Enhanced α1 adrenergic sensitivity in sensorimotor gating deficits in neonatal ventral hippocampus-lesioned rats

Abstract

Neonatal ventral hippocampus (nVH) lesion in rats is a widely used animal model of schizophrenia due to the predominantly post-pubertal emergence of many schizophrenia-like behaviours. Our previous studies have shown increased ligand binding of alpha1 adrenergic receptors (AR) in the frontal cortex of post-pubertal, but not pre-pubertal, nVH-lesioned rats, compared to sham-lesioned control rats. Moreover, pretreatment with the alpha1 adrenergic receptor antagonist prazosin reversed amphetamine-induced hyperlocomotion in controls, but failed to do so in lesioned animals. This led to our hypothesis that nVH lesions may lead to post-pubertal hyperactivity of alpha1 adrenergic receptors. In order to test the functional relevance of alpha1 adrenergic hyperactivity to schizophrenia-like behaviours of nVH-lesioned animals, we conducted prepulse inhibition (PPI) studies in post-pubertal (postnatal days 56-120) sham and lesioned animals in response to systemic injections of alpha1 adrenergic receptor antagonist and agonist, prazosin and cirazoline, respectively. Our results show that PPI deficits in nVH-lesioned animals were reversed with prazosin treatment, without a significant effect on PPI in sham animals. Further, at various doses, cirazoline had a significantly greater PPI disruptive effect in nVH-lesioned animals than in sham animals. Together, these results suggest that nVH-lesioned animals show a hyperactive alpha1 adrenergic receptor system that may mediate sensorimotor gating abnormalities reported in these animals.

Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat

“…The neural circuits regulating PPI include the hippocampus, nucleus accumbens, frontal cortex, and amygdala (Braff 2010; Swerdlow et al 2001). Given the fact that these areas exhibit ENA following a single dose of phenobarbital on P7 (Forcelli et al, 2011a), and that nVH lesions also cause long term changes in several of these areas (Negrete-Díaz et al 2010; Kamath et al 2008; Powell et al 2006), it is not surprising that both treatments lead to disruptions in PPI. The fact that we did not see a worsening of the lesion effect in phenobarbital-exposed animals may be due to the severity of the lesion effect by itself.…”

“…As described previously (Kamath et al 2008), PPI of the ASR was measured using a commercially available system (SR-LAB; San Diego Instruments, San Diego, CA) in two sound-attenuating chambers, each equipped with a cylindrical Plexiglas animal enclosure and a small electric fan, which generated a 70 dB background noise and provided ventilation. Sound pressure levels (dB(A) weighting) were measured at the position of the rats ears.…”

Effects of Neonatal Antiepileptic Drug Exposure on Cognitive, Emotional, and Motor Function in Adult Rats

“…The reduction is considered to reflect sensorimotor gating, a function shown to be abnormal in a number of psychiatric disorders (Swerdlow et al, 2000). Testing was conducted as described previously (Kamath et al, 2008) by using SR-Lab (San Diego Instruments, San Diego, CA). Background noise (70 dB) and ventilation were provided by an electric fan.…”

“…Locomotor and exploratory functions were assessed by using accelerating rotorod and open-field tasks; cognitive functions were assessed by using the Morris water maze and fear-conditioning paradigms; emotionality was assessed by using the elevated plus maze and social behavior tasks; and sensorimotor gating was assessed by prepulse inhibition (PPI) of the acoustic startle response. The latter three assessments have been used to detect abnormalities that reflect aspects of human neuropsychiatric disorders (Sams-Dodd, 1999;Kamath et al, 2008). This is of particular interest because patients with a history of early life seizures exhibit a high incidence of neuropsychiatric symptoms, but it is unclear whether such symptoms are triggered by seizures, AED therapy, and/or an underlying pathology (Vestergaard et al, 2005).…”

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

“…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.…”