Jo Talledo

Amphetamine Effects on Prepulse Inhibition Across-Species: Replication and Parametric Extension

Despite the similarities of prepulse inhibition (PPI) of the startle reflex and its apparent neural regulation in rodents and humans, it has been difficult to demonstrate cross-species homology in the sensitivity of PPI to pharmacologic challenges. PPI is disrupted in rats by the indirect dopamine (DA) agonist amphetamine, and while studies in humans have suggested similar effects of amphetamine, these effects have been limited to populations characterized by smoking status and specific personality features. In the context of a study assessing the time course of several DA agonist effects on physiological variables, we failed to detect PPI-disruptive effects of amphetamine in a small group of normal males. The present study was designed to reexamine this issue, using a larger sample and a paradigm that should be more sensitive for detecting drug effects. PPI in rats was shown to be disrupted by the highest dose of amphetamine (3.0 mg/kg) at relatively longer prepulse intervals (>30 ms). In humans, between-subject comparisons of placebo (n=15) vs 20 mg amphetamine (n=15) failed to detect significant PPI-disruptive effects of amphetamine, but significant PPI-disruptive effects at short (10–20 ms) prepulse intervals were detected using within-subject analyses of postdrug PPI levels relative to each subjects baseline PPI. Post hoc comparisons failed to detect greater sensitivity to amphetamine among subjects characterized by different personality and physiological traits. Bioactivity of amphetamine was verified by autonomic and subjective changes. These results provide modest support for cross-species homology in the PPI-disruptive effects of amphetamine, but suggest that these effects in humans at the present dose are subtle and may be best detected using within-subject designs and specific stimulus characteristics.

Antipsychotic Effects on Prepulse Inhibition in Normal ‘Low Gating’ Humans and Rats

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg po) on PPI in 20 normal men with a ‘low PPI’ trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20–30 ms) in ‘low gating’ human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal ‘low gating’ appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.

The effects of memantine on prepulse inhibition.

Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in the levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. PPI was measured in male Sprague–Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, s.c.). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either (1) placebo vs 20 mg of the NMDA antagonist memantine (n=19) or (2) placebo vs 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Memantine had dose- and interval-dependent effects on PPI in rats. Compared with vehicle, 10 mg/kg increased short-interval (10–20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg, but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies in humans, as well as apparent inconsistencies in the NMDA regulation of PPI across species.

Startle modulation in Caucasian-Americans and Asian-Americans: a prelude to genetic/endophenotypic studies across the 'Pacific Rim'.

Objectives Deficient prepulse inhibition (PPI) of startle in schizophrenia patients and unaffected family members may be a useful endophenotype in studies seeking to identify vulnerability genes for schizophrenia. Before expanding such studies to include Pacific Rim populations with distinct genetic origins compared with North American Caucasian populations, we examined PPI and related startle measures in normal North American Caucasian and Asian men. Methods One hundred and seventy-four consecutive carefully screened right-handed male 18–35 year olds completed tests of startle and PPI using bilateral electromyography measures of orbicularis oculi. Subjects identified their racial background. Results Startle in Caucasian subjects was of significantly larger magnitude and shorter latency compared with Asian subjects; the percent PPI was significantly greater in Asian versus Caucasian subjects at 60 and 120 ms prepulse intervals. Group differences in PPI but not reflex latency were eliminated when groups were matched for startle magnitude on pulse alone trials. Caucasian-American and Asian-American groups did not differ significantly in resting blink rate, resting electromyography activity, or startle reflex habituation. Conclusions Robust phenotypic differences in acoustic startle magnitude and latency between Caucasian-American and Asian-American populations must be considered in studies using startle and PPI as endophenotypes across these populations.

Prestimulus modification of the startle reflex: relationship to personality and physiological markers of dopamine function.

