Intermittent dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to dopaminergic drugs.

Eating a high fat diet can lead to obesity, type 2 diabetes, and dopamine system dysfunction. For example, rats eating high fat chow are more sensitive than rats eating standard chow to the behavioral effects (e.g., locomotion and yawning) of dopaminergic drugs (e.g., quinpirole and cocaine). Daily dietary supplementation with 20% (w/w) fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole-induced yawning and cocaine-induced locomotion; however, doctors recommend that patients take fish oil just two to three times a week. To test the hypothesis that intermittent (i.e., 2 days per week) dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to quinpirole and cocaine, rats eating standard chow (17% kcal from fat), high fat chow (60% kcal from fat), and rats eating standard or high fat chow with 20% (w/w) intermittent (e.g., 2 days per week) dietary fish oil supplementation were tested once weekly with quinpirole [0.0032-0.32 mg/kg, intraperitoneally (i.p.)] or cocaine (1.0-17.8 mg/kg, i.p.) using a cumulative dosing procedure. Consistent with previous reports, eating high fat chow enhanced sensitivity of rats to the behavioral effects of quinpirole and cocaine. Intermittent dietary supplementation of fish oil prevented high fat chow-induced enhanced sensitivity to dopaminergic drugs in male and female rats. Future experiments will focus on understanding the mechanism(s) by which fish oil produces these beneficial effects.

Electrical Stimulation Evokes Rotational Behavior In Tandem with Exocytotic-like Increases in Dopamine Measured by In Vivo Intracerebral Microdialysis.

BACKGROUND: Electrical Stimulation is a traditional tool in neuroscience and is commonly used in vivo to evoke behavior and in vitro to study neural mechanisms. In vivo intracerebral microdialysis, also a traditional technique, is used to assay neurotransmitter release. However, the combination of these techniques is highly limited to studies using anesthetized animals; therefore, evoking and measuring exocytotic neurotransmitter release in awake models is lacking. Combining these techniques in an awake animal preparation is presented here with evidence to support the mechanistic action of electrical stimulation in vivo. NEW METHODS: This report presents converging evidence to validate the combination of intracerebral electrical stimulation with microdialysis as a novel procedure to study exocytotic-like dopamine release in behaving animals. RESULTS: It is shown that electrical stimulation of the medial forebrain bundle can be used to evoke frequency- and intensity-dependent exocytotic-like dopamine overflow and rotational behavior that are sensitive to Na+ channel blockade and Ca++ availability. COMPARISON WITH EXISTING METHODS: Studies using modern techniques to evoke neurotransmitter release, combined with in vivo intracerebral microdialysis, and measured behavioral output are scarce. In contrast, commonly used pharmacological methods often are less precise and inefficient to evoke exocytotic dopamine release and behavior. Here we demonstrate, the combination of in vivo intracerebral microdialysis with electrical stimulation as a simple approach to simultaneously assess physiologically relevant neurotransmitter 'release' and behavior. CONCLUSIONS: Research that aims to understand how dopamine neurotransmission is altered in behavioral disorders can utilize this innovative combination of electrical stimulation with in vivo intracerebral microdialysis.

The Effects of Eating a High Fat Diet on Sensitivity of Male and Female Rats to Methamphetamine and Dopamine D1 Receptor Agonist SKF 82958.

Rats eating high fat chow are more sensitive to the behavioral effects of dopaminergic drugs, including methamphetamine and the dopamine D2/D3 receptor agonist quinpirole, than rats eating standard chow. However, limited work has explored possible sex differences regarding the impact of diet on drug sensitivity. It is also unknown whether eating high fat chow enhances sensitivity of rats to other dopamine (e.g., D1) receptor agonists. To explore these possibilities, male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat) were tested once per week for 6 weeks with dopamine D1 receptor agonist SKF 82958 (0.01-3.2 mg/kg) or methamphetamine (0.1-3.2 mg/kg) using cumulative dosing procedures. Eating high fat chow increased sensitivity of male and female rats to methamphetamine-induced locomotion; however, only female rats eating high fat chow were more sensitive to SKF 82958-induced locomotion. SKF 82958-induced eye blinking was also marginally, although not significantly, enhanced among female rats eating high fat chow, but not males. Further, although dopamine D2 receptor expression was significantly increased for SKF 82958-treated rats eating high fat chow regardless of sex, no differences were observed in dopamine D1 receptor expression. Taken together, the present study suggests that although eating high fat chow enhances sensitivity of both sexes to dopaminergic drugs, the mechanism driving this effect might be different for males versus females. These data further demonstrate the importance of studying both sexes simultaneously when investigating factors that influence drug sensitivity. SIGNIFICANCE STATEMENT: Although it is known that diet can impact sensitivity to some dopaminergic drugs, sex differences regarding this effect are not well characterized. This report demonstrates that eating a high fat diet enhances sensitivity to methamphetamine, regardless of sex; however, sensitivity to dopamine D1 receptor agonist SKF 82958 is increased only among females eating high fat chow, but not males. This suggests that the mechanism(s) driving diet-induced changes in drug sensitivity might be different between sexes.

Dietary supplementation with fish oil reverses high fat diet-induced enhanced sensitivity to the behavioral effects of quinpirole.

