Sex differences in sucrose-induced locomotor sensitization and cross-sensitization with the D2/D3 agonist quinpirole in rats

doi:10.21203/rs.3.rs-5004624/v1

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Sex differences in sucrose-induced locomotor sensitization and cross-sensitization with the D2/D3 agonist quinpirole in rats

https://doi.org/10.21203/rs.3.rs-5004624/v1

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Background: Female-biased sex differences are known to exist in the prevalence of eating-related disorders and the experience of food cravings. Similarly, in rodents, females display a greater preference and motivation for the highly palatable sweet food, sucrose, than do males. Locomotor sensitization, the increase in locomotor activity that occurs with repeated administrations of drugs of abuse, is thought to occur through drug-induced sensitization of the mesolimbic dopamine pathway and reflect enhancements in drug craving. Pre-exposure to sucrose has been shown to enhance locomotor sensitization induced by dopaminergic agonists, however, it is unknown if sex differences exist in this effect.

Methods: Female (n = 16) and male (n = 16) Long-Evans rats received 30 min daily access to sucrose (0.3 M) or water for nine consecutive days followed by daily administration of the D2/D3 agonist, quinpirole (0.5 mg/kg), for nine consecutive days. On the first, fifth, and ninth day of the sucrose and quinpirole phases, rats were placed in automated activity monitors for 30 min after fluid access and drug administration, respectively, to assess locomotor activity. Mixed model analyses of variance were used to evaluate differences in locomotor activity between Female + Sucrose, Female + Water, Male + Sucrose, and Male + Water treated rats.

Results: Female + Sucrose rats showed significantly greater weight-adjusted fluid consumption of sucrose than did Male + Sucrose rats. Female + Sucrose rats exhibited a significant increase in locomotor activity across the sucrose phase and significantly greater locomotor activity relative to other groups. In the quinpirole phase, both groups pre-exposed to sucrose (Female + Sucrose, Male + Sucrose) showed greater activity than their same-sex control pre-exposed to water (Female + Water, Male + Water). Further, both female groups generally displayed greater activity than both male groups in the quinpirole phase.

Conclusions: A female-biased sex difference was identified in the effect of locomotor sensitization induced by sucrose (0.3 M), but not for sucrose pre-exposure on quinpirole sensitization (0.5 mg/kg). These results suggest that differences may exist between sexes in the mesolimbic response to sucrose, perhaps underlying sex differences in food cravings and eating-related disorder prevalence.

sucrose

mesolimbic dopamine pathway

sex differences

dopamine agonist

locomotor activity

Highly palatable foods like sugar and fat activate the same brain pathway as addictive drugs – the mesolimbic dopamine pathway. Drug-induced activation of this pathway is thought to be involved in drug craving in addiction. While ‘food addiction’ is not currently considered a mental health disorder like drug addiction, similarities between highly palatable foods and addictive drugs has led to certain foods being considered ‘addictive’. Compared to men, women have a greater prevalence of eating-related disorders and preference for sweet foods, and experience more intense food cravings. Similarly, in animal models, female rats show a greater preference for and motivation to obtain sweet solutions than do males – suggesting that sex differences in sweet food preferences and cravings in humans may be biologically-based. A behaviour for investigating drug-related craving in animals is locomotor sensitization – the increase in locomotor activity that occurs with drug-induced activation of the mesolimbic dopamine pathway. Highly palatable foods enhance the effect of drug-induced sensitization, however sex differences in this effect have not been explored. The present experiment evaluated sex differences in locomotor sensitization induced by sucrose (table sugar) and its enhancement of drug-induced sensitization. It was found that female rats displayed a greater effect of sucrose sensitization than males, suggesting that a sex difference may exist in the response of the mesolimbic pathway to highly palatable foods and perhaps underlie the sex differences observed in humans. This experiment contributed to a better understanding of the interaction of highly palatable foods and addictive drugs, and described sex differences therein.

Locomotor sensitization is a useful behavioural index of drug-induced neuroadaptations related to drug craving in rodents.
In humans, women have a greater prevalence of eating-related disorders, experience stronger food cravings, and have a greater preference for sweet foods than do men.
The present experiment investigated sex differences in locomotor sensitization induced by sucrose (0.3 M) and its cross-sensitization with quinpirole, a D2/D3 agonist.
Sucrose induced an effect of locomotor sensitization in female rats, but not males. In both males and females, pre-exposure to sucrose enhanced quinpirole sensitization.
These results suggest that sex differences in sweet food cravings and preferences may be attributable to differences in the response of craving-related brain systems to sweet foods.

In rodents, the repeated administration of common drugs of abuse produces an increase in extracellular dopamine (DA) at the nucleus accumbens (NAcc) and induces a sensitization of locomotor activity [1–3]. The development of locomotor sensitization is thought to depend on drug-induced sensitization of the mesolimbic dopamine pathway and thus serves as a useful behavioural index of the neuroadaptations underlying drug craving in addiction [2, 4, 5]. Natural rewards, such as highly palatable foods (sugar, fat), produce an increase in extracellular DA at the NAcc [6, 7] and enhance the sensitization of locomotor activity induced by drugs of abuse [8–10], suggesting that the motivational functions of the mesolimbic DA pathway are common to both natural and drug rewards. Though typically implicated in the pathology of drug-related addiction, the overlap in function between natural and drug reward in the mesolimbic DA pathway suggests that this pathway may also be involved in mediating the pathological motivational processes in addictions to natural reward.

Sex differences are known to exist in both the prevalence of eating-related disorders and relevant features of food addiction, such as food cravings and preferences. Globally, women have a higher prevalence of both obesity and binge-eating disorder than men [11, 12]. Women are also thought to experience stronger and more frequent food cravings [13–15] and have greater difficulty regulating cravings [14, 16]. The types of food that men and women prefer are also thought to differ – women report a greater preference for sweet foods [17, 18] and are more likely to exceed recommended total sugar intake than men [19].

