Evidence of hypoglycemic anhedonia and modulation by bupropion in rats.

BACKGROUND: Disorders characterized by dysfunction of glucose metabolism are often comorbid with depression. The current study investigated whether a hypoglycemic state caused by 2-deoxy-d-glucose (2-DG) can result in anhedonic behaviors responsive to stimulation of monoamine activity. METHODS: In experiment 1, male Sprague-Dawley rats were tested for maintenance of intra-oral self-administration (IOSA) of a sweet solution after pre-treatment with 300 or 500 mg/kg 2-DG, a blocker of glucose metabolism. Experiment 2 determined whether exposure to an environment previously paired with the effects of 2-DG (0, 200 or 300 mg/kg) can influence IOSA, and whether 2-DG can modify taste reactivity to same sweet solution. Finally, experiment 3 examined whether 0 or 30 mg/kg bupropion, a monoamine-reuptake blocker, would attenuate the effect of 300 mg/kg 2-DG on IOSA and taste reactivity. RESULTS: It was found that 2-DG produced a sustained decrease in IOSA when animals were tested drug-free. This decrease in IOSA did not appear linked to place conditioning or to alterations in taste reactivity, and it was partially normalized by pre-treatment with bupropion. CONCLUSIONS: Taken together, these results in rats suggest that rapid hypoglycemia can induce an anhedonic state characterized by impaired consummatory responses to nutritional incentive stimuli and that can be alleviated by the antidepressant bupropion.

Dietary n-6/n-3 Ratio Influences Brain Fatty Acid Composition in Adult Rats.

There is mounting evidence that diets supplemented with polyunsaturated fatty acids (PUFA) can impact brain biology and functions. This study investigated whether moderately high-fat diets differing in n-6/n-3 fatty acid ratio could impact fatty acid composition in regions of the brain linked to various psychopathologies. Adult male Sprague Dawley rats consumed isocaloric diets (35% kcal from fat) containing different ratios of linoleic acid (n-6) and alpha-linolenic acid (n-3) for 2 months. It was found that the profiles of PUFA in the prefrontal cortex, hippocampus, and hypothalamus reflected the fatty acid composition of the diet. In addition, region-specific changes in saturated fatty acids and monounsaturated fatty acids were detected in the hypothalamus, but not in the hippocampus or prefrontal cortex. This study in adult rats demonstrates that fatty acid remodeling in the brain by diet can occur within months and provides additional evidence for the suggestion that diet could impact mental health.

Reverse translation of major depressive disorder symptoms: A framework for the behavioural phenotyping of putative biomarkers.

BACKGROUND: Reverse translating putative biomarkers of depression from patients to animals is complex because Major Depressive Disorder (MDD) is a highly heterogenous condition. This review proposes an approach to reverse translation based on relating relevant bio-behavioural functions in laboratory rodents to MDD symptoms. METHODS: This systematic review outlines symptom clusters assessed by psychometric tests of MDD and antidepressant treatment response including the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. Symptoms were related to relevant behavioural assays in laboratory rodents. RESULTS: The resulting battery of tests includes passive coping, anxiety-like behaviours, sleep, caloric intake, cognition, psychomotor functions, hedonic reactivity and aversive learning. These assays are discussed alongside relevant clinical symptoms of MDD, providing a framework through which reverse translation of a biomarker can be interpreted. LIMITATIONS: Certain aspects of MDD may not be quantified by tests in laboratory rodents, and their biological significance may not always be of clinical relevance. CONCLUSIONS: Using this reverse translation approach, it is possible to clarify the functional significance of a putative biomarker in rodents and hence translate its contribution to specific clinical symptoms, or clusters of symptoms.

An exploration of the aversive properties of 2-deoxy-D-glucose in rats.

Hypoglycemia can alter arousal and negatively impact mood. This study tests the hypothesis that acute drops in glucose metabolism cause an aversive state mediated by monoamine activity. In experiment 1, male Sprague-Dawley rats were either food deprived (FD) or pre-fed (PF) and tested on conditioned place avoidance (CPA; biased place conditioning design; 3 pairings drug/vehicle, each 30 min-long) induced by the glucose antimetabolite 2-deoxy-D-glucose (2-DG; 0, 300 or 500 mg/kg, SC). Locomotion and blood glucose were also assessed. Experiment 2 examined whether clonidine (noradrenergic α2 agonist, 0, 10 or 40 µg/kg, SC) or bupropion (monoamine reuptake blocker, 0, 10 or 30 mg/kg, SC) could alter CPA induced by 500 mg/kg 2-DG. In experiment 3, blood corticosterone (CORT) was measured in response to 500 mg/kg 2-DG, alone or in combination with 40 µg/kg clonidine or 30 mg/kg bupropion. Finally, experiment 4 controlled for possible place conditioning induced by 10 or 40 µg/kg clonidine, or 10 or 30 mg/kg bupropion injected without 2-DG. It was found that 2-DG increased blood glucose and produced a robust CPA. The feeding status of the animals modulated these effects, including CORT levels. Both clonidine and bupropion attenuated the effects of 2-DG on CPA and CORT, but only bupropion reversed suppression of locomotion. Taken together, these results in rats suggest that impaired glucose metabolism can negatively impact arousal and mood via effects on HPA and monoamine systems.

Bupropion and naltrexone combination alters high fructose corn syrup self-administration and gene expression in rats.

Contrave® is an adjunct pharmacotherapy for obesity that contains bupropion (BUP) and naltrexone (NTX). To further explore the psychopharmacology of this drug combination, male Sprague-Dawley rats were implanted with subcutaneous osmotic mini-pumps releasing: 40 mg/kg/day BUP, 4 mg/kg/day NTX, or 40 + 4 mg/kg/day BUP and NTX (BN). During 12 days of exposure, the animals were tested on operant intraoral self-administration (IOSA) of high fructose corn syrup (HFCS) on continuous (FR1) and progressive ratio (PR) schedules, on home cage drinking of HFCS, and on HFCS taste reactivity. Locomotion activity was also assessed. At the conclusion of the study, mRNA expression of genes involved in reward processing, appetite and mood were quantified. It was found that BN produced effects that could largely be ascribed to either BUP or NTX independently. More specifically, BN-induced reductions of HFCS IOSA on a FR1 schedule and home cage drinking, as well as alterations of MOR and POMC mRNA in the nucleus accumbens core and hypothalamus respectively, were attributable to NTX; while alterations of hippocampal BDNF mRNA was attributable to BUP. But, there was also some evidence of drug synergy: only BN caused persistent reductions of HFCS IOSA and drinking; BN produced the least gain of body weight; and only BN-treated rats displayed altered D2R mRNA in the caudate-putamen. Taken together, these observations support the use of BUP + NTX as a mean to alter consumption of sugars and reducing their impact on brain systems involved in reward, appetite and mood.