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. 2016 Oct 4;6(10):e911.
doi: 10.1038/tp.2016.176.

Enhanced sensitivity to drugs of abuse and palatable foods following maternal overnutrition

D Peleg-Raibstein  1 , G Sarker  1 , K Litwan  1 , S D Krämer  2 , S M Ametamey  2 , R Schibli  2 , C Wolfrum  1
Affiliations

Enhanced sensitivity to drugs of abuse and palatable foods following maternal overnutrition

D Peleg-Raibstein et al. Transl Psychiatry. .

Abstract

Epidemiological studies have shown an association between maternal overnutrition and increased risk of the progeny for the development of obesity as well as psychiatric disorders. Animal studies have shown results regarding maternal high-fat diet (HFD) and a greater risk of the offspring to develop obesity. However, it still remains unknown whether maternal HFD can program the central reward system in such a way that it will imprint long-term changes that will predispose the offspring to addictive-like behaviors that may lead to obesity. We exposed female dams to either laboratory chow or HFD for a period of 9 weeks: 3 weeks before conception, during gestation and lactation. Offspring born to either control or HFD-exposed dams were examined in behavioral, neurochemical, neuroanatomical, metabolic and positron emission tomography (PET) scan tests. Our results demonstrate that HFD offspring compared with controls consume more alcohol, exhibit increased sensitivity to amphetamine and show greater conditioned place preference to cocaine. In addition, maternal HFD leads to increased preference to sucrose as well as to HFD while leaving the general feeding behavior intact. The hedonic behavioral alterations are accompanied by reduction of striatal dopamine and by increased dopamine 2 receptors in the same brain region as evaluated by post-mortem neurochemical, immunohistochemical as well as PET analyses. Taken together, our data suggest that maternal overnutrition predisposes the offspring to develop hedonic-like behaviors to both drugs of abuse as well as palatable foods and that these types of behaviors may share common neuronal underlying mechanisms that can lead to obesity.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Offspring born to mouse dams exposed to maternal HFD develop a mild metabolic phenotype. (a) Schematic diagram illustrating the maternal HFD model employed. (b) Body weight development in HFD compared with control offspring. The scatter plot to the right show the sex differences between female and male offspring. Control N=92m and 52f and HFD N=64m and 43f. (c, d) Fat composition and distribution measured by CT-Scan in HFD and control offspring. (e–i) Metabolic parameters measured from blood samples taken from adult HFD and control offspring at PND 120. CT, computerized tomography; CTR, control; f, female; FFA, free fatty acid; HFD, high-fat diet; m, male; PND, postnatal day. N=9 m per group; *P<0.05, ***P<0.0001.
Figure 2
Figure 2
Offspring born to mouse dams exposed to maternal high-fat diet (HFD) show increased preference and consumption of palatable foods and drugs of abuse. (a) High-fat food preference test: mice from both groups were offered the choice between HFD and normal chow. N=(6m, 6f) per group. (b) Sucrose consumption test: in a free-choice protocol mice could choose either water or an ascending series of sucrose concentrations (1, 2 and 3%). The bar graph to the right show the sex differences between female and male offspring. N=16 (8m, 8f) per group. (c) Saccharine consumption test: animals were exposed to a free-choice protocol in which mice could choose either water or an ascending series of saccharine concentrations (0.5 and 1%). N=10 m per group. (d) Alcohol consumption test: animals were exposed to a free-choice protocol in which mice could choose either water or an ascending series of alcohol concentrations (2, 5 and 8%). N=10 m per group. (e) Conditioned place preference (CPP): measurement of conditioned place preference for cocaine in HFD compared with control offspring. N=48 per group. (f) Locomotor sensitization to cocaine: distance traveled on the first day of cocaine treatment and following 21 days of cocaine withdrawal in response to a 20 mg kg−1 cocaine challenge injection. N=17 per group. N=16 per group. (g) Locomotor reaction to systemic treatment with amphetamine: locomotor activity in the open field expressed as distance traveled (cm) per 10-min bin during the initial baseline phase, following saline administration and following a systemic injection of amphetamine (2.5 mg kg−1, intraperitoneal (i.p.)). N=5 m per group. *P<0.05; **P<0.001; ***P<0.0001. All values are means±s.e.m. f, female; m, male.