Sex differences in food preferences are known to be influenced by sociocultural, environmental, and psychological factors [20] – however, evidence from neuroimaging studies suggests that there may be a biological basis to the sex difference in food craving [16, 21, 22]. Findings from animal studies support the notion of a biologically-based, female-biased sex difference in the preference and motivation for sweet solutions such as sucrose, glucose, and saccharin [23, 24]. Sex differences in rodents, such as that of sucrose taste reactivity [25], are known to be modulated by estrous cycling in females and may reflect differences in the organizational and activational effects of sex hormones on mesolimbic DA transmission [26].

An area of research that has focused mainly on male subjects is that of sucrose-facilitated enhancement of drug-induced locomotor sensitization [8, 9, 27]. Cross-sensitization – the enhancement of drug-induced locomotor sensitization through the co-administration of another sensitizing substance – has been demonstrated with sucrose on locomotor sensitization induced by amphetamine [8], cocaine [9], and the D2/D3 agonist, quinpirole [27]. The cross-sensitizing effects of sucrose are thought to be mediated by the induced release of extracellular DA at the NAcc and related to the concentration and period of access to sucrose. Specifically, sucrose-induced NAcc DA release is thought to increase with higher concentrations of sucrose [28] and shorter periods of access to sucrose [29, 30].

Foley et al. [27] investigated the effect of 30 min daily access to sucrose (0.3 M) on quinpirole-induced locomotor sensitization in male rats. Compared to animals pre-exposed to water, those pre-exposed to sucrose for nine days showed greater locomotor activity when administered quinpirole in a later phase [27]. This suggests that nine-day access to sucrose at a concentration of 0.3 M and for a period of 30 min daily is sufficient to produce an increase in NAcc DA release that sensitizes the mesolimbic dopamine pathway – however, sucrose-induced locomotor sensitization has not been compared between female and male rats. Further, while female-biased sex differences are known to exist in the basal effects of quinpirole – evoked striatal DA release [31] and locomotor sensitization [32, 33] – sex differences in sucrose-quinpirole cross-sensitization have not been evaluated.

In the context of food addiction, the identification of sex differences in the mesolimbic response to sucrose could help to explain the female-biased sex differences that exist in the preference for sweet foods, experience of food cravings, and prevalence of eating-related disorders in humans. The goal of this study was to determine if sex differences exist in: (1) sucrose-induced locomotor sensitization, and (2) sucrose-quinpirole cross-sensitization.

2.1 Animals

Adult female Long-Evans rats (n = 16, 258–316 g, 16 weeks of age) and age-matched adult male Long-Evans rats (n = 16, 318–419 g) were used in separate, sex-specific cohorts (Charles River). Animals were pair-housed in standard translucent propylene cages (45 x 22 x 20 cm) in a colony room with a 12:12 light/dark cycle maintained at 21 ± 1°C. At all times except when specified and during testing sessions, animals had ad libitum access to rat chow (ProLab RMH3000) and tap water. Following arrival, animals adjusted for one week in the colony room prior to four consecutive days of handling. During handling, animals were given number markings on their tails with a non-toxic marker. All experimental procedures were carried out in accordance with the guidelines set forth by the Canadian Council of Animal Care and were approved by the Institutional Animal Care Committee.

2.2 Drugs

Tap water was used in drinking boxes for water deprivation adaptation and for the animals receiving water in the sucrose phase. Tap water was used in all home cage bottles for water access during the sucrose phase. For the sucrose solution, granulated table sugar (Lantic Inc., Canada) was dissolved in distilled water to a concentration of 0.3 M. Quinpirole hydrochloride (Tocris, Catalogue number: 1061, CAS number: 85798-08-9) was dissolved in NaCl (0.9%) to a concentration of 0.5 mg/ml. Quinpirole was administered subcutaneously at a dose of 0.5 mg/kg (1 ml/kg). The dose of quinpirole used was based on the results of prior studies evaluating sensitization and sex differences [27, 32].

2.3 Procedure

The procedures followed in the sucrose and quinpirole phases of the study are shown in Fig. 1.

Water Restriction Adaptation

Animals were first adapted to a water restriction schedule through five consecutive days of decreasing water access. Water bottles were removed from home cages and animals were placed in Plexiglas drinking boxes for water access twice per day. In each of the two daily water access sessions, animals were given access to water for 1 hr, 1 hr, 45 min, 40 min, and 30 min on adaptation days 1 through 5, respectively. Following the first drinking session on adaptation days 4 and 5, animals were placed in activity monitors for 30 min. Drinking sessions were started in the morning of each day in the procedure.

Sucrose (S) Phase

Following adaptation to water restriction, animals were given 30 min daily access to sucrose (0.3 M ~ 10.3%) or water for nine consecutive days in drinking boxes. Drinking sessions and activity testing was started in the morning of each day in the procedure. Sucrose has been shown to enhance quinpirole-induced sensitization in male rats at 0.3 M [27] and produce sex differences in preference and operant responding at 10% (0.29 M) [24]. On days 1, 5, and 9 of the sucrose phase (S1, S5, S9), locomotor activity was assessed for 30 min following fluid access. Immediately following fluid access and prior to locomotor activity assessment, animals were placed in home cages on a cart in the locomotor activity room for 30 min to adjust to the bright lights of the room. At the end of the procedure each day (i.e., after drinking box sessions or activity assessment), animals were returned to the colony rooms and given 1 hr access to water in their pair-housed home cages. In a previous investigation [27], individually-housed animals were given 30 min access to water in home cages at the end of the procedure each day. In the present study, animals were pair-housed – home cage water access time was doubled from 30 min to 1 hr to account for pair-housing. Importantly, as the animals were pair-housed, the amount of water that each animal consumed in home cage water access could not be determined. Fluid consumption in home cage water access was recorded for each pair to ensure the animals were sufficiently hydrated, consistent with institutional guidelines for animal care. At the end of the procedure on day 9, water access was returned to ad libitum for the remainder of the experiment. Animals were then given three days in the colony room home cages to adjust to ad libitum water access before the experimental procedure continued.

Quinpirole (Q) Phase

Following the ad libitum adjustment period, animals were given daily injections of quinpirole (0.5 mg/kg, 0.5 mg/ml, s.q.) for nine consecutive days. Quinpirole at a dose of 0.5 mg/kg has been shown to produce sex differences in locomotor sensitization [32] and induces sensitization that is enhanced through pre-exposure to sucrose [27]. On days 1, 5, and 9 of the quinpirole phase (Q1, Q5, Q9), locomotor activity was assessed for 30 min following drug administration. Animals were given 30 min immediately following drug administration to adjust to the locomotor activity room prior to activity assessment. Drug administration and activity testing were carried out in the morning of each day in the procedure.

