Selective activation of D1 dopamine receptors impairs sensorimotor gating in Long-Evans rats

Abstract

Background and purpose: Sensorimotor gating is a perceptual process aimed at filtering out irrelevant information. In humans and animal models, this function can be operationally measured through the prepulse inhibition (PPI) of the acoustic startle reflex. Notably, PPI deficits are associated with numerous neuropsychiatric conditions characterized by gating disturbances, including schizophrenia and Tourette syndrome. Ample evidence has shown that dopamine plays a key role in PPI regulation and, in particular, rodent studies indicate that this neurotransmitter modulates PPI through D1 and D2 dopamine receptors. In mice, the relative contributions of these two families of receptors are strain-dependent. Conversely, the role of D1 receptors in the regulation of PPI across different rat strains remains unclear.

Experimental approach: We tested the effects of selective D1 and D2 receptor agonists and antagonists on the startle reflex and PPI of Sprague-Dawley, Wistar and Long-Evans rats.

Key results: In contrast with Sprague-Dawley and Wistar rats, the full D1 receptor agonist SKF82958 elicited significant PPI deficits in Long-Evans rats, an effect sensitive to the selective D1 antagonist SCH23390.

Conclusions and implications: Our results suggest that, in Long-Evans rats, D1 receptor activation may be sufficient to significantly impair PPI. These data emphasize the role of D1 receptors in the pathophysiology of neuropsychiatric disorders featuring alterations in sensorimotor gating, and uphold the importance of the genetic background in shaping the role of dopamine receptors in the regulation of this key information-processing function.

Linked articles: This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.

Figure 1

Scheme of the PPI paradigm. The green horizontal bar represents the 70 dB background noise; the blue vertical bars represent the 120 dB pulse trials; the red vertical bars represent the three prepulse levels of 74 dB, 78 dB and 82 dB. The complete session is outlined at the top with a portion enlarged to detail a subset of the trials. The acclimatization represents 5 min of exposure to the background noise; block 1 represents five pulse‐alone trials; block 2 represents 50 trials containing a pseudorandom sequence of no stimulus trials, pulse alone trials and prepulse‐pulse trials; block 3 represents five pulse‐alone trials.

Figure 2

Effects of the D ₁ receptor full agonist SKF82958 or its vehicle, saline (SAL), on startle reflex and PPI of the startle in SD, WIS and LE rats. Values represent mean ± SEM for each experimental group. Doses of SKF82958 (1 or 5 mg·kg⁻¹, s.c.) are indicated below the horizontal axis. *P < 0.05 in comparison with saline‐treated controls. For more details, see text.

Figure 3

Involvement of D ₁ receptors in the effects of SKF82958 (SKF; 5 mg·kg⁻¹, s.c.) in SD rats and 1 mg·kg⁻¹, s.c.) in WIS and LE rats) on the regulation of startle reflex and PPI in different rat strains, as tested through the combined treatment with the selective D ₁ receptor antagonist SCH23390 (SCH; 0.1 mg·kg⁻¹, IP). Values represent mean ± SEM for each experimental group. Doses of SKF are indicated in mg·kg⁻¹. *P < 0.05, significantly different as indicated. For more details, see text.

Figure 4

Involvement of D ₂ receptors in the effects of SKF82958 (SKF) on the regulation of startle reflex and PPI in different rat strains, as tested through the combined treatment with the selective D ₂ receptor antagonist L741,626 (L; 1 mg·kg⁻¹, s.c.). Values represent mean ± SEM for each experimental group. PPI values are represented as the means of all prepulse‐loudness values. Doses of SKF are indicated in mg·kg⁻¹. VEHL, vehicle for L741,626; *P < 0.05, significantly different as indicated. For more details, see text.

Figure 5

Effects of the D ₁ receptor partial agonist SKF38393 or its vehicle,saline (SAL), on startle reflex and PPI of the startle in SD, WIS and LE rats. Values represent mean ± SEM for each experimental group. Doses of SKF38393 (in mg·kg⁻¹, s.c.) are indicated below the horizontal axis. For more details, see text.

Figure 6

Involvement of D ₂ receptors in the effects of quinpirole (QUI) on the regulation of startle reflex and PPI in different rat strains, as tested through the combined treatment with the selective D ₂ receptor antagonist L741,626 (L; 1 mg·kg⁻¹, s.c.). Values represent mean ± SEM for each experimental group. PPI values are represented as the means of all prepulse‐loudness values. VEHL, vehicle for L741,626; *P < 0.05, significantly different as indicated. For more details, see text.

Figure 7

Effects of the non‐selective dopaminergic agonist apomorphine or its vehicle (VEHA) on startle reflex and PPI of the startle in SD, WIS and LE rats. Values represent mean ± SEM for each experimental group. Doses of apomorphine (in mg·kg⁻¹, s.c.) are indicated below the horizontal axis. *P < 0.05, in comparison to vehicle‐treated controls. For more details, see text.