Time-Dependent Changes in Receptor/G-Protein Coupling in Rat Brain following Chronic Monoamine Transporter Blockade

Abstract

The potent tropane analog, WF-23 [2␤-propanoyl-3␤-(2-naphthyl) tropane], blocks dopamine, serotonin, and norepinephrine transporters with high affinity in vitro and blocks transporters for at least 2 days following a single in vivo administration. Previous studies demonstrated desensitization of monoamine receptor-coupled G-proteins in brain following chronic treatment of rats with WF-23. The current study sought to determine the time course of this desensitization and the behavioral effects of receptor desensitization. Rats were treated with 1 mg/kg WF-23 and injected i.

Inhibiting Subthalamic D5Receptor Constitutive Activity Alleviates Abnormal Electrical Activity and Reverses Motor Impairment in a Rat Model of Parkinson's Disease

“…However, it is not known whether these phenomena play a causal role in parkinsonian motor symptoms. Recent evidence in behaving rodents complements earlier data obtained in DA-depleted anesthetized animals and points to a pathological persistence of a post-decision stabilized state of cortical-basal ganglia networks (Mallet et al, 2008;Cruz et al, 2011;Leventhal et al, 2012). However, the parkinsonian symptoms are alleviated by subthalamic nucleus (STN) ablation (Bergman et al, 1990), high-frequency electrical stimulation (Benazzouz et al, 1993;Limousin et al, 1998), and pharmacological inhibition (Levy et al, 2001;Luo et al, 2002), suggesting that STN has a critical role in the symptoms.…”

“…STN, a pivotal nucleus of basal ganglia, exhibits a marked proclivity to sustained burst firing in patients and nonhuman primate and rodent models of the disease (Bergman et al, 1994;Magill et al, 2001;Ni et al, 2001a,b;Galvan and Wichmann, 2008). The mechanism underlying pathological burst activity in STN is unknown.…”

“…In several brain systems, burst firing patterns, which represent a prolonged period of densely populated spikes, have been shown to contribute to enhanced synaptic neurotransmitter release compared with tonic single-spike firing (Dutton and Dyball, 1979;Lundberg et al, 1986;Gonon, 1988). In the STN, the enhanced proportion of burst firing recorded after DA depletion may reflect functional neuronal hyperactivity exerting an exaggerated excitatory drive on the output structures of basal ganglia.…”

Human Methamphetamine Pharmacokinetics Simulated in the Rat: Single Daily Intravenous Administration Reveals Elements of Sensitization and Tolerance

“…METH administration (Segal et al, 2005). In addition, O'Connor et al (2005) recently reported that repeated administration of the long-acting DAT inhibitor, WF-23, resulted in a progressive reduction in striatal D2 receptor-stimulated […”

Chronic baclofen desensitizes GABAB-mediated G-protein activation and stimulates phosphorylation of kinases in mesocorticolimbic rat brain

“…Effects of baclofen treatment on GABA B activation of G-proteins in various regions were determined by [ 35 S]GTPγS autoradiography using baclofen as GABA B agonist (Sim et al, 1996a). We have used similar methods in the past to detect the development of region-selective and time-dependent desensitization of GPCRs following prolonged treatment with their respective agonists (Maher et al, 2001; 2005; Martin et al, 2007; O'Connor et al, 2005; Selley et al, 1997). The pharmacological specificity of baclofen-stimulated [ 35 S]GTPγS binding is confirmed in Figure 1, which shows autoradiograms of baclofen-stimulated [ 35 S]GTPγS binding in rat brain coronal sections assayed in the presence and absence of the GABA B antagonist CGP-54626 (Brugger et al, 1993).…”