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. 2023 Jun 5;24(11):9773.
doi: 10.3390/ijms24119773.

Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats

Sevag Hamamah  1 , Andras Hajnal  2 , Mihai Covasa  1   3
Affiliations

Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats

Sevag Hamamah et al. Int J Mol Sci. .

Abstract

Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control Long-Evans Tokushima (LETO) rats, OLETF rats have pronounced avidity for over-consuming palatable sweet solutions, have greater dopamine release to psychostimulants, reduced dopamine 2 receptor (D2R) binding, and exhibit increased sensitivity to sucrose reward. This supports altered dopamine function in this strain and its general preference for palatable solutions such as sucrose. In this study, we examined the relationship between OLETF's hyperphagic behavior and striatal dopamine signaling by investigating basal and amphetamine stimulated motor activity in prediabetic OLETF rats before and after access to sucrose solution (0.3 M) compared to non-mutant control LETO rats, as well as availability of dopamine transporter (DAT) using autoradiography. In the sucrose tests, one group of OLETF rats received ad libitum access to sucrose while the other group received an amount of sucrose equal to that consumed by the LETO. OLETFs with ad libitum access consumed significantly more sucrose than LETOs. Sucrose exerted a biphasic effect on basal activity in both strains, i.e., reduced activity for 1 week followed by increased activity in weeks 2 and 3. Basal locomotor activity was reduced (-17%) in OLETFs prior to sucrose, compared to LETOs. Withdrawal of sucrose resulted in increased locomotor activity in both strains. The magnitude of this effect was greater in OLETFs and the activity was increased in restricted compared to ad-libitum-access OLETFs. Sucrose access augmented AMPH-responses in both strains with a greater sensitization to AMPH during week 1, an effect that was a function of the amount of sucrose consumed. One week of sucrose withdrawal sensitized AMPH-induced ambulatory activity in both strains. In OLETF with restricted access to sucrose, withdrawal resulted in no further sensitization to AMPH. DAT availability in the nucleus accumbens shell was significantly reduced in OLETF compared with aged-matched LETO. Together, these findings show that OLETF rats have reduced basal DA transmission and a heightened response to natural and pharmacological stimulation.

Keywords: OLETF; amphetamine; dopamine; locomotor activity; obesity; sucrose.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Baseline locomotor activity prior to sucrose administration (A). Prior to sucrose administration ambulatory distance was measured in OLETF and LETO rats over 1 min intervals in daily 20 min sessions (pooled data for the 3 sessions are shown). (B) Ambulatory distance over a 20 min period in the 3 experimental groups (LETO, OLETF ad lib, and OLETF restricted rats) prior to sucrose administration (red bars), 1 week after sucrose administration (green bars), and 3 weeks after sucrose administration (dark blue bars), as well as 1 week after the commencement of a sucrose withdrawal period. The percentage values overlayed on the bars represent comparisons to the LETO rats’ baseline activity. * p < 0.01, # p < 0.05.
Figure 2
Figure 2
Ambulatory distance in response to AMPH administration (0.5 mg/kg) over a 5 min period prior to sucrose administration, 1 week after sucrose administration, 3 weeks after sucrose administration, and 1 week after the first week withdrawal between LETO, OLETF ad lib, and OLETF restricted rats. (A) Horizontal activity in response to AMPH and saline vehicle in the LETO, OLETF ad lib, and OLETF restricted rats. The percentage values overlayed on the bars represent comparisons to saline injections. (B) Changes in horizontal activity 15 min after AMPH. * LETO compared to OLETF and OLETF restricted; # OLETF with ad libitum sucrose compared with OLETF with restricted sucrose access.
Figure 3
Figure 3
DAT binding assays. (A) DAT labeled 125I-RTI-55 binding absolute density values (nCi/mg tissue equivalent) for OLETF and LETO, respectively, are as follows: NAcc shell; NAcc core; dorsal lateral striatum (DLS); ventral tegmental area (VTA); pars compacta of substantia nigra (SNpc). (B) Correlation between DAT binding and body weight. Correlation between DAT binding and body weight in OLETF (circled with dashed red line) and LETO rats. Regression line is for all data points denoting a significant negative correlation. R = −0.745, p < 0.001. * denotes statistical significance.
Figure 4
Figure 4
Sucrose and chow intake and changes in body weight over 20 days in OLETF ad libitum fed, OLETF restricted sucrose fed, and LETO sucrose fed rats and 5 days of sucrose withdrawal. (A) Sucrose intake (mL/24 h); (B) chow intake (g/24 h); (C) change in body weight (percent of baseline).
Figure 5
Figure 5
Blood glucose (mmol/L), insulin (ng/mL), leptin (ng/mL), and corticosterone (ng/mL) values in relatively age-matched OLETF and LETO rats. * Statistically different between strains (p < 0.05).
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