Prepulse inhibition (PPI), a measure of sensorimotor gating, is regulated by dopamine (DA) in rodents. We examined the relationship of PPI in humans to putative markers of brain DA function: (1) novelty seeking (NS; Cloningers Tridimensional Personality Questionnaire (TPQ)), which is associated with specific DA receptor subtypes, and is reduced in Parkinsons Disease; (2) blink rate, which is increased in primates by DA agonists, and is reduced in Parkinsons Disease. PPI, TPQ and blink rate were measured in 79 normal adult males. A significant negative correlation was observed between resting blink rate and mean PPI, but not between NS and PPI. Blink rate correlated positively with resting EMG level, but this did not account for the relationship between blink rate and PPI. In normal male humans, PPI is inversely related to a physiological marker of resting DA tone (blink rate), but not to a putatively DA-linked personality trait (high NS).

Memantine Effects On Sensorimotor Gating and Mismatch Negativity in Patients with Chronic Psychosis

Patients with chronic psychotic disorders (CPD) exhibit deficient sensorimotor gating (measured by prepulse inhibition (PPI) of startle) and mismatch negativity (MMN). In healthy subjects (HS), N-methyl-D-aspartate (NMDA) antagonists like memantine and ketamine increase PPI, and under some conditions, memantine enhances MMN; these findings present a challenge to understanding the basis for deficient PPI and MMN in psychotic disorders, as reduced NMDA activity is implicated in the pathogenesis of these disorders. Here we assessed for the first time the effects of memantine on PPI and MMN in CPD subjects. Baseline PPI was measured in HS and patients with a diagnosis of schizophrenia or schizoaffective disorder, depressed type. Subjects (total n=84) were then tested twice, in a double-blind crossover design, comparing either: (1) placebo vs 10 mg of memantine or (2) placebo vs 20 mg memantine. Tests included measures of acoustic startle magnitude and habituation, PPI, MMN, autonomic indices, and subjective self-rating scales. Memantine (20 mg) significantly enhanced PPI in CPD subjects, and enhanced MMN across subject groups. These effects on PPI were age dependent and most evident in older CPD patients, whereas those on MMN were most evident in younger subjects. The lower dose (10 mg) either had no detectable effect or tended to degrade these measures. The NMDA antagonist, memantine, has dose-dependent effects on preconscious, automatic measures of sensorimotor gating and auditory sensory processing that are associated with enhanced cognition and function in CPD patients. Ongoing studies will determine whether these memantine-induced changes predict acute pro-cognitive or otherwise clinically beneficial effects in CPD patients.

Weak prepulses inhibit but do not elicit startle in rats and humans

BACKGROUND Inhibition of startle by weak prestimuli is called prepulse inhibition (PPI). It has recently been reported that 10- to 20-dB prepulses trigger eye-blink motor activity and PPI in normal human subjects. Motor activity after prepulses correlated negatively with PPI in four of nine possible conditions. We now report the relationship between prepulse-elicited startle (PPES) and PPI using weak prepulses. METHODS We assessed PPI and PPES using 1- to 5-dB prepulses in humans and in rats after treatment with vehicle or apomorphine. RESULTS Prepulses inhibited startle in an intensity-dependent fashion but elicited no startle activity in humans or rats. Apomorphine eliminated PPI in rats and produced a well-documented increase in stimulus-independent motor activity but did not stimulate PPES. CONCLUSIONS In humans and rats, PPES is not a necessary condition for either the elicitation or the disruption of PPI.

Single-Dose Memantine Improves Cortical Oscillatory Response Dynamics in Patients with Schizophrenia

