Effects of the neurotensin NTS₁ receptor agonist PD149163 on visual signal detection in rats

Abstract

Antipsychotic drugs provide limited efficacy for cognitive impairment in schizophrenia. Recent studies have found that the neurotensin NTS1 receptor agonist and putative atypical antipsychotic drug PD149163 reverses deficits in sensory-gating and novel object recognition, suggesting that this compound may have the potential to improve cognitive functioning in schizophrenia. The present study sought to extend these investigations by evaluating the effects of PD149163 on sustained attention using a visual signal detection operant task in rats. PD149163, the atypical antipsychotic drug clozapine, and the dopamine D2/3 receptor antagonist raclopride all significantly decreased percent "hit" accuracy, while none of these compounds altered "correct rejections" (compared to vehicle control). Clozapine and raclopride significantly increased response latency, while high doses of PD149163 and raclopride significantly increased trial omissions. Nicotine, which was tested as a positive control, significantly improved overall performance in this task and did not affect response latency or trial omissions. The present findings suggest that neurotensin NTS1 receptor agonists, like antipsychotic drugs, may inhibit sustained attention in this task despite having different pharmacological mechanisms of action.

Keywords: Antipsychotic; Attention; NTS(1) receptor; Neurotensin; PD149163; Visual signal detection.

Figure 1

The compound structures of the neurotensin NTS₁ receptor agonist PD149163 (left), atypical antipsychotic drug clozapine (center), and dopamine D_2/3 antagonist and typical antipsychotic drug raclopride (right).

Figure 2

The procedures for either a signal trial (top), defined as a change in signal light intensity, or blank trial (bottom), defined as no change in signal light intensity, are shown. Both trial types started immediately following the completion of the previous trial. The signal trial (top) started with a pre-signal interval, followed by a brief increase in illumination of the signal light (i.e. signal). After the signal, there was a post-signal interval and then the levers were presented for the animal to emit a response. For signal trials, a correct response was defined as a “hit” and resulted in the delivery of food pellet, while an incorrect response was defined as a “miss” and resulted in a “timeout.” Blank trials (bottom) were identical to signal trials, except that no signal followed the pre-signal interval (i.e. no increase in illumination). For blank trials, a correct response was defined as a “correct rejection” and resulted in a food pellet, while an incorrect response was defined as a “false alarm” and resulted in a “timeout.” Response omissions resulted in a “timeout.”

Figure 3

The effects of PD149163 (top), clozapine (middle), or raclopride (bottom) on percent hits (left panels) and percent correct rejections (right panels). Statistically significant main effects of dose for percent hits are noted. #P<0.05 versus 0.625mg/kg; ++P<0.01 versus 2.5 mg/kg. See figure 2 for a description of these procedures.

Figure 4

The effects of nicotine on correct percent hits (left) and percent correct rejections (right). Statistically significant main effects of dose for percent hits are noted. *P<0.05 versus vehicle.