Extended access to methamphetamine self-administration affects sensorimotor gating in rats

Abstract

Disturbed information processing observed in neuropsychiatric disorders is reflected by deficient sensorimotor gating, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). Long-term, higher dose methamphetamine (METH) abuse patterns are associated with cognitive impairments, mania and/or schizophrenia-like psychosis. The present study investigated in rats METH-induced impairment of sensorimotor gating using an intravenous self-administration (IVSA) escalating dose procedure. In this procedure, rats escalated drug intake during weekly extended access periods to METH IVSA (1, 3, and 6h), where PPI was assessed after each access period and thus at various times of drug exposure. Despite increased drug intake over the course of extended access to METH, disruption of sensorimotor gating was only seen after the access period of 6h. The data suggest that METH-induced impairment of sensorimotor gating in IVSA-tasks is rather attributed to continuous and higher dose exposure than to actual amounts of drug present at the time of testing. IVSA procedures, comprising stepwise stimulant escalation may serve as a useful translational model in rats that approximate important aspects of human abuse pattern in the context of stimulant-induced cognitive and behavioral deficits.

Fig. 1

Course of escalation of METH intake following extended drug availability at a dose of 0.05 mg/kg/infusion. Active lever pressing and total METH intake (mg/kg) during the different extended access sessions is presented in (A), active lever pressing and METH intake (mg/kg) during the first hour is depicted in (B). Data are expressed as means ± SEM, whereas each dot represents lever pressing and METH intake (mg/kg) at the respective time points. Differences in active lever pressing between long-term access (3, 6-h) and the last session of the short-term (1-h) access period are indicated as asterisks (ANOVA, Tukey’s post hoc t-test, p < 0.05).

Fig. 2

PPI of the ASR in rats after extended access to METH IVSA. Animals were always tested after six days of different access periods. Data are expressed as mean ± SEM. Animal numbers of the access/control group for ASR testing correspond to the ones of the PPI testing (see A-C). Differences in PPI between the METH group and controls are indicated by asterisks (A-C), differences in ASR between access times within the METH group by triangles (D) (ANOVA, Tukey’s post hoc t-test, p < 0.05).

Fig. 3

Effects of METH on activity readings between startle trials (“Nostim” levels) during limited and extended access to METH self-administration. Data are expressed as means ± SEM. Difference in NOSTIM activity between the METH group and controls is indicated by asterisk (ANOVA, Tukey’s post hoc t-test, p < 0.05).

Fig. 4

Estimated METH intake during the last 30 min before PPI and ASR testing. Data are expressed as means ± SEM. Difference in drug intake between short- (1-h) and long-term access (6-h) is indicated by asterisk. (ANOVA, Tukey’s post hoc t-test, p < 0.05).