Vaginal Cytology

Vaginal cytology was assessed in female rats (n = 16) on the first three and last three days of each phase (S-Phase: S1-S3, S7-S9; Q-Phase: Q1-Q3, Q7-Q9). Consistent with recommended techniques [34], vaginal swabbing was performed with wetted, sterile cotton-tipped swabs and contents were transferred to a glass microscopy slide for analysis. EstrousNet, an automated deep learning network was used to classify estrous cycle stages [35]. EstrousNet classification has been reported to be more accurate than human classification and shows high accuracy across animal species and strains [35]. Microscopy slides were photographed through a light microscope with a 12MP smartphone camera (Apple iPhone SE, 2020) and examined via the EstrousNet GUI program in MATLAB Online (2023). See Additional File 1 for EstrousNet classification data.

2.4 Apparatus

Drinking Apparatus

Eight clear Plexiglas boxes (45 x 22 x 20 cm) and lids with air holes were used as drinking boxes. Drinking bottles were mounted through a hole in the box wall with the drinking spout located 8 cm above the box floor. Bottles were weighed before and after each drinking session to calculate the amount of fluid consumed. Animals were acclimated to the drinking boxes over five days of water access in the drinking boxes during the water restriction adaptation phase.

Locomotor Activity Apparatus

Eight VersaMax Animal Activity Monitors (AccuScan Model DCM-8) were used to measure locomotor activity variables. VersaMax chambers consisted of a clear Plexiglas box (40 x 40 x 30.5 cm) and lid with air holes surrounded on each side by 16 infrared beam sensors (2.54 cm apart, 4.5 cm above chamber floor) to measure horizontal activity and 16 infrared beam sensors on two opposite sides (2.54 cm apart, 15 cm above chamber floor) to measure vertical activity. Animals were acclimated to the activity monitors for 30 min on days 4 and 5 of the water restriction adaptation phase. Activity assessment with the VersaMax system has been shown to be both valid [36] and reliable [37, 38]

2.5 Behavioural Measures

Fluid Intake Measures

Volume fluid intake was calculated as the difference in drinking bottle weight before and after a drinking session. Both absolute (ml) and weighted (ml/100g body weight) measures of fluid intake were used. See Additional File 2 for fluid intake data.

Locomotor Activity Measures

Locomotor variables of interest included Total Distance (TD, cm, total path-dependent horizontal activity distance), Number of Horizontal Movements (NHM, number of horizontal movements separated by a rest period of at least 1 sec), and Number of Vertical Movements (NVM, number of vertical movements separated by a period of at least 1 sec below the vertical sensors). In each activity session, locomotor activity data was collected in six consecutive 5 min blocks for a total sample duration of 30 min (1st, 0–5 min; 2nd, 5–10 min; 3rd, 10–15 min; 4th, 15–20 min; 5th, 20–25 min; 6th, 25–30 min). In S-Phase activity measures, animals showed a decrease in activity from 0 min to 10 min, after which activity normalized for the remainder of the session. The 1st and 2nd time blocks were removed from all S-Phase analyses so as to identify differences in activity after normalization. The sum of time blocks (S-Phase: 3rd, 4th, 5th, 6th; Q-Phase: 1st, 2nd, 3rd, 4th, 5th, 6th) were used to establish a session total for each day which was then compared between groups and across sessions. See Additional File 3 for locomotor activity data.

2.6 Statistical Analysis

Mixed model analyses of variance (ANOVA) from the afex package [39] were used to evaluate differences in activity and fluid consumption through the experiment. Within-subjects factors included S-Phase Activity Day (3 levels: S1, S5, S9), Q-Phase Activity Day (3 levels: Q1, Q5, Q9) Activity Time Block (S-Phase: 4 levels: 15 min, 20 min, 25 min, 30 min; Q-Phase: 6 levels: 5 min, 10 min, 15 min, 20 min, 25 min, 30 min) and Fluid Consumption Day (9 levels: S1-S9). The between-subjects factor for all models were Sex (2 levels: male, female) and Fluid (2 levels: sucrose, water). Greenhouse-Geisser corrections were applied to the degrees of freedom and F-test p-values of within-subjects effects and interaction effects where Mauchly’s Test of Sphericity was violated. Estimated marginal means were calculated with the emmeans package [40] for the between-subject factors, establishing four groups: Female-Sucrose (F-S), Female-Water (F-W), Male-Sucrose (M-S), Male-Water (M-W). Tukey’s HSD post hoc tests were used to evaluate differences between groups for all of the models. All statistical analyses and visualizations were performed using R Statistical Software [41].

On Q5, an error in the VersaMax system disrupted the collection of data for the M-S group. After 20 min in the VersaMax chambers, locomotor activity data collection was restarted for an additional 30 min to collect the full sample of data. There were two instances of missing fluid consumption data: one F-S rat on S6 and one M-W rat on S7. Mean substitution was performed for these two cases of missing data using the fluid consumption means derived from their respective groups (i.e., F-S S6 mean and M-W S7 mean).

3.1 Vaginal Cytology

The distribution of estrous cycle stage in female rats is shown in Fig. 2.

EstrousNet classification of estrous cycle staging revealed a generally even distribution of stages across the experiment and evidence of estrous cycling in female rats.

3.2 Fluid Consumption

Absolute Fluid Consumption

A 2 x 2 x 9 ANOVA was used to evaluate absolute fluid consumption between groups across nine days of fluid access (Table 1; Fig. 3). For S2 through S9, F-S rats consumed significantly more fluid than F-W rats (S2-S8: all p’s < .001; S9: p < .05). M-S rats did not significantly differ in fluid consumption compared to M-W rats, except on S1 where M-W rats consumed more fluid than M-S rats (p < .001). F-S rats consumed more fluid than M-S rats on S1 (p < .001) and S6 (p < .05).

