Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges

The nucleus accumbens can be dissociated into at least two subregions: a 'core' and a 'shell'. Using temporary chemical inactivation of these subregions, we investigated whether they are differentially involved in the regulation of prepulse inhibition (PPI) of the acoustic startle reflex and activity. For this purpose, rats were bilaterally implanted with guide cannulae aimed at either the core or the shell and infused with the GABA A receptor agonist muscimol (0.5 mg/0.2 ml per side). The control group consisted of vehicle infused and unoperated rats. To ascertain the region selectivity of the infusions, 0.2 ml of [ 3 H]muscimol was infused into either the core or the shell of an additional group of rats. The behavioral results demonstrated that in comparison to the control group, inactivation of the core led to a loss of the prepulse intensity dependency of PPI. Moreover, core inactivation resulted in akinesia directly after infusion, but in hyperactivity 24 and 72 h thereafter in contrast to the control group. In both experiments, inactivation of the shell was ineffective compared to controls. Analysis of the autoradiograms revealed that the spread of drug into the other subregion was minimal, supporting the region selectivity of the inactivation. These results lend further support to the existence of a functional dissociation between the core and the shell, with the former being preferentially involved in PPI and locomotion. The persistent hyperactivity after the muscimol infusion into the core could be explained by compensatory mechanisms taking place in the nucleus accumbens.

Section: Effects Of Muscimol Infusion In the Core Or The Shell On Ppicontrasting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

The Effects of Temporary Inactivation of the Core and the Shell Subregions of the Nucleus Accumbens on Prepulse Inhibition of the Acoustic Startle Reflex and Activity in Rats

Pothuizen

Jongen-Rêlo

Feldon

2005

“…Cocaine, but not amphetamine, elicited more expression of c-fos in the shell than in the core of nucleus accumbens . The nucleus accumbens is a key modulator of PPI (for review Swerdlow et al, 2001). The disruptive effects of amphetamine seem to correlate in time with DA increase in the nucleus accumbens in the rat .…”

Section: Discussionmentioning

confidence: 99%

“…PPI deficits are observed in psychotic disorders, such as schizophrenia, and are associated with dopamine (DA) dysregulation Swerdlow et al, 2001). PPI deficits are modeled in mice and rats following treatment with psychotomimetic drugs, such as d-amphetamine, cocaine, or phencyclidine .…”

Section: Introductionmentioning

confidence: 99%

Contributions of Dopamine D1, D2, and D3 Receptor Subtypes to the Disruptive Effects of Cocaine on Prepulse Inhibition in Mice

Doherty

Masten

Powell

et al. 2007

Deficits in prepulse inhibition (PPI) of startle, an operational measure of sensorimotor gating, are characteristics of schizophrenia and related neuropsychiatric disorders. Previous studies in mice demonstrate a contribution of dopamine (DA) D 1 -family receptors in modulating PPI and DA D 2 receptors (D2R) in mediating the PPI-disruptive effects of amphetamine. To examine further the contributions of DA receptor subtypes in PPI, we used a combined pharmacological and genetic approach. In congenic C57BL/6 J wildtype mice, we tested whether the D1R antagonist SCH23390 or the D2/3R antagonist raclopride would attenuate the effects of the indirect DA agonist cocaine (40 mg/kg). Both the D1R and D2/3R antagonists attenuated the cocaine-induced PPI deficit. We also tested the effect of cocaine on PPI in wild-type and DA D1R, D2R, or D3R knockout mice. The cocaine-induced PPI deficit was influenced differently by the three DA receptor subtypes, being absent in D1R knockout mice, partially attenuated in D2R knockout mice, and exaggerated in D3R knockout mice. Thus, the D1R is necessary for the PPI-disruptive effects of cocaine, while the D2R partially contributes to these effects. Conversely, the D3R appears to inhibit the PPI-disruptive effects of cocaine. Uncovering neural mechanisms involved in PPI will further our understanding of substrates of sensorimotor gating and could lead to better therapeutics to treat complex cognitive disorders such as schizophrenia.

“…Despite the large number of studies on the neurotransmitter and neuroanatomical substrates of PPI Swerdlow et al, 2001), relatively little is known about the role of the norepinephrine (NE) system in regulating sensorimotor gating. This paucity is surprising, given the prominent role of NE in processes relevant to attention and cognitive functioning.…”

Section: Introductionmentioning

confidence: 99%

Disruption of Prepulse Inhibition after Stimulation of Central but not Peripheral α-1 Adrenergic Receptors

Alsene

Carasso²,

Connors

et al. 2006

Prepulse inhibition (PPI) refers to the attenuation of startle when a weak prestimulus precedes the startling stimulus. PPI is deficient in several psychiatric illnesses involving poor sensorimotor gating. Previous studies indicate that a1 adrenergic receptors regulate PPI, yet the extent to which these effects are mediated by central vs peripheral receptors is unclear. The present studies compared the effects of intracerebroventricular (ICV) vs intraperitoneal (IP) delivery of several a1 receptor agonists on PPI. Male Sprague-Dawley rats received either cirazoline (0, 10, 25, 50 mg/5 ml), methoxamine (0, 30, 100 mg/5 ml), or phenylephrine (0, 3, 10, 30 mg/5 ml) ICV immediately before testing. Separate groups received either cirazoline (0, 0.25, 0.50, 0.75 mg/kg), methoxamine (0, 2, 5, 10 mg/kg), or phenylephrine (0, 0.1, 2.0 mg/kg) IP 5 min before testing. PPI, baseline startle responses, and piloerection, an index of autonomic arousal, were measured. Cirazoline disrupted PPI; effective ICV doses were approximately six times lower than effective IP doses. Methoxamine disrupted PPI after ICV infusion but failed to affect PPI with IP doses that were up to 30-fold higher than the effective ICV dose. Phenylephrine disrupted PPI with ICV administration, but did not alter PPI after IP injection of even a 20-fold higher dose. None of the ICV treatments altered baseline startle magnitude, but phenylephrine and methoxamine lowered startle after administration of high systemic doses. Piloerection was induced by cirazoline via either route of administration, and by IP methoxamine and phenylephrine, but not by ICV infusion of methoxamine or phenylephrine