Opioid receptors have been a target of pharmacological manipulation in alcohol use disorder (AUD) recovery protocols for many years. Aerobic exercise, a common adjunct in AUD recovery, is known to modulate opioid receptors (ORs) both during both acute and long term exposure. The three subtypes of ORs: mu (MOR), delta (DOR), and kappa (KOR) are all expressed on neurons in the mesocorticolimbic circuitry. Kappa-opioid receptors are expressed directly on dopamine (DA) neuron terminals in the nucleus accumbens (NAc). Mu and Delta ORs are expressed on cholinergic interneurons (CINs) and GABA neurons in the NAc. In alcohol dependent rodents, KORs are hypersensitized. It is theorized that this hypersensitization contributes to EtOH seeking behavior. In contrast, aerobic exercise desensitizes the KORs. Given the high degree of pharmacological overlap between opioid receptors, it is also hypothesized that EtOH and aerobic exercise may have effects on MORs and DORs as well. Here, it is investigated whether a routine of voluntary aerobic exercise decreases EtOH induced changes to KOR modulation of dopamine (DA) release in the nucleus accumbens (NAc) along with possible mechanisms through which this might occur. The responsiveness of MORs and DORs in EtOH dependence, and how aerobic exercise modulates those effects is also investigated. Exercise attenuated EtOH induced hypersensitization of KORs in the NAc. Exercise decreases expression of KORs, which may account for the changes in KOR sensitization. The MOR agonist DAMGO decreased DA reuptake ex vivo, but not signal amplitude while DOR agonist DPDPE had no effect on either reuptake or signal amplitude. Overall, dependent animals that were allowed to exercise, consumed less EtOH in a drinking in the dark model. These data suggest that exercise is a useful adjunct to AUD recovery protocols, and that its effects are likely mediated by KORs. The findings related to MORs and DORs suggest that MORs, but not DORs, may act through acetyl choline receptors to modulate DA reuptake in the NAc, however much more work is needed to characterize this effect.

Der Morbus Parkinson ist die häufigste Erkrankung der Basalganglien und wird durch einen Abbau der dopaminergen Neurone in der Substantia nigra des Mittelhirns verursacht. Um Wege zu finden, die Nebenwirkungen bisheriger Therapien dieser Erkrankung zu vermeiden, sollten neue Angriffspunkte für pharmakologische Interventionen gesucht werden. Prinzipiell ist dabei jeder Schritt einer Signaltransduktions-Kaskade zu prüfen. Dazu gehören präsynaptische Transmitterfreisetzung, G-Protein-gesteuerte Effektormechanismen oder Veränderungen prä- und postsynaptischer Potentiale, wie sie durch ein bestimmtes lokales Ionenkanalmuster festgelegt werden. Aufgrund ihrer enormen molekularen Vielfalt bei gleichzeitig weiter, aber spezifischer Verbreitung, stellen Kaliumkanäle interessante Angriffspunkte für neue therapeutische Strategien dar. Die vorliegende Arbeit untersucht die zelluläre und subzelluläre Verteilung aller Mitglieder der Kir2-Familie, einer Gruppe von Proteinen, die einwärts-gleichrichtende Kaliumkanäle bildet. Zu diesem Zweck wurden polyklonale, monospezifische, affinitätsgereinigte Antikörper gegen den wenig konservierten carboxyterminalen Anteil der Kir2.1-, Kir2.2-, Kir2.3- und Kir2.4-Proteine hergestellt. Alle Untereinheiten der Kir2-Familie wurden an den Somata und Dendriten der meisten striatalen Neurone nachgewiesen. Zwei dieser Kanäle zeigten jedoch ein inhomogenes Verteilungsmuster: Das "patch"-Kompartiment des Striatums wurde von der Expression des Kir2.3-Kanals ausgespart, und das Kir2.4-Protein wurde am stärksten auf den tonisch aktiven, cholinergen striatalen Interneuronen exprimiert. Diese beiden Strukturen stellen die Schlüsselstellen für die Kontrolle und Regulation der dopaminergen und cholinergen Transmission im Striatum dar, weswegen ihnen eine zentrale Rolle für die efferenten Projektionen der Basalganglien zukommt. Die nachgewiesene heterogene Lokalisation der Kir2.3- und Kir2.4-Untereinheit an diesen strategisch relevanten Strukturen macht diese Kanäle zu viel versprechenden Angriffspunkten für zukünftige Pharmakotherapien. / Parkinson’s disease is the most frequent movement disorder caused by loss of dopaminergic neurons in the midbrain. Intentions to avoid side effects of conventional therapy should aim to identify additional targets for potential pharmacological intervention. In principle, every step of a signal transduction cascade, such as presynaptic transmitter release, type and occupation of postsynaptic receptors, G protein-mediated effector mechanisms, and the alterations of pre- or postsynaptic potentials as determined by the local ion channel composition, have to be considered. Due to their diversity and their widespread but distinct localizations, potassium channels represent interesting candidates for new therapeutic strategies. As a first step, the present report aimed to study the cellular and subcellular distribution of the individual members of the Kir2 family in the striatum, a group of proteins forming inwardly rectifying potassium channels. For this purpose polyclonal, monospecific, affinity purified antibodies against the less conserved carboxyterminal sequences from the Kir2.1, Kir2.2, Kir2.3, and Kir2.4 proteins were prepared. All subunits of the Kir2 family were detected on somata and dendrites of most striatal neurons. However, the distribution of two of them was not homogeneous. Striatal patch areas were largely devoid of the Kir2.3 protein, and the Kir2.4 subunit was most prominently expressed on the tonically active, giant cholinergic interneurons of the striatum. These two structures are among the key players in regulating dopaminergic and cholinergic neurotransmission within the striatum, and therefore are of major importance for the output of the basal ganglia. The heterogeneous localization of the Kir2.3 and the Kir2.4 subunits with respect to these strategic structures pinpoints these channel proteins as promising targets for future pharmacological efforts.