Weighted Fluid Consumption

A 2 x 2 x 9 ANOVA was used to evaluate weighted fluid consumption (ml per 100g body weight) between groups across nine days of fluid access (Table 1; Fig. 3). F-S rats displayed greater weighted fluid consumption than M-S rats on all fluid access days (S1, S3-S6: p < .001; S2, S7-S9: p < .01). F-S rats displayed greater weight-adjusted fluid consumption than F-W rats on S2-S9 (S2-S8: p < .001; S9: p < .01). M-S rats did not significantly differ in weight-adjusted fluid consumption compared to M-W rats, except on S1 where M-W rats consumed significantly more fluid than M-S rats (p < .001).

Summary of Results

Female rats given sucrose consumed significantly more fluid (ml) than females given water. Male rats given sucrose did not consume more fluid (ml) than males given water. Female rats given sucrose showed significantly greater weight-adjusted fluid consumption (ml/100g body weight) than males given sucrose.

Table 1

Fluid Consumption
Effect	df	F	p	η²_p
Absolute Fluid Consumption
Sex	1, 28	24.08	< .001	.462
Fluid	1, 28	27.20	< .001	.493
Sex × Fluid	1, 28	52.64	< .001	.653
Day	5.88, 164.74	42.61	< .001	.603
Sex × Day	5.88, 164.74	6.36	< .001	.185
Fluid × Day	5.88, 164.74	21.12	< .001	.430
Weighted Fluid Consumption
Sex	1, 28	17.86	< .001	.389
Fluid	1, 28	28.56	< .001	.505
Sex × Fluid	1, 28	44.46	< .001	.614
Day	5.87, 164.43	35.80	< .001	.561
Sex × Day	5.87, 164.43	4.67	< .001	.143
Fluid × Day	5.87, 164.43	20.33	< .001	.421

3.3 S-Phase Locomotor Activity

Total Distance (TD)

A 2 x 2 x 3 ANOVA was used to evaluate differences in total distance (TD, cm) between groups across S1, S5, and S9 (Table 2; Fig. 4). F-S rats displayed a greater TD than M-S rats on S1 (p < .001), S5 (p = 0.059) and S9 (p < .001), and F-W rats on S9 (p < .01). M-S rats did not significantly differ from M-W rats in TD on S1, S5, and S9 (all p’s > .05). Across days, F-S rats showed an increase in TD from S5 to S9 (p < .05) while other groups did not significantly differ.

A series of 2 x 2 x 4 ANOVAs were used to evaluate differences in total distance (TD, cm) between groups across time blocks on S1, S5, and S9 (Table 2; Fig. 4). On S1, F-S rats travelled a greater TD than M-S rats at 15 min (p < .01), 20 min (p < .01), and 25 min (p < .001). On S5, F-S rats travelled a greater TD than M-S rats at 30 min (p < .05) and F-W rats at 20 min (p < .05). On S9, F-S rats travelled a greater TD than M-S rats at 20 min (p < .05), 25 min (p < .05), and 30 min (p < .01), and F-W rats at 15 min (p < .05), 20 min (p < .05), and 30 min (p < .01). M-S rats did not significantly differ from M-W rats in TD for any time block on S1, S5, and S9 (all p’s > .05).

Summary of Results

Female rats given sucrose, but not other groups, showed a significant increase in total distance. Female rats given sucrose showed significantly greater total distance than males given sucrose and females given water. Male rats given sucrose did not significantly differ in total distance from males given water.

Table 2

S-Phase Total Distance (TD)
Effect	df	F	p	η²_p
S-Phase TD
Sex	1, 28	19.91	< .001	.416
Fluid	1, 28	5.83	.023	.172
Sex × Day	1.78, 49.87	6.68	.004	.193
S1 TD
Sex	1, 28	33.62	< .001	.546
S9 TD
Sex	1, 28	11.50	.002	.291
Fluid	1, 28	9.14	.005	.246
Sex × Fluid	1, 28	7.75	.009	.217

Number of Horizonal Movements (NHM)

A 2 x 2 x 3 ANOVA was used to evaluate differences in the number of horizontal movements (NHM) between groups across S1, S5, and S9 (Table 3; Fig. 5). F-S rats displayed a greater NHM than M-S rats on S1 (p < .01), S5 (p < .05), and S9 (p < .001), and F-W rats on S5 (p < .01) and S9 (p < .001). M-S rats did not significantly differ from M-W rats in NHM on S1, S5, and S9 (all p’s > .05). Across days, F-S rats showed an increase in NHM from S5 to S9 (p < .05) while other groups did not significantly differ.

A series of 2 x 2 x 4 ANOVAs were used to evaluate differences between groups in the number of horizontal movements (NHM) across time blocks on S1, S5, and S9 (Table 3; Fig. 5). On S1, F-S rats displayed a greater NHM than M-S rats at 15 min (p < .05), 20 min (p < .01), and 25 min (p < .001). On S5, F-S rats displayed a greater NHM than F-W rats at 15 min (p < .05). On S9, F-S rats displayed a greater NHM than M-S rats at all time blocks (15 min, 20 min, 25 min: p < .05; 30 min: p < .01) and F-W rats at 15 min (p < .01) and 30 min (p < .001). M-S rats did not significantly differ from M-W rats in NHM for any time block on S1, S5, and S9 (all p’s > .05).

Summary of Results

Female rats given sucrose, but not other groups, showed a significant increase in number of horizontal movements. Female rats given sucrose showed a significantly greater number of horizontal movements than males given sucrose and females given water. Male rats given sucrose did not significantly differ in number of horizontal movements from males given water.

