impairment of motoric readiness (or agility, thus lengthening of the magazine latency to retrieve the reward) following the acute effect of buspirone, as seen in the present study. Further, as this effect was also counteracted by IR, it implies that early life social experience contributes to the buspirone-induced motoric reactivity.
In the present study, desipramine was used to compare the effects of buspirone
that represented distinctive pharmacological manipulations, i.e., NRI versus
5-HT
In terms of clinical implication, results reported here suggest that early life
social experience should be taken into account when accessing motoric waiting
impulsivity, particularly when it comes to the pharmacological manipulation of
5-HT
Several limitations should be addressed in the interpretation of the results.
First, there was a lack of dose-response curve to validate the data. Second, a
two-week subchronic regimen was employed in the present study, but a longer
period of intervention is suggested. Finally, as protein expression of
5-HT
The present study demonstrated that social isolation during early life reversed
buspirone but not desipramine-induced time-dependent effects of motoric waiting
impulsivity, indicating a role for early life social experience in 5-HT
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
CST and YPL designed the study and wrote the pro- tocol. YWL performed the experiment. CST and YPL worked for the clinical interpretation. CCL and YWL worked for the data analysis. CCL and YPL worked for writing drafts of the manuscript. All authors contributed to editorial changes in the manuscript. All au- thors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.
Ethics approval had been granted by the Laboratory Animal Center from the National Defense Medical Center, Taiwan (IACUC-15-054).
Not applicable.
This study was supported by grants from Ministry of Science and Technology (MOST 111-2410-H-350-001, MOST 108-2410-H-350-001-MY2) and Cheng Hsin General Hospital and National Defense Medical Center (CH-NDMC-108-9, CH-NDMC-109-7, CH-NDMC-110-9, CH-NDMC-111-09) of Taiwan.
Che-Se Tung is serving as one of the Editorial Board members of this journal. We declare that Che-Se Tung had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Gernot Riedel. The other authors declare no conflict of interest.
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