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. 2021 Jan 25;9(2):112.
doi: 10.3390/biomedicines9020112.

Kisspeptin-8 Induces Anxiety-Like Behavior and Hypolocomotion by Activating the HPA Axis and Increasing GABA Release in the Nucleus Accumbens in Rats

Katalin Eszter Ibos  1 , Éva Bodnár  1 , Zsolt Bagosi  1 , Zsolt Bozsó  2 , Gábor Tóth  2 , Gyula Szabó  3 , Krisztina Csabafi  1
Affiliations

Kisspeptin-8 Induces Anxiety-Like Behavior and Hypolocomotion by Activating the HPA Axis and Increasing GABA Release in the Nucleus Accumbens in Rats

Katalin Eszter Ibos et al. Biomedicines. .

Abstract

Kisspeptins (Kp) are RF-amide neuropeptide regulators of the reproductive axis that also influence anxiety, locomotion, and metabolism. We aimed to investigate the effects of intracerebroventricular Kp-8 (an N-terminally truncated octapeptide) treatment in Wistar rats. Elevated plus maze (EPM), computerized open field (OF), and marble burying (MB) tests were performed for the assessment of behavior. Serum LH and corticosterone levels were determined to assess kisspeptin1 receptor (Kiss1r) activation and hypothalamic-pituitary-adrenal axis (HPA) stimulation, respectively. GABA release from the nucleus accumbens (NAc) and dopamine release from the ventral tegmental area (VTA) and NAc were measured via ex vivo superfusion. Kp-8 decreased open arm time and entries in EPM, and also raised corticosterone concentration, pointing to an anxiogenic effect. Moreover, the decrease in arm entries in EPM, the delayed increase in immobility accompanied by reduced ambulatory activity in OF, and the reduction in interactions with marbles show that Kp-8 suppressed exploratory and spontaneous locomotion. The increase in GABA release from the NAc might be in the background of hypolocomotion by inhibiting the VTA-NAc dopaminergic circuitry. As Kp-8 raised LH concentration, it could activate Kiss1r and stimulate the reproductive axis. As Kiss1r is associated with hyperlocomotion, it is more likely that neuropeptide FF receptor activation is involved in the suppression of locomotor activity.

Keywords: HPA axis; HPG axis; Kiss1 receptor; anxiety; kisspeptin; locomotion; nucleus accumbens.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure A1
Figure A1
HPLC trace of Kisspeptin-8. Column: Phenomenex Luna C18, 5 μ, 100 Å, 4.6 mm × 250 mm, flow rate: 1 mL/min, wavelength: 220 nm, A eluent: 0.1% TFA in water, B eluent: 0.1% TFA/80% ACN/water, gradient: 30–55% eluent B in eluent A over 25 min.
Figure A2
Figure A2
The ESI-MS trace of Kp-8 peptide.
Figure A3
Figure A3
Cumulative data of 60-min open field test: (a) total distance of ambulation, (b) total time of ambulation, (c) total time spent immobile, (d) number of rearings, (e) percentage of distance travelled in the central zone, (f) percentage of time spent in the central zone, n = 12–13.
Figure 1
Figure 1
Elevated plus maze results: (a) percentage of entries into open arms, (b) percentage of time spent in the open arms, (c) total number of entries into arms, (d) total time spent in the arms of the maze, n = 7–9, * p < 0.05 vs. control, ** p < 0.01 vs. control.
Figure 2
Figure 2
Open field test results in 5-min intervals: (a) total distance travelled in the arena, (b) total ambulation time. The color of * refers to the treatment group which significantly differs from the control group. n = 12–13, * p < 0.05 vs. control, ** p < 0.01 vs. control.
Figure 3
Figure 3
Open field test results in 5-min intervals: (a) total time spent immobile, (b) total number of rearings. The color of * refers to the treatment group which significantly differs from the control group. n = 12–13, * p < 0.05 vs. control.
Figure 4
Figure 4
Open field test results in 5-min intervals: (a) percentage of distance travelled in the central zone of the arena, (b) percentage of time spent in the central zone of the arena, (c) average velocity of ambulation. The color of * refers to the treatment group which significantly differs from the control group. n = 12–13, * p < 0.05 vs. control.
Figure 5
Figure 5
Results of marble burying test: (a) number of buried marbles (at least 50% covered with bedding material), (b) number of marble burying sessions, (c) duration of marble burying activity, n = 9–10.
Figure 6
Figure 6
Results of marble burying test: (a) number of marble moving sessions, (b) duration of marble moving activity, (c) total number of interactions with marbles, (d) total duration of interactions with marbles, * p < 0.05 vs. control. n = 9–10.
Figure 7
Figure 7
ELISA results: (a) serum corticosterone concentration (pg/mL), n = 4–5, ** p < 0.01 vs. control, (b) serum LH concentration (mIU/mL), n = 4–9, ** p < 0.01 vs. control.
Figure 8
Figure 8
Fractional dopamine release from the ventral tegmental area. n = 4–5.
Figure 9
Figure 9
Fractional dopamine release from the nucleus accumbens. n = 7–8.
Figure 10
Figure 10
Fractional GABA release from the nucleus accumbens. ** p < 0.01 vs. control, n = 5.
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