Table 3

S-Phase Number of Horizontal Movements (NHM)
Effect	df	F	p	η²_p
S-Phase NHM
Sex	1, 28	16.78	< .001	.375
Fluid	1, 28	13.04	.001	.318
Sex × Fluid	1, 28	7.04	.013	.201
Sex × Day	1.83, 51.15	5.72	.007	.170
Sex × Fluid × Day	1.83, 51.15	4.81	.014	.147
S1 NHM
Sex	1, 28	27.19	< .001	.493
Fluid	1, 28	5.70	.024	.169
S5 NHM
Fluid	1, 28	7.04	.013	.201
Sex × Fluid	1, 28	5.72	.024	.170
S9 NHM
Sex	1, 28	10.67	.003	.276
Fluid	1, 28	15.06	< .001	.350
Sex × Fluid	1, 28	12.20	.002	.304

Number of Vertical Movements (NVM)

A 2 x 2 x 3 ANOVA was used to evaluate differences in the number of vertical movements (NVM) between groups across S1, S5, and S9 (Table 4; Fig. 6). F-S rats displayed a greater NVM than M-S rats on S9 (p < .01) and F-W rats on S5 (p < .01) and S9 (p < .001). M-S rats did not significantly differ from M-W rats in NVM on S1, S5, and S9 (all p’s > .05). Across days, F-S rats showed an increase in NVM from S5 to S9 (p < .01) while other groups did not significantly differ.

A series of 2 x 2 x 4 ANOVAs were used to evaluate differences between groups in the number of vertical movements (NVM) across time blocks on S1, S5, and S9 (Table 4; Fig. 6). On S1, F-S rats displayed a greater NVM than M-S rats and F-W at 25 min (M-S: p < .01; F-W: p < .05). On S5, F-S rats displayed a greater NVM than F-W rats at 20 min (p < .05). On S9, F-S rats displayed a greater NVM than M-S rats at 20 min, 25 min, and 30 min (all p’s < .05) and F-W rats at all time blocks (15 min, 25 min: p < .05; 30 min: p < .01; 20 min: p < .001). M-S rats did not significantly differ from M-W rats in NVM for any time block on S1, S5, and S9 (all p’s > .05).

Summary of Results

Female rats given sucrose, but not other groups, showed a significant increase in number of vertical movements. Female rats given sucrose showed a significantly greater number of vertical movements than males given sucrose and females given water. Male rats given sucrose did not significantly differ in number of vertical movements from males given water.

Table 4

S-Phase Number of Vertical Movements (NVM)
Effect	df	F	p	η²_p
S-Phase NVM
Sex	1, 28	6.54	.016	.189
Fluid	1, 28	16.74	< .001	.374
Sex × Fluid	1, 28	5.71	.024	.169
Day	1.83, 51.15	5.42	.009	.162
Fluid × Day	1.83, 51.15	5.62	.008	.167
Sex × Fluid × Day	1.83, 51.15	3.84	.031	.120
S1 NVM
Sex	1, 28	8.87	.006	.241
Fluid	1, 28	5.17	.031	.156
S5 NVM
Fluid	1, 28	10.27	.003	.268
Sex × Fluid	1, 28	4.58	.041	.141
S9 NVM
Sex	1, 28	6.57	.016	.190
Fluid	1, 28	23.84	< .001	.460
Sex × Fluid	1, 28	9.31	.005	.250

3.4 Q-Phase Locomotor Activity

Total Distance (TD)

A 2 x 2 x 3 ANOVA was used to evaluate differences in total distance (TD, cm) between groups across Q1, Q5, and Q9 (Table 5; Fig. 7). F-S rats displayed a greater TD than M-S rats on Q1 (p < .05), Q5 (p < .01) and Q9 (p < .001) and F-S rats on Q5 (p < .05). M-S rats did not significantly differ from M-W rats in TD on Q1, Q5, and Q9 (all p’s > .05). Across days, F-S, F-W, and M-S rats showed an increase in TD from Q1 to Q9 (F-S: p < .001; F-W: p < .001; M-S: p < .01) while M-W rats did not significantly differ (p > .05).

A series of 2 x 2 x 6 ANOVAs were used to evaluate differences in total distance (TD, cm) between groups across time blocks on Q1, Q5, and Q9 (Table 5; Fig. 7). On Q1, F-S rats displayed a greater TD than M-S rats at 5 min 10 min, and 20 min (all p’s < .05). On Q5, F-S rats displayed a greater TD than M-S rats at 15 min (p < .01) and 20 min (p < .001) and F-W rats at 20 min (p < .05). On Q9, F-S rats displayed a greater TD than M-S rats at 5 min (p < .05), 10 min (p < .01), 15 min (p < .01), and 20 min (p < .001). M-S rats did not significantly differ from M-W rats in TD travelled for any time block on Q1, Q5, and Q9 (all p’s > .05).

Summary of Results

All groups except for males pre-exposed to water showed a significant increase in total distance. Females pre-exposed to sucrose displayed significantly greater total distance than males pre-exposed to sucrose and females pre-exposed to water. Male rats pre-exposed to sucrose did not significantly differ in total distance from males pre-exposed to water.

Table 5

Q-Phase Total Distance (TD)
Effect	df	F	p	η²_p
Q-Phase TD
Sex	1, 28	39.05	< .001	.582
Fluid	1, 28	7.23	.012	.205
Day	1.76, 49.17	59.75	< .001	.681
Sex × Day	1.76, 49.17	20.52	< .001	.423
Q1 TD
Sex	1, 28	10.28	.003	.269
Q5 TD
Sex	1, 28	25.09	< .001	.473
Fluid	1, 28	8.90	.006	.241
Block	2.00, 56.06	10.21	< .001	.267
Sex × Block	2.00, 56.06	16.28	< .001	.368
Fluid × Block	2.00, 56.06	4.71	.013	.144
Q9 TD
Sex	1, 28	40.60	< .001	.592
Fluid	1, 28	5.16	.031	.156
Block	3.12, 87.32	26.43	< .001	.486
Sex × Block	3.12, 87.32	19.47	< .001	.410
Fluid × Block	3.12, 87.32	3.81	.012	.120

Horizontal Movement

A 2 x 2 x 3 ANOVA was used to evaluate differences in the number of horizontal movements (NHM) between groups across Q1, Q5, and Q9 (Table 6; Fig. 8). M-S rats displayed a trend towards greater NHM than M-W rats on Q9 (p = 0.06). F-S rats did not significantly differ in NHM compared to M-S rats and F-W rats (all p’s > .05). Across days, M-S rats showed an increase in NHM from Q1 to Q9 (p < .01) while other groups did not significantly differ (all p’s > .05).