Aberrant gamma-band (30–80 Hz) oscillations may underlie cognitive deficits in schizophrenia (SZ). Gamma oscillations and their regulation by NMDA receptors can be studied via their evoked power (γEP) and phase locking (γPL) in response to auditory steady-state stimulation; these auditory steady-state responses (ASSRs) may be biomarkers for target engagement and early therapeutic effects. We previously reported that memantine, an NMDA receptor antagonist, enhanced two biomarkers of early auditory information processing: prepulse inhibition and mismatch negativity (MMN) in SZ patients and healthy subjects (HS). Here, we describe memantine effects on γEP and γPL in those subjects. SZ patients (n=18) and HS (n=14) received memantine 20 mg (p.o.) and placebo over 2 test days in a double-blind, randomized, counterbalanced, cross-over design. The ASSR paradigm (1 ms, 85 dB clicks in 250–0.5 s trains at a frequency of 40 Hz; 0.5 s inter-train interval) was used to assess γEP and γPL. SZ patients had reduced γEP and γPL; memantine enhanced γEP and γPL (p<0.025 and 0.002, respectively) in both SZ and HS. In patients, significant correlations between age and memantine effects were detected for γEP and γPL: greater memantine sensitivity on γEP and γPL were present in younger SZ patients, similar to our reported findings with MMN. Memantine acutely normalized cortical oscillatory dynamics associated with NMDA receptor dysfunction in SZ patients. Ongoing studies will clarify whether these acute changes predict beneficial clinical, neurocognitive and functional outcomes. These data support the use of gamma-band ASSR as a translational end point in pro-cognitive drug discovery and early-phase clinical trials.

Effects of Amphetamine on Sensorimotor Gating and Neurocognition in Antipsychotic-Medicated Schizophrenia Patients

Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects. Moderators predicting AMPH sensitivity were assessed, including the rs4680 single-nucleotide polymorphism for catechol-O-methyltransferase (COMT). After placebo, patients exhibited PPI deficits with 60 ms prepulse intervals; these deficits were ‘rescued’ by amphetamine. The magnitude of amphetamine-enhanced PPI was greater in patients than in HS (p<0.032), and was associated with positive symptoms (p<0.007), antipsychotic load (p<0.015), hedonic effects of AMPH (p<0.003), and with the presence of at least one methionine allele in rs4680 (p<0.008). No significant effects of amphetamine on MCCB performance were detected in either group, though pro-attentional effects of amphetamine in patients were associated with greater amphetamine-enhanced TCT learning. Amphetamine acutely ‘normalized’ PPI in antipsychotic-medicated schizophrenia patients; no concurrent acute neurocognitive changes were detected by the MCCB. Findings suggest that in the context of appropriate antipsychotic medication, a low dose of amphetamine enhances brain processes associated with higher function in schizophrenia patients, without accompanying changes in MCCB performance.

Tolcapone-Enhanced Neurocognition in Healthy Adults: Neural Basis and Predictors

Abstract Background Failure of procognitive drug trials in schizophrenia may reflect the clinical heterogeneity of schizophrenia, underscoring the need to identify biomarkers of treatment sensitivity. We used an experimental medicine design to test the procognitive effects of a putative procognitive agent, tolcapone, using an electroencephalogram-based cognitive control task in healthy subjects. Methods Healthy men and women (n=27; ages 18–35 years), homozygous for either the Met/Met or Val/Val rs4680 genotype, received placebo and tolcapone 200 mg orally across 2 test days separated by 1 week in a double-blind, randomized, counterbalanced, within-subject design. On each test day, neurocognitive performance was assessed using the MATRICS Consensus Cognitive Battery and an electroencephalogram-based 5 Choice-Continuous Performance Test. Results Tolcapone enhanced visual learning in low-baseline MATRICS Consensus Cognitive Battery performers (d=0.35) and had an opposite effect in high performers (d=0.5), and enhanced verbal fluency across all subjects (P=.03) but had no effect on overall MATRICS Consensus Cognitive Battery performance. Tolcapone reduced false alarm rate (d=0.8) and enhanced frontal P200 amplitude during correctly identified nontarget trials (d=0.6) in low-baseline 5 Choice-Continuous Performance Test performers and had opposite effects in high performers (d=0.5 and d=0.25, respectively). Tolcapone’s effect on frontal P200 amplitude and false alarm rate was correlated (rs=-0.4, P=.05). All neurocognitive effects of tolcapone were independent of rs4680 genotype. Conclusion Tolcapone enhanced neurocognition and engaged electroencephalogram measures relevant to cognitive processes in specific subgroups of healthy individuals. These findings support an experimental medicine model for identifying procognitive treatments and provide a strong basis for future biomarker-informed procognitive studies in schizophrenia patients.