Convergence and divergence in the neurochemical regulation of prepulse inhibition of startle and N40 suppression in rats

Abstract

Prepulse inhibition of startle ('PPI'), a cross-species measure of sensorimotor gating, is impaired in schizophrenia patients. Suppression of P50 event-related potentials (ERPs) in response to the second of two clicks ('P50 gating') is also impaired in schizophrenia. Suppression of N40 ERPs to the second of two clicks ('N40 gating') is thought by some to be a rat homolog of human P50 gating. Emerging evidence suggests differences in the neurobiology of deficits detected by PPI vs P50 (or N40) gating. We recorded PPI and N40 gating contemporaneously in rats, to assess convergence and divergence in the neurochemical regulation of these measures. Dose-response studies examined the effects of apomorphine (APO), phencyclidine (PCP) or the 5HT2A agonist DOI on PPI, and on motor responses to stimuli (S1 and S2) that elicit N40 gating. Effects of optimal drug doses on PPI and N40 gating were then assessed in other rats with implanted cortical surface electrodes. APO, PCP and DOI caused dose-dependent disruptions of both PPI and gating of motor responses to N40 stimuli. Reduced PPI reflected diminished prepulse effectiveness, demonstrated by increased startle levels on prepulse+pulse trials. In contrast, reduced gating of motor responses to N40 stimuli reflected a reduced motor response to S1. In separate rats, robust PPI, N40 potentials and N40 gating could be detected within one test. PPI and N40 gating were disrupted by APO, PCP, and DOI. Again, drug effects on PPI reflected increased startle on prepulse+pulse trials, while those on N40 gating reflected reduced ERP responses to S1. In conclusion, when PPI and N40 gating were studied concurrently in rats, drug effects on PPI reflected reduced inhibition of startle by the prepulse, while diminished N40 gating reflected S1 response suppression. Despite similarities in drug sensitivity, these results suggest that distinct neurobiological mechanisms underlie drug-induced deficits in PPI and N40 gating.

Figure 1

Percent PPI in dose–response studies with APO (a), PCP (b) and DOI (c). (*) p < 0.05 vs vehicle dose.

Figure 2

Raw startle magnitude on PULSE trials (0 dB prepulse) and trials in which PULSE was preceded by 5, 10, or 15 dB prepulses, in rats treated with APO (a) or PCP (b). Note that in both (a) and (b): (1) vehicle-treated rats exhibit an orderly, intensity-dependent suppression of startle, and (2) rats treated with active drug doses exhibit a dose-dependent reduction in sensitivity to the startle-inhibiting effects of prepulses. This drug-induced reduction in the ability of prepulses to inhibit startle provides clear evidence for a loss of sensorimotor gating.

Figure 3

Raw startle magnitude on PULSE trials (0 dB prepulse) and trials in which PULSE was preceded by 5, 10, or 15 dB prepulses, in rats treated with DOI. (a) DOI produces a dose-dependent reduction in startle magnitude on PULSE trials that complicates a clear interpretation of drug effects on sensorimotor gating. (b) Startle magnitude from a subgroup of rats whose startle magnitude on PULSE trials was not significantly reduced by DOI (1.0 mg/kg). Note that for this group, a DOI-induced loss of sensorimotor gating is evident via the reduced ability of prepulses to inhibit startle magnitude (dose × trial interaction: F = 6.05, df 3,15, p < 0.007; posthoc comparisons: p < 0.002 (5 dB) and p < 0.008 (10 dB)). A comparable or slightly diminished separation was observed for the 0.5 mg/kg dose of DOI (p < 0.002 (5 dB) and p < 0.04 (10 dB)), but not for the 0.25 mg/kg dose (NS, all prepulse intensities).

Figure 4

Motor activity on trials with S1 and S2 ‘clicks’. Left side of figure shows ‘click motor activity’: peak response units 100 ms after S1 or S2 ‘clicks’ on same scale as startle magnitude in Figures 2–3. Note that motor activity on ‘click’ trials in vehicle-treated rats was: (1) 0.5–1.0% of the magnitude exhibited in response to PULSE trials; (2) greatly suppressed on S2 vs S1 trials. Also note that S2 amplitude appeared to be enhanced preferentially in a dose-dependent manner by (a) APO, (b) PCP, and (c) DOI. Right side of figure shows the same data, minus response units exhibited on NOSTIM trials (‘click minus nostim’). Note that, by removing NOSTIM background activity, S2 ‘gating’ remains intact in vehicle-treated rats, and the most evident drug effect is a suppression of motor activity in response to S1 clicks.

Figure 5

Raw startle magnitude on PULSE trials (0 dB prepulse) and trials in which PULSE was preceded by 5, 10, or 15 dB prepulses, in rats treated with vehicle or a single dose of APO (a), PCP (b), or DOI (c). Note comparability to Figures 2–3. Insets reveal mean %PPI, collapsed across prepulse intensities (*p < 0.05 vs vehicle). APO study used a within-subject design, while PCP and DOI studies used between-subject designs in order to limit total number of tests for each rat.

Figure 6

N40 ERP responses. (a) Grand average ERP waveforms in response to S1 and S2, across all rats treated with vehicle (top), APO, PCP, or DOI. Note in vehicle treated rats, the peak negativity to S1 at 40 ms poststimulus (stimulus at arrow), and reduced (‘gated’) amplitude to S2. This gating was disrupted by APO, PCP, and DOI, as a result of reduced S1 amplitude. This was evident in grand average waveforms, and in peak N40 amplitudes, shown in b. (b) Peak N40 amplitudes in response to S1 and S2 stimuli, in rats treated with vehicle or APO (left), PCP (middle), or DOI (right). Note significant reduction in S1 amplitude after treatment with APO and DOI (*p < 0.05 vs vehicle), and similar trend for this effect after treatment with PCP.