A dose–response study of separate and combined effects of the serotonin agonist 8-OH-DPAT and the dopamine agonist quinpirole on locomotor sensitization, cross-sensitization, and conditioned activity

Abstract

Chronic treatment with the dopamine D2/D3 agonist, quinpirole, or the serotonin 1A agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), induces behavioral sensitization. It is not known whether both drugs produce sensitization through a shared mechanism. Here, we examine whether quinpirole and 8-OH-DPAT show cross-sensitization and impact sensitization, as would be expected from shared mechanisms. Male rats (N=208) were assigned randomly to 16 groups formed by crossing four doses of quinpirole (0, 0.03125, 0.0625, or 0.125 mg/kg) with four doses of 8-OH-DPAT (0, 0.03125, 0.625, or 0.125 mg/kg). After a course of 10 drug treatments administered twice per week in locomotor activity chambers, all groups were challenged on separate tests with quinpirole (0.1 mg/kg), 8-OH-DPAT (0.1 mg/kg), or saline, and locomotor activity was evaluated. Challenge tests with quinpirole and 8-OHDPAT showed no cross-sensitization between the drugs. Chronic quinpirole (0.125 mg/kg) administration induced a sensitized quinpirole response that was attenuated dose-dependently by chronic 8-OH-DPAT cotreatment. Cotreatment with quinpirole (0.0625 mg/kg) and 8-OH-DPAT (all doses) induced quinpirole sensitization. Chronic 8-OH-DPAT (0.125 mg/kg) induced a sensitized 8-OHDPAT response that was prevented by chronic cotreatment with the lowest but not the highest dose of quinpirole. Cotreatment with 8-OHDPAT (0.0625) and quinpirole (0.125 mg/kg) induced sensitization to 8-OH-DPAT. The saline challenge test showed elevated locomotor activity in chronic quinpirole (0.125 mg/kg) and 8-OHDPAT (0.0625, 0.125 mg/kg) alone groups, and in seven of nine cotreated groups. The absence of cross-sensitization suggests separate mechanisms of sensitization to quinpirole and 8-OH-DPAT. Cotreatment effects suggest that induction of sensitization can be modulated by serotonin 1A and D2/D3 activity.

Dopaminergic Modulation of Orofacial Mechanical Hypersensitivity Induced by Infraorbital Nerve Injury

“…The A11 nucleus contains almost 2.5 times more GABA-containing neurons as compared with dopamine-containing neurons, and noxious facial stimulation activates GABA-containing neurons in the A11 nucleus [15], suggesting that GABA-containing neurons in the A11 nucleus might be involved in the regulation of dopaminergic neuron activity. Dopamine D2 agonist and GABA A receptor agonist were reported to affect motor function [33][34][35][36]. Therefore, the change of head-withdrawal threshold measured in our study might be the result of not only attenuation of mechanical hypersensitivity but also change of motor function by quinpirole and muscimol.…”

Memantine and Riluzole Exacerbate, Rather Than Ameliorate Behavioral Deficits Induced by 8-OH-DPAT Sensitization in a Spatial Task

“…If the drug application was discontinued after the end of the habituation phase, sensitization to 8-OH-DPAT during habituation had no effect on spatial performance and locomotion during acquisition. Contrarily, Johnson and Szechtman [39] found that chronic administration of 8-OH-DPAT at low doses (0.0625, 0.125 mg/kg) per 8 days produced hyperlocomotion and compulsive checking even when tested after several days without the 8-OH-DPAT. However, it should be noted that the difference between spontaneous behavior (open field) and motivated behavior (carousel maze) might add up to the divergence of results.…”

Changes in gut microbiota during development of compulsive checking and locomotor sensitization induced by chronic treatment with the dopamine agonist quinpirole

“…For instance, using the 2-deoxyglucose technique to measure local cerebral glucose utilization in quinpirole-sensitized animals (Carpenter et al, 2003;Richards et al, 2005), alterations had been found in cortical (the cingulate -4-cortex-area 1, frontal cortex-area 3, lateral orbital cortex, medial/ventral orbital cortex, and parietal cortex) and subcortical areas (ventral pallidum and nucleus accumbens); more recently, changes in the cortico-striato-thalamico-cortical circuit had been observed by PET neuroimaging in quinpirole-sensitized rats (Servaes et al, 2016). Others report in quinpirole-sensitized animals: increased high-affinity states of dopamine D2 receptors (D2 High ) (Seeman et al, 2006;Perreault et al, 2007;Culver et al, 2008); decreased dopamine levels in the left pre-frontal cortex (Sullivan et al, 1998); reduced dopamine and glutamate neurotransmission in the nucleus accumbens (Escobar et al, 2015); as well alterations in dopamine-serotonin interaction (Alkhatib et al, 2013;Tucci et al, 2013;Johnson and Szechtman, 2016). However, it remains to be established which of those findings, if any, are necessary for the pathophysiology of compulsive checking (Szechtman et al, 2014).…”