REGULATION OF DOPAMINERGIC AND IMMUNE MARKERS IN THE RAT STRIATUM: EXPLORING THE MODULATORY EFFECTS OF D2R ANTAGONISM, SERT INHIBITION, ENVIRONMENTAL ENRICHMENT AND MICROGLIAL ACTIVATION

Abstract

<p>Several classes of psychotropic medications are known to produce neurological side effects. It has long been recognized that antipsychotic drugs classically block the D₂ subtype of DA receptors inducing a range of acute and subacute extrapyramidal syndromes (EPS), including parkinsonism and akathisia, as well as chronic syndromes such as tardive dyskinesia. More recently, SSRI-type drugs, which, as the name suggests, inhibit the serotonin transporter (SERT), and have been found to induce a similar profile of EPS. It is unclear how medications with such different pharmacological actions can produce similar neurological side effects. The goal of this thesis was to study the neurochemical alterations induced by antipsychotic and SSRI medications, with a specific focus on the nigrostriatal pathway, the causative location of parkinsonism.</p> <p>Environmental enrichment and exercise (EE) has been shown to have protective effects in various neurological settings. In the first experiment, we studied the changes induced by SERT inhibition compared to those induced by a non-pharmacological form of therapy, namely, environmental enrichment with exercise. The SSRI, fluoxetine (FLX) significantly reduced the levels of tyrosine hydroxylase (TH) and phosphorylated glycogen synthase kinase-3β (pGSK-3β-inactive), while increasing phosphorylated TH (pTH) in the striatum (STR). EE also reduced TH and increased pTH, but contrary to FLX, it significantly increased striatal pGSK-3β protein expression.</p> <p>Microglia, the brain’s primary immune cells, have been implicated in several neuroinflammatory conditions, including Parkinson’s disease. The purpose of the second experiment was to explore the modulatory effects of microglia on neuroleptic-induced changes in the nigrostriatal system. The typical antipsychotic, haloperidol (HAL), did not affect the overall levels of TH, though it did induce a robust increase in pTH. The microglial NADPH oxidase inhibitor, apocynin (APO), significantly attenuated this increase in pTH. HAL also induced a significant increase in striatal pGSK-3β, while apocynin, rather surprisingly, induced a stark decrease in pGSK-3β protein expression.</p> <p>The results of this thesis indicate that both pTH and pGSK-3β are intriguing markers to study in the context of dopamine neurotransmission. In addition, EE proved to be a valuable modality in which to compare the downstream effects of pharmacological treatment. It is also clear that microglia fulfill an undefined, but fascinating role as modulators of neural transmission.</p>