Figure 3
Figure 3
Maternal high-fat diet (HFD) exposure leads to alterations in the dopaminergic system. (a) mRNA expression of the transcription factor deltaFosB was significantly elevated in the nucleus accumbens (NAc) and dorsal striatum of HFD offspring compared with controls. Pregnant mice were exposed to HFD or normal laboratory chow (control) diet, and immunoreactivities of (b, c), tyrosine hydroxylase (TH), (d) dopamine transporter (DAT), (e) D1R and (f) dopamine receptors D2 (D2R) were assessed in the adult offspring (postnatal day 70, PND70). N=16 (8m, 8f) per group. (g–n) Representative images of coronal brain sections of adult (PND70) offspring derived from control and HFD-exposed mothers stained for D2R (g, h) in the NAC core and shell subregions and for D1R in the medial prefrontal cortex (mPFC) region (i, j) by immunohistochemistry. (k, l) Representative images of coronal brain sections for TH protein by immunohistochemistry in the dorsal striatum (dSTR; k, l) and the ventral tegmental area (VTA; m, n) of control and HFD offspring. (o–s) Levels of dopamine (DA) and its metabolites, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined in post-mortem brain tissue using high-performance liquid chromatography (HPLC). Monoamine contents were measured in the dSTR, NAc, VTA, substantia nigra (SN) and hypothalamus. All monoamine levels are expressed as ng mg−1 fresh tissue weight. N=16 (8m, 8f) per group. (t) Positron emission tomography (PET) images (binding potentials, BPnd) superimposed on MRI templates (gray). Average PET images of three scans (with lowest tracer concentration) per group. (u) PET data (BPnd) normalized to the respective average accumulation under baseline conditions (%) to compare the relative response to amphetamine in both offspring groups. N=6f per group. *P<0.05; ** P<0.001; ***P<0.0001. All values are means±s.e.m. f, female; m, male.
Figure 4
Figure 4
The effects of post-weaning HFD for 11 weeks on offspring born to either control or HFD-exposed mothers. (a) Body weights of control and HFD offspring were exposed to either chow or HFD diet for 11 weeks. Weights were weekly monitored. No difference was observed between control and HFD exposed to post-weaning chow diet. In addition, no difference in body weight was observed between control and HFD offspring exposed to HFD. The scatter plot to the right shows the sex differences between female and male offspring. Body composition of control and HFD offspring exposed to 11 weeks of post-weaning HFD. (b) No differences in fat mass and (c) lean mass utilized by CT-scan were detected. Post-weaning HFD did not lead to any difference in fasted plasma metabolic parameters between control and HFD offspring in any of the parameters measured: cholesterol (d), free fatty acid (FFA; e), triglycerides, (f) insulin (g) and glucose levels (h). Control N=30 (16m, 14f); HFD N=28 (14m, 14f). All values are means±s.e.m. CT, computerized tomography; f, female; HFD, high-fat diet; m, male.
Figure 5
Figure 5
Food choice in offspring born to mouse dams exposed to high-fat diet (HFD) develop severe obesity and insulin resistance. (a). Control and HFD offspring during adulthood (postnatal day (PND) 70–160) were exposed to a choice paradigm; animals were given the choice in their home cage between control and HFD and between water to a 1% sucrose solution. (b–f) Fat composition and distribution as measured by computerized tomography (CT) scan. (g–i) Metabolic parameters measured from blood samples taken from HFD and control offspring at PND 160 (j). Insulin tolerance test (ITT) was performed in HFD and control offspring. Insulin (0.75  U kg−1 of body weight) was administered by intraperitoneal (i.p.) injection. Blood glucose levels were monitored at indicated times. (k) Plasma homeostasis model assessment of insulin resistance (HOMA-IR) was calculated by the fasting glucose and insulin levels. (l, m) Representative hematoxylin and eosin staining of liver sections of control (l) and HFD (m) offspring after a 13-week exposure to a choice diet. N=7 m per group; *P<0.05, **P<0.001. All values are means±s.e.m. m, male.
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