Disparate effects of pramipexole on locomotor activity and sensorimotor gating in Sprague–Dawley rats

Abstract

Prepulse inhibition (PPI) of acoustic startle and locomotor activity are both widely studied in the preclinical development of dopaminergic agents, including those acting at D3 dopamine receptors. In mice, the dopamine D3 receptor-preferential agonist pramipexole (PPX) alters locomotor activity in a biphasic manner at doses that have no effect on PPI. The present study examined the time-course of PPX effects on locomotion and PPI in rats. In adult male Sprague–Dawley rats, PPX (0, 0.1, 0.3, 1.0 mg/kg) was injected prior to measurement of locomotor activity for 90 min in photobeam chambers. Based on disparate early vs. late effects of PPX on locomotion, the effects of PPX (0 vs. 0.3 mg/kg) on PPI were tested 20 and 80 min after injection. All doses of PPX decreased locomotor activity for 30 min compared to vehicle, and the higher doses stimulated hyperlocomotion later in the session; the late hyperlocomotion, but not the early hypolocomotion, was blocked by the D2-selective antagonist, L741626 (1.0 mg/kg sc). In contrast to its locomotor effects, PPX caused a similar reduction in PPI at 20 and 80 min after administration. These findings suggest both a temporal and pharmacological dissociation between PPX effects on locomotor activity and PPI; these two behavioral measures contribute non-redundant information to the investigation of D3-related behavioral pharmacology.

Identification of key residues involved in the activation and signaling properties of dopamine D3 receptor

“…These results are consistent with our recent studies comparing tolerance-inducing D3 receptor agonist, PD128907, and, ES609, a novel D3 receptor agonist that does not induce tolerance [19]. Other groups have also shown that D3/D2 agonists such as pramipexole, which we have shown to induce D3 receptor tolerance [20], elicits hypoactivity followed by hyperactivity [23][24][25][26]. While a D2 receptor-selective antagonist blocked the hyperactivity, it did not affect the initial hypoactivity [24].…”

“…Agonists such as cis-PBZI, that exhibit partial agonism at pre-synaptic D2S receptor and full agonism at post-synaptic D2L and D3 receptors, might be particularly effective for treating motor disorders with dopaminergic deficits. Previous studies have shown that increase in rodent locomotor activity is mediated by concurrent stimulation of dopamine D1 and D2 receptors [1,38,39] and inhibited by dopamine D3 receptors [1,[23][24][25][26]. If concurrent stimulation of D1 and D2 receptors results in increased locomotor activity and D3 receptor activation inhibits locomotion, loss of D3 receptor function due to tolerance induction might result in increased locomotor activity.…”

“…We have recently used drd3-EGFP model to show that D3 receptor tolerance property is observed in the D3 receptor-MAPK signaling pathway and at behavior level [19]. Administration of D3 receptor agonist, including cis-PBZI, induces hypoactivity in rodents; however, it has been shown that administration of classical tolerance and SRTinducing D3 receptor agonists such as PD128907, 7-OH-DPAT and quinpirole elicits a biphasic locomotor behavior in which the initial hypoactive phase is followed by a hyperactive phase [23][24][25][26]. The results in Fig.…”

“…In this paper, we compared the ability of cis and trans isomers of 8-OH-PBZI to activate D2S and D2L receptor signaling. Administration of classical tolerance and SRT-eliciting D3 receptor agonists to rodents, induces an initial decrease, followed by an increase in locomotor activity [23][24][25][26]. We have hypothesized that the biphasic locomotor response to D3 receptor agonist might be a result of D3 receptor tolerance property wherein the initial inhibitory modulation of D1-and D2 receptor-driven locomotor activity by D3 receptor is attenuated as the D3 receptor undergoes tolerance [19].…”

Evaluation of Activity Patterns in Quinpirole-Treated Rats

“…Furthermore, phenomena such as desensitization [3] or sensitization [4] [5] of dopamine receptors add additional uncertainty on the outcome of a given treatment. Even in controlled experimental conditions, a given dose of a dopaminergic drug may elicit biphasic patterns of behavioral activity [6] [7], different doses may produce opposite responses, and the effect of chronic treatments may differ from the effect of acute drug administration [8] [9].…”