A series of 2 x 2 x 6 ANOVAs were used to evaluate differences between groups in the number of horizontal movements (NHM) across time blocks on Q1, Q5, and Q9 (Table 6; Fig. 8). No significant differences in NHM were found on Q1 for any time block (all p’s > .05). On Q5, F-S rats showed a greater NHM than M-S rats at 15 min (p < .05). On Q9, M-S rats displayed a greater NHM than M-W rats at 20 min (p < .05). F-S rats did not significantly differ in NHM compared to M-S rats and F-W rats for any time block on Q9 (all p’s > .05).

Summary of Results

Male rats pre-exposed to sucrose, but not other groups, showed a significant increase in number of horizontal movements. Across Q-Phase days, no significant differences in number of horizontal movements were found between groups.

Table 6

Q-Phase Number of Horizontal Movements (NHM)
Effect	df	F	p	η²_p
Q-Phase NHM
Sex	1, 28	22.80	< .001	.449
Day	1.59, 44.44	20.26	< .001	.420
Q1 NHM
Sex	1, 28	12.97	.001	.317
Block	3.89, 108.87	24.59	< .001	.468
Sex × Block	3.89, 108.87	4.90	.001	.149
Q5 NHM
Sex	1, 28	12.47	.001	.308
Block	2.81, 78.82	7.60	< .001	.214
Q9 NHM
Sex	1, 28	5.99	.021	.176
Sex × Fluid	1, 28	5.54	.026	.165
Block	3.02, 84.56	9.22	< .001	.248

Vertical Movement

A 2 x 2 x 3 ANOVA was used to evaluate differences in the number of vertical movements (NVM) between groups across Q1, Q5, and Q9 (Table 7; Fig. 9). F-S rats displayed a greater NVM than M-S rats on Q1 (p < .05) and Q9 (p < .05). F-S rats did not significantly differ in NVM compared to F-W rats (all p’s > .05). M-S rats did not significantly differ from M-W rats in NVM (all p’s > .05). Across days, F-S, F-W, and M-S rats showed an increase in NVM from Q1 to Q9 (F-S: p < .001; F-W: p < .001; M-S: p < .001) while M-W rats did not significantly differ (p > .05).

A series of 2 x 2 x 6 ANOVAs were used to evaluate differences between groups in the number of vertical movements (NVM) across time block across Q1, Q5, and Q9 (Table 7; Fig. 9). On Q1, F-S rats displayed a greater NVM than M-S rats at 5 min (p < .001) and 10 min (p < .05) and F-W rats at 5 min (p < .001). No significant differences in NVM were found on Q5 for any time block (all p’s > .05). On Q9, F-S rats displayed a greater NVM than M-S rats at 20 min (p < .01). Further, M-S rats displayed a greater NVM than M-W rats at 15 min and 20 min (both p’s < .05). F-S rats did not significantly differ in vertical movement compared to F-W rats for any time block on Q9 (all p’s > .05).

Summary of Results

All groups except males pre-exposed to water showed a significant increase in number of vertical movements. Females pre-exposed to sucrose displayed significantly greater number of vertical movements than males pre-exposed to sucrose.

Table 7

Q-Phase Number of Vertical Movements (NVM)
Effect	df	F	p	η²_p
Q-Phase NVM
Sex	1, 28	17.12	< .001	.379
Fluid	1, 28	8.75	.006	.238
Day	1.48, 41.36	37.89	< .001	.575
Sex × Day	1.48, 41.36	6.27	.008	.183
Fluid × Day	1.48, 41.36	4.87	.021	.148
Q1 NVM
Sex	1, 28	11.94	.002	.299
Q5 NVM
Sex	1, 28	4.77	.037	.146
Fluid	1, 28	8.36	.007	.230
Block	2.13, 59.59	5.36	.006	.161
Sex × Block	2.13, 59.59	13.02	< .001	.317
Sex × Fluid × Block	2.13, 59.59	3.13	.048	.101
Q9 NVM
Sex	1, 28	21.62	< .001	.436
Fluid	1, 28	8.57	.007	.234
Block	3.70, 103.63	19.93	< .001	.416
Sex × Block	3.70, 103.63	8.51	< .001	.233
Fluid × Block	3.70, 103.63	5.64	< .001	.168

The main finding of this study was the identification of sex differences in sucrose-induced locomotor sensitization. Compared to males, females exhibited a robust effect of locomotor sensitization in response to sucrose consumption across nine days of 30 min daily access. Females given access to sucrose showed an increase in locomotor activity and greater levels of activity than males given access to sucrose.

4.1 Fluid Consumption and Sucrose Preference

A sex difference was identified in sucrose consumption across the nine days of fluid access. Females given access to sucrose displayed greater absolute consumption (ml) of fluid than those given access to water, while both male groups (sucrose and water) did not differ in absolute fluid consumption. Further, females given access to sucrose displayed greater weight-adjusted consumption (ml/100 g body weight) than males given access to sucrose. Together, these results suggest that females may have a greater preference for sucrose (0.3 M) than do males and will consume greater amounts of a sucrose solution than water.

The existence of a female-biased sex difference in the preference for sweet solutions has been well-established [23] and more recently, has been described in the context of sucrose [24]. In a two-bottle choice task of water and sucrose (10% ~ 0.29M), female Long-Evans rats displayed greater weight-adjusted consumption (ml/g body weight) of sucrose than males across a 48-hour period of access to both bottles. Similarly, females displayed greater weight-adjusted consumption of sucrose than males in a daily 1-hour binge-access paradigm across a period of 14 days [24]. In rats receiving intraoral infusions of sucrose (0.3 M), taste reactivity responses have been found to differ between estrous/metestrous females, diestrous/proestrous females, and intact males [25]. This suggests that the estrous stage of females and presumed differences in sex hormone levels may be mediating the sex differences observed in sucrose palatability and preference.

From a translational perspective, similar findings in humans have been described with respect to sex differences in the preference for sweet foods. Across Spanish and American participants, women report greater cravings for sweet foods compared to savoury foods, while men report the opposite [17]. Similarly, American women reported a greater preference for sweet, snack-related comfort foods while men reported a greater preference for savoury, meal-related comfort foods [18]. While not evaluating sweet food preference directly, a UK Biobank analysis revealed greater non-adherence to recommended total sugar intake among women compared to men [19], perhaps reflecting a consumption-related outcome of the female-biased sex difference in sweet food preference. Menstrual cycle regulation of food cravings and preferences in humans has shown inconsistent findings [42, 43].

