Separable noradrenergic and dopaminergic regulation of prepulse inhibition in rats: implications for predictive validity and Tourette Syndrome

Abstract

PPI is regulated by both norepinephrine and dopamine substrates that are neurochemically separable. The PPI-protective effects of clonidine suggest that the noradrenergic regulation of PPI may have utility for predicting therapeutic benefit in TS for drugs other than antipsychotics. Clonidine's failure to prevent the PPI-disruptive effects of apomorphine or phencyclidine further support the specificity of these PPI models for detecting drugs with antipsychotic properties.

Pharmacological Stimulation of Locus Coeruleus Reveals a New Antipsychotic-Responsive Pathway for Deficient Sensorimotor Gating

“…It was found that APO (Po0.01) and DOI (Po0.01) significantly reduced PPI (vehicle values ¼ 69±3; APO ¼ 34 ± 10; DOI ¼ 48 ± 5), that the SCH23390/APO (60 ± 7) and haloperidol/APO (59 ± 8) values were significantly higher than those for the vehicle/APO condition (Po0.05), and that the ritanserin/DOI condition (68±5) was significantly higher than the vehicle/DOI (Po0.05). These results agree with previous reports indicating that the presently used doses are sufficiently high to normalize PPI deficits produced by DA or 5-HT agonists, and further confirm that the failure of DA and 5-HT receptor antagonists to reverse LC-mediated PPI deficits is not just due to underdosing with these compounds (Bakshi and Geyer, 1997;Swerdlow et al, 2006).…”

“…Thus, the current results suggest the exciting possibility that LC-mediated PPI deficits are transduced through a novel DA-and 5-HT2-independent pathway that may operate in parallel to previously characterized substrates of PPI. The notion of parallel monoaminergic mechanisms for PPI has been suggested previously by systemic pharmacological studies using agonists and antagonists for DA and NE (Bakshi and Geyer, 1997;Carasso et al, 1998;Swerdlow et al, 2006), but the present studies for the first time implicate a specific neuroanatomical substrate in this dissociation.…”

“…Dopamine and serotonin antagonists in behaviorally active dose ranges (Bakshi and Geyer, 1997;Swerdlow et al, 2006) failed to alter LC-mediated PPI disruption, suggesting that transsynaptic activation of D1, D2, or 5-HT2 receptors does not underlie the present effects. This finding is noteworthy because to date, a majority of studies into the neural substrates of PPI have focused on DA-and 5-HTbased manipulations (Geyer, 2008).…”

“…Doses were calculated as salts, and systemic injection volume was 1 ml/kg. Doses and injection parameters of antipsychotics and monoamine receptor antagonists previously have been found to antagonize behavioral effects of psychotomimetics, dopamine, or serotonin agonists (Bakshi and Geyer, 1997;Swerdlow et al, 2006;Swerdlow et al, 2008). For microinfusions, injectors (connected via tubing to a microdrive pump) extended 3 mm past cannulae tips, and delivered drugs at 0.1 ml/min over 2 min, with a 1-min post-infusion period before reinsertion of stylets and immediate placement of rats into testing chambers.…”

“…Recent studies indicate that systemic manipulations of NE modulate PPI; a1 receptor agonists disrupt PPI in rats and, in mice, deletion of a2 receptors, which can function as presynaptic autoreceptors, reduces PPI and potentiates the PPI-disruptive effects of amphetamine via presumed augmentation of NE release (Alsene et al, 2006;Carasso et al, 1998;Kamath et al, 2008;Lahdesmaki et al, 2004;Mishima et al, 2004;Sallinen et al, 1998;Swerdlow et al, 2006). Nevertheless, the specific anatomical substrates of NE regulation of PPI are unknown.…”