Consuming a high fat diet can lead to many negative health consequences, such as obesity, insulin resistance, and enhanced sensitivity to drugs acting on dopamine systems. It has recently been demonstrated that dietary supplementation with fish oil, which is rich in omega-3 fatty acids, can prevent this high fat diet-induced enhanced sensitivity to dopaminergic drugs from developing. However, it is not known whether fish oil supplementation can reverse this effect once it has already developed. To test the hypothesis that dietary supplementation with fish oil will reverse high fat diet-induced enhanced sensitivity to quinpirole, a dopamine D2/D3 receptor agonist, male Sprague-Dawley rats were fed either standard chow (17% kcal from fat), high fat chow (60% kcal from fat), standard chow, or high fat chow supplemented with 20% (w/w) fish oil. Body weight, food consumption, and sensitivity to quinpirole-induced (0.0032-0.32 mg/kg) penile erections were examined throughout the course of the experiment. Eating high fat chow enhanced sensitivity of rats to quinpirole-induced penile erections (i.e. resulted in a leftward shift of the ascending limb of the dose-response curve). Dietary supplementation with fish oil successfully treated this effect, as dose-response curves were not different for rats eating standard chow and rats eating high fat chow with fish oil. These results suggest that in addition to preventing the negative health consequences of eating a high fat diet, fish oil can also reverse some of these consequences once they have developed.

Sex differences in high fat diet-induced impairments to striatal Akt signaling and enhanced sensitivity to the behavioral effects of dopamine D2/D3 receptor agonist quinpirole.

Eating a high fat laboratory chow enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g., cocaine). Further, in male rats, eating high fat chow impairs expression of insulin signaling phosphorylated protein kinase B (pAkt), which is vital for maintaining dopamine homeostasis. Eating high fat chow enhances sensitivity of female rats to drugs that act indirectly on dopamine receptors (e.g., cocaine); however, less is known about sensitivity of females to drugs that act directly on dopamine receptors (e.g., quinpirole). Further, it is not known if pAkt expression is impaired in female rats eating high fat chow. Some quinpirole-induced behaviors (e.g., penile erections and yawning) are either absent or occur at very low frequency in adult female rats. It is not known if quinpirole sensitivity in adolescent rats is more comparable between sexes. The present report examined another unconditioned behavioral effect (i.e., rearing) induced by once-weekly cumulative doses of quinpirole (0.0032-0.32mg/kg) in male and female Sprague-Dawley rats eating standard laboratory chow (17% kcal from fat) or high fat chow (60% kcal from fat), for several weeks throughout development, (spanning adolescence and early adulthood). Following behavioral assessments, pAkt expression was examined using western blot protein analysis. Eating high fat chow increased sensitivity of male rats to the quinpirole-induced yawning, as compared to male rats eating standard chow. However, other unconditioned behavioral effects of quinpirole (yawning and hypothermia) remained unchanged. Female rats yawned significantly less than male rats, and eating a high fat chow had no effect on any quinpirole-induced unconditioned behavioral effect in female rats. Eating high fat chow also reduced pAkt levels in male, but not female rats. Taken together, these data suggest that alternative behavioral and biochemical assays should be considered to measure sensitivity of female rats to the behavioral effects of dopamine receptor agonists, and further demonstrate the importance of studying drug sensitivity in both male and female subjects.

Dietary supplementation with fish oil prevents high fat diet-induced enhancement of sensitivity to the behavioral effects of quinpirole.

Eating a diet high in fat can lead to negative health consequences, including obesity and insulin resistance. Omega-3 polyunsaturated fatty acids (such as those found in fish oil) prevent high fat diet-induced obesity and insulin resistance in rats. Eating a high fat diet also enhances sensitivity of rats to the behavioral effects of drugs that act on dopamine systems (e.g. quinpirole, a dopamine D2/D3 receptor agonist). To test the hypothesis that dietary supplementation with fish oil prevents high fat diet-induced enhanced sensitivity to the behavioral effects of quinpirole (0.0032-0.32 mg/kg), male rats ate standard laboratory chow, high fat chow, standard chow with fish oil, or high fat chow with fish oil (20% w/w). After 5 weeks, rats eating high fat chow were more sensitive (e.g. leftward shift of the quinpirole dose-response curve) than rats eating standard chow to yawning induced by quinpirole. Dietary supplementation with fish oil prevented this effect. That is, quinpirole dose-response curves were not different between rats eating high fat chow supplemented with fish oil and standard chow fed controls. These data add to a growing literature showing the complex relationship between diet and dopamine systems, and the health benefits of fish oil.

Ketamine administration during the second postnatal week induces enduring schizophrenia-like behavioral symptoms and reduces parvalbumin expression in the medial prefrontal cortex of adult mice.

Dysfunctions in the GABAergic system are considered a core feature of schizophrenia. Pharmacological blockade of NMDA receptors (NMDAR), or their genetic ablation in parvalbumin (PV)-expressing GABAergic interneurons can induce schizophrenia-like behavior in animals. NMDAR-mediated currents shape the maturation of GABAergic interneurons during a critical period of development, making transient blockade of NMDARs during this period an attractive model for the developmental changes that occur in the course of schizophrenia's pathophysiology. Here, we examined whether developmental administration of the non-competitive NMDAR antagonist ketamine results in persistent deficits in PFC-dependent behaviors in adult animals. Mice received injections of ketamine (30mg/kg) on postnatal days (PND) 7, 9 and 11, and then tested on a battery of behavioral experiments aimed to mimic major symptoms of schizophrenia in adulthood (between PND 90 and 120). Ketamine treatment reduced the number of cells that expressed PV in the PFC by ∼60% as previously described. Ketamine affected performance in an attentional set-shifting task, impairing the ability of the animals to perform an extradimensional shift to acquire a new strategy. Ketamine-treated animals showed deficits in latent inhibition, novel-object recognition and social novelty detection compared to their SAL-treated littermates. These deficits were not a result of generalized anxiety, as both groups performed comparably on an elevated plus maze. Ketamine treatment did not cause changes in amphetamine-induced hyperlocomotion that are often taken as measures for the positive-like symptoms of the disorder. Thus, ketamine administration during development appears to be a useful model for inducing cognitive and negative symptoms of schizophrenia.