Sammendrag
Environmental substances like polychlorinated biphenyls and dietary fatty acids have been suspected to influence cognitive functions in humans, although much of their specific effects on synaptic functions are still unclear. There are many contradicting studies of the cognitive benefits of polyunsaturated fatty acids. In some studies it is emphasized that children with cognitive impairments such as ADHD, may have impaired fatty acid metabolism, implicating that the genetic status may be of importance. Ingestion of polychlorinated biphenyls have been associated with negative effects on cognitive processes, although the effects seems to be highly dependent on their molecular structure exposure time, duration, doses. In this thesis, the effect of dietary fat content and polychlorinated biphenyl 153 was investigated in neostriatal dopaminergic synapses and included measurements of related neurotransmitters like e.g glutamate and serotonin.
We included both male and female rats of two different genotypes namely the Wistar Kyoto rats and the spontaneously hypertensive rats as an animal model of ADHD, to investigate if genetic and hormonal status may influence the effect of these compounds. Initially the dietary study involved two distinct diets, one with a low level of dietary fatty acids (5%, w/w) with the other one supplemented with omega-3 polyunsaturated fatty acids (equal amounts of EPA and DHA) containing a high level of fatty acids (21%, w/w). The omega-3 supplementation led to gender dependent improvement in behaviour in the male SHRs, and included reduced levels of reinforcer-controlled activity, impulsiveness and inattention, with no or opposite effects in the female SHRs. Further biochemical studies on the neostriatal dopaminergic system, involved in reinforcement of behaviour, confirmed that the male SHRs had a reduction of the dopamine content in concert with enhanced homovanillic acid and calculated turnover ratio of dopamine, all of which were absent in the female SHRs. To further investigate if the effects achieved by omega-3 supplementation (this time with 80% DHA and 20% EPA), could be specific for omega-3 fat, we included an extra diet composed of high levels of fatty acids (21%, w/w) containing mainly lard which is rich in both saturated (40%) and polyunsaturated fats (60%) but with low levels of omega-3. In this second round we discovered that in the male WKY rats, both the lard and omega-3 enriched diets gave reduced levels of dopamine, tyrosine hydroxylase and vesicular monoamine transporter-2, without changing the extracellular dopamine metabolite homovanillic acid in neostriatum. In contrast to the lard enriched diet, omega-3 enrichment induced an additional 2-fold increase in dopamine turnover ratio in the male WKYs, as well as a significant decrease in the levels of the dopamine transporter. Another finding was that the young male SHRs at p30 were hypodopaminergic compared to age and gender matched WKYs. In these male SHRs, the 40% lower dopamine turnover ratio was reversed 2-fold, to a similar extent by both lard and omega-3 enriched diets, without any significant effects on the protein levels.
These findings show that dietary fatty acid composition may strongly influence the neostriatal dopaminergic system in a gender and genotype dependent way, with both type of fatty acids as well as the amounts influencing the synaptic responses. Polychlorinated biphenyls (PCBs) can be separated into ortho- and non orthosubstituted PCBs, where most of the ortho-substituted being neurotoxic and possibly interrupt cognitive functions. In this thesis we employed the ortho-substituted PCB 153, which is one of the most abundant PCB found in mammalian milk. Biochemical studies were performed on dopamine and serotonin neurotransmitters as well as amino acids in the neostriatum of both genders from the Wistar Kyoto (WKY) and the spontaneously hypertensive rat (SHR) genotypes. Exposure to PCB 153 led to increases in homovanillic acid and 5-hydroxyindoleacetic acid in all groups except the female SHRs, whereas levels of dopamine and serotonin neurotransmitters as well as amino acids were unchanged in all genotypes and genders. PCB-153 also induced a decrease in the neostriatal D5 receptor in both genders and genotypes, without changing the D1 receptor. In contrast, levels of the dopamine transporter were reduced in the male WKYs, together with an insignificant reduction of the mean in the male SHRs. In addition, a gender-specific decrease of the PSD-95 protein occurred in the PCB-exposed male rats. Levels of tyrosine hydroxylase and vesicular monoamine transporter-2 were unchanged in all animals examined. Therefore, postnatal PCB exposure had major effects on both dopamine and serotonin turnover as well as specific PCB-sensitive synaptic proteins. Differences occurred between the effects obtained in both genotypes, as well as between genders. Altogether, this set of studies shows that both PCB 153 and dietary fatty acids, environmental compounds suspected to influence cognitive functions, may modulate neostriatal dopaminergic synapses in distinct gender and genotype dependent ways.