4.2 Sucrose-Induced Locomotor Sensitization

A sex difference was identified in the effect of sucrose-induced locomotor sensitization. Daily access to sucrose (0.3 M) for 30 min produced an increase in locomotor activity in female rats but not male rats. For female and male groups given access to sucrose, only females displayed greater activity than their same-sex control group given access to water. While females displayed greater activity than males on S1, the female group given access to water displayed levels of activity on S5 and S9 that did not differ from male-sucrose and male-water groups. This suggests that while females show greater baseline activity initially, once sufficiently acclimated to the activity monitors there is not an observable sex difference in locomotor activity. Therefore, the observed effect of sucrose-induced locomotor sensitization in females is presumably due to sucrose access rather than a sex difference in baseline locomotor activity.

Locomotor sensitization is thought to be related to the enhancement of mesolimbic dopamine (DA) signalling induced by daily 30 min access to sucrose. An increase in NAcc extracellular DA is known to be induced by brief periods of sucrose access [30] and blunted in response to ad libitum sucrose access [29]. In animals sham-fed sucrose, the increase in NAcc extracellular DA is comparable to real-fed animals [44] and increases linearly with sucrose concentration [28], suggesting that the increase in NAcc DA is more so related to the period of access and orosensory effects of sucrose rather than its post-ingestive effects. As sensitization is thought to depend on enhanced mesolimbic DA signalling, this suggests that sucrose-induced locomotor sensitization increases with greater concentrations of sucrose and shorter periods of access to sucrose.

A limitation of the sucrose administration procedure in the present study is the free-access, consumption-contingent dosing of sucrose. Since the administration of sucrose and water in the daily 30 min fluid access sessions was dependent on the animals’ motivation to consume the fluid, the dose of sucrose that animals received was uncontrolled. Though females and males consumed similar absolute amounts of sucrose (ml), they differed significantly in their weight-adjusted consumption (ml/100g body weight) of sucrose, resulting in the female-sucrose group receiving a greater dose of sucrose than the male-sucrose group. Given that the increase in NAcc extracellular DA is thought to be more greatly related to the orosensory and access period effects of sucrose consumption rather than its post-ingestive effects, this limitation is somewhat addressed. Both female and male rats received access to the same concentration of sucrose and for the same amount of time each day, suggesting that the factors thought to be most involved in mediating NAcc DA release and locomotor sensitization were effectively controlled for between sexes.

The existence and interaction of potential differences in post-ingestive effects of sucrose on NAcc DA release between sexes cannot be fully excluded from the present study. This limitation could be addressed in a future study where animals are administered the same dose of sucrose through injection, though this may eliminate orosensory and access period effects, or are implanted with a gastric fistula in a sham-feeding paradigm such that possible consumption-contingent, post-ingestive effects of sucrose are eliminated. Furthermore, the incorporation of microdialysis techniques would help to quantify the relationship between sucrose consumption, induced NAcc DA release, and locomotor sensitization.

4.3 Sucrose-Quinpirole Cross-Sensitization

The finding of sucrose-quinpirole cross-sensitization supports the results of a previous investigation by Foley et al. [27] that showed cross-sensitization in male rats. The present study provides evidence that the effect of sucrose-quinpirole cross-sensitization generalizes to female rats. In both sex groups, pre-exposure to sucrose enhanced the development of quinpirole-induced locomotor sensitization. Animals pre-exposed to sucrose showed greater activity levels than their same-sex control group pre-exposed to water. There was not evidence of a sex-specific enhancement of quinpirole sensitization following pre-exposure to sucrose.

Quinpirole produces a dose-dependent, biphasic response with low doses (0.1 mg/kg) facilitating locomotor inhibition and higher doses (0.5 mg/kg) facilitating locomotor excitation [45, 46]. The threshold between hypoactive and hyperactive effects of quinpirole is thought to be 0.125 mg/kg [45] and locomotor sensitizing effects are not found to differ between hyperactive doses of 0.25, 0.5, and 2.5 mg/kg [47]. Sex differences are known to exist in the locomotor responses to quinpirole – females show greater locomotor sensitization to 0.5 mg/kg [32] and reduced suppression to 0.03 and 0.1 mg/kg. [48]. Sex differences in the behavioural responses to quinpirole could be attributable to differences in quinpirole-induced DA release – quinpirole (0.5 mg/kg) administration has been shown to have a greater release of evoked DA in the striatum following electrical stimulation in female rats compared to males [31].

The absence of a clear sex difference in sucrose-quinpirole cross-sensitization suggests that while female-biased sex differences may exist in both sucrose-induced (0.3 M) and quinpirole-induced locomotor sensitization (0.5 mg/kg), there does not exist an interaction in which sucrose pre-exposure differentially enhances quinpirole sensitization between males and females – at least for the doses used in this study. Across sessions in the S-Phase, significant Sex × Fluid × Day interactions were identified whereas in the Q-Phase only Sex × Day and Fluid × Day interactions reached significance. Similarly, within the 30 min sessions in the S-Phase, significant Sex × Fluid interactions were consistently observed across activity measures on S5 and S9 whereas in the Q-Phase this was only observed for Q9 Horizontal Movement. This suggests that the effect of sucrose access on locomotor activity differed between males and females but the enhancing effect of sucrose pre-exposure on quinpirole sensitization was similar between sexes. There are some reasons to consider why Sex × Fluid interactions were not broadly observed in the Q-Phase.

First, quinpirole (0.5 mg/kg) appears to be a more potent activator of the mesolimbic dopamine pathway than sucrose (0.3 M). While sucrose increased the total distance travelled in female-sucrose rats by 34% from the fifth to ninth day of sucrose access, quinpirole increased the total distance travelled in female-water rats by 540% from the first to ninth day of quinpirole administration. It is plausible that the sensitizing effects of quinpirole on the mesolimbic dopamine pathway may have masked sex differences in the effect of sucrose pre-exposure on quinpirole sensitization. Alternatively, potential ceiling effects related to sucrose-induced DA release and quinpirole binding at D2/D3 receptors that may have limited the full expression of locomotor sensitization in the Q-Phase [49, 50].

