Ventral striatal noradrenergic mechanisms contribute to sensorimotor gating deficits induced by amphetamine

Abstract

The psychotomimetic drug D-amphetamine (AMPH), disrupts prepulse inhibition (PPI) of the startle response, an operational measure of sensorimotor gating that is deficient in schizophrenia patients. Historically, this effect has been attributed to dopaminergic substrates; however, AMPH also increases norepinephrine (NE) levels, and enhancement of central NE transmission has been shown recently to disrupt PPI. This study examined the extent to which NE might participate in AMPH-induced disruptions of PPI and increases in locomotor activity, another classic behavioral effect of AMPH, by determining whether antagonism of postsynaptic NE receptors blocked these effects. Separate groups of male Sprague-Dawley rats received either the α1 receptor antagonist, prazosin (0, 0.3, 1 mg/kg), or the β receptor antagonist timolol (0, 3, 10 mg/kg) before administration of AMPH (0 or 1 mg/kg) before testing for PPI or locomotor activity. As an initial exploration of the anatomical substrates underlying possible α1 receptor-mediated effects on AMPH-induced PPI deficits, the α1 receptor antagonist terazosin (0 or 40 μg/0.5 μl) was microinfused into the nucleus accumbens shell (NAccSh) in conjunction with systemic AMPH administration before startle testing in a separate experiment. Prazosin, but not timolol, blocked AMPH-induced hyperactivity; both drugs reversed AMPH-induced PPI deficits without altering baseline startle responses. Interestingly, AMPH-induced PPI deficits also were partially blocked by terazosin in NAccSh. Thus, behavioral sequelae of AMPH (PPI disruption and hyperactivity) may be mediated in part by NE receptors, with α1 receptors in NAccSh possibly having an important role in the sensorimotor gating deficits induced by this psychotomimetic drug.

Figure 1

Effects of pretreatment with the α1 receptor antagonist, prazosin (PRAZ), on (a) prepulse inhibition and (b) startle magnitude after amphetamine (AMPH) administration. Values represent means ± SEM for each drug condition. Doses are in mg/kg. Prepulse intensity indicates decibels above the background noise level. ^*P<0.05, ^**P<0.01, ^***P<0.001 relative to VEH+VEH condition; ⁺P<0.05 relative to VEH+AMPH condition.

Figure 2

Effects of pretreatment with the β receptor antagonist, timolol (TIM), on (a) prepulse inhibition and (b) startle magnitude after amphetamine (AMPH) administration. Values represent means ± SEM for each drug condition. Doses are in mg/kg. Prepulse intensity indicates decibels above the background noise level. ^*P<0.05, ^**P<0.01, ^***P<0.001 relative to VEH+VEH condition; ⁺P<0.05 relative to VEH+AMPH condition.

Figure 3

Effects of pretreatment with the α1 receptor antagonist, prazosin (PRAZ), on amphetamine (AMPH)-induced locomotion (a) and rearing (b). Values represent means ± SEM for each drug condition. Doses are in mg/kg. Arrows indicate the timepoint in the test session at which drugs were administered. ^*P<0.05, ^**P<0.01, ^***P<0.001 relative to VEH+VEH condition; ⁺P<0.05, ⁺⁺P<0.01, relative to VEH+AMPH condition.

Figure 4

Effects of pretreatment with the β receptor antagonist, timolol (TIM), on amphetamine (AMPH)-induced locomotion (a) and rearing (b). Values represent means ± SEM for each drug condition. Doses are in mg/kg. Arrows indicate the timepoint in the test session at which drugs were administered. ^*P<0.05, ^**P<0.01, ^***P<0.001 relative to VEH+VEH condition.

Figure 5

Effects of intra-nucleus accumbens shell (NAccSh) infusion of the α1 receptor antagonist, terazosin (TERAZ), on (a) prepulse inhibition and (b) startle magnitude after systemic amphetamine (AMPH) administration. Values represent means ± SEM for each drug condition. Prepulse intensity indicates decibels above the background noise level. ^*P<0.05, ^**P<0.01, ^***P<0.001, relative to VEH+VEH condition; ⁺P<0.05 relative to VEH+AMPH condition.

Figure 6

Injector tip locations within the nucleus accumbens shell for rats in experiment 5. Numbers are mm from bregma.