Effects of Dopamine D2/D3 Blockade on Human Sensory and Sensorimotor Gating in Initially Antipsychotic-Naive, First-Episode Schizophrenia Patients

Abstract

It has been suggested that psychophysiological measures of sensory and sensorimotor gating, P50 gating and prepulse inhibition of the startle reflex (PPI), underlie core features of schizophrenia and are linked to dopaminergic pathways in the striatum and prefrontal cortex. In the present study, the effects of a potent D2/D3 receptor antagonist, amisulpride, were investigated on PPI and P50 gating in a large sample of antipsychotic-naive, first-episode patients with schizophrenia. A total of 52 initially antipsychotic-naive, first-episode schizophrenia patients were assessed for their P50 gating, PPI, and habituation/sensitization abilities at baseline and after 2 and 6 weeks of treatment with flexible doses of amisulpride. In addition, 47 matched healthy controls were assessed at baseline and after 6 weeks. At baseline, the patients showed significantly reduced PPI, yet normal levels of P50 gating, habituation, and sensitization. Treatment with amisulpride showed no effects on these measures, either at 2 or 6 weeks of follow-up. This is the first study investigating the effects of monotherapy with a relatively selective dopamine D2/D3 receptor antagonist (amisulpride) on sensory and sensorimotor gating deficits in a longitudinal study of a large group of initially antipsychotic-naive, first-episode patients with schizophrenia. Our finding that amisulpride effectively reduced symptom severity in our patients without reducing their PPI deficits indicates that increased activity of dopamine D2 receptors may be involved in symptomatology of patients with schizophrenia, but not in their sensorimotor gating deficits.

Auditory processing in autism spectrum disorder: Mismatch negativity deficits

“…Previously, we reported increased sensitization in this same ASD cohort [Madsen et al, ], as well as attenuated P50 amplitude in the children with Asperger's syndrome [Madsen et al, ]. Furthermore, other studies from our laboratory have indicated the usefulness of our CPTB battery for studying schizophrenia, by showing differences between antipsychotic naïve, first‐episode patients with this disorder and healthy controls [During et al, ; Oranje & Glenthoj, ].…”

“…The procedures concerning MMN assessment as used in the current study were identical to the ones previously described by During, Glenthoj, Andersen, and Oranje [2014]. In short, subjects were seated in a comfortable armchair in a sound-insulated room (sound reduction level of 40 dB) situated next to the control room.…”

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

“…In patients with schizophrenia, classical antipsychotics working through D2/D3 receptor blockade reduce the psychotic symptoms without affecting PPI deficits. 29,30 The findings for the new generation of antipsychotics with multireceptor profiles are more mixed, 29,31,32 and a cross-sectional study by Kumari and colleagues 33 provided indirect evidence of clozapine being superior to haloperidol for PPI deficits in patients with schizophrenia, which is not reflected by the present data from the Df(h22q11)/+ mice.…”

Targeting phosphodiesterase type 4 for improving cognitive fronto-striatal functioning

“…Excess dopamine will thus lead to excessive throughput impairing normal gating. This hypothesis is supported by the fact that dopamine D2 receptor antagonists can prevent the amphetamine-induced deficits in sensory gating (During, Glenthoj, Andersen, & Oranje, 2014;Freedman et al, 1987;Light et al, 1999;Witten et al, 2016). Dopamine D2 receptor antagonism prevents inhibition of inhibitory interneurons.…”

“…Dopamine D2 receptor antagonism prevents inhibition of inhibitory interneurons. Note, however, that in the field of schizophrenia research dopaminergic drugs generally show no gating enhancing effects, outside of the amphetamine-deficit model, in schizophrenia patients, healthy humans and animals, and animal models of schizophrenia other than the amphetamine-deficit model (Adler et al, 1990;Arango, Summerfelt, & Buchanan, 2003;During et al, 2014;Freedman et al, 1983;Light et al, 1999;Oranje et al, 2004;Sanchez-Morla et al, 2009;Siegel et al, 2005;Simosky, Stevens, Adler, & Freedman, 2003). Thus, so far D2 antagonism has not convincingly proven to be effective on sensory gating in healthy subjects (either animal or man; e.g.…”