Second, animals were no longer given access to sucrose during the Q-Phase – they were pre-exposed to sucrose, not concurrently receiving sucrose and quinpirole. Given that sucrose appears to be a weak activator of the mesolimbic pathway, it is possible that its locomotor sensitizing effects are not maintained following the termination of sucrose access. The effect of post-access maintenance of sucrose-induced sensitization was not investigated in the present study – immediately after the end of the sucrose phase, animals were returned to ad libitum water access and began to receive quinpirole. An alternative procedure of cross-sensitization, employing concurrent rather than sequential administration, may reveal sex differences in the enhancing effect of sucrose access on quinpirole sensitization.

Third, only a single concentration of sucrose (0.3 M) was used. Sucrose concentration and total consumption is known to follow an inverted U-shaped curve — intermediate concentrations (10%) are more greatly consumed than low (2.5, 5%) and high concentrations (20%) — however, the size of lick clusters (number of licks between pauses in consumption) has been shown to increase with more concentrated solutions of sucrose [51]. Similarly, sex differences in operant responding for sucrose have been identified at high concentrations, such as 15% and 30% [24]. This suggests that while consumption-based preference may decrease with greater concentrations of sucrose, palatability and motivation to obtain sucrose are maintained at a high concentration, perhaps reflecting the role of concentration-related orosensory effects on the release of NAcc extracellular DA [28]. The use of a more concentrated sucrose solution, such as 15%, 20%, or 30%, may lead to greater post-access maintenance of sucrose sensitization in the Q-Phase and produced sex differences in the effect of sucrose pre-exposure on quinpirole sensitization.

Together, these limitations in the procedure – the use of a single concentration of sucrose and single dose of quinpirole, and their sequential rather than concurrent administration – may explain the absence of significant Sex × Fluid interactions in the Q-Phase. An investigation across multiple concentrations and doses of sucrose and quinpirole is necessary to determine if potential sex differences in sucrose-quinpirole cross-sensitization are dose-dependent. As sex differences in sucrose preference are known to differ between estrous stages in females [25], investigations of estrous cycle and sex hormone effects on sucrose sensitization should be carried out.

4.4 Perspectives and Significance

Female rats showed an effect of sucrose-induced locomotor sensitization that was not observed in males. As the expression of locomotor sensitization is thought to depend on the sensitization of the mesolimbic dopamine pathway, this suggests that a sex difference exists in the mesolimbic response to sucrose. More broadly, these findings suggest that the female-biased sex differences in the experience of food cravings and prevalence of certain eating-related disorders could be attributable, at least in part, to sex differences in the mesolimbic responses to highly palatable foods. This study provides a basis for future investigations that can further evaluate the role of sucrose access and cross-sensitization factors in mediating sex differences in sucrose-induced locomotor sensitization and sucrose-quinpirole cross-sensitization.

Female rats given access to sucrose showed an effect of locomotor sensitization that was not observed in males given access to sucrose. Sex differences in the effect of sucrose pre-exposure on quinpirole sensitization were less clear and warrant further exploration of procedural and dose-related factors in mediating potential sex differences.

Ethics approval and consent to participate

All experimental procedures were performed in accordance with Canadian Council of Animal Care guidelines and were approved by the Institutional Animal Care Committee at the University of Western Ontario.

Consent for publication

Not applicable.

Availability of data and materials

The datasets supporting the conclusions of this article are included within the article (and its additional files).

Competing interests

The authors declare that they have no competing interests.

Funding

Funding for this project was provided by the Natural Science and Engineering Research Council of Canada (NSERC) grants awarded to MK and KPO. VM was supported by the NSERC Canada Graduate Scholarship-Master’s Program scholarship. MH was supported by the Ontario Graduate Scholarship Program. IRB was supported by the NSERC Canada Graduate Scholarship-Doctoral Program.

Author’s contributions

VM collected data, performed analyses, and drafted the manuscript. MH and IRB assisted with the experimental procedures. IRB, MK, and KPO contributed to experimental design and provided feedback on the manuscript. All authors read and approved the final manuscript.

Acknowledgements

Not applicable.

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No competing interests reported.

AdditionalFile1.csv
Additional File 1 Format: .csv Title: Estrous Stage Data Description: Estrous cycle stage for each female rat on S1-S3, S7-S9, Q1-Q3, and Q7-Q9 classified using the automated EstrousNet deep learning network.
AdditionalFile2.csv
Additional File 2 Format: .csv Title: Fluid Intake Data Description: Absolute (ml, a) and weighted (ml/100g body weight, w) fluid consumption in drinking boxes for each rat on S1-S9.
AdditionalFile3.csv
Additional File 3 Format: .csv Title: Locomotor Activity Data Description: Total Distance (TD), Number of Horizontal Movements (NHM), and Number of Vertical Movements (NVM) for each rat on each of the six 5 min time blocks on S1, S5, S9, Q1, Q5, and Q9.

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Sex differences in sucrose-induced locomotor sensitization and cross-sensitization with the D2/D3 agonist quinpirole in rats

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Abstract

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Plain English Summary

Highlights

1. BACKGROUND

2. METHODS

2.1 Animals

2.2 Drugs

2.3 Procedure

2.4 Apparatus

2.5 Behavioural Measures

2.6 Statistical Analysis

3. RESULTS

3.1 Vaginal Cytology

3.2 Fluid Consumption

3.3 S-Phase Locomotor Activity

Number of Horizonal Movements (NHM)

Number of Vertical Movements (NVM)

3.4 Q-Phase Locomotor Activity

Horizontal Movement

Vertical Movement

4. DISCUSSION

4.1 Fluid Consumption and Sucrose Preference

4.2 Sucrose-Induced Locomotor Sensitization

4.3 Sucrose-Quinpirole Cross-Sensitization

4.4 Perspectives and Significance

5. CONCLUSIONS

Declarations

Ethics approval and consent to participate

Consent for publication

Availability of data and materials

Competing interests

Funding

Author’s contributions

Acknowledgements

References

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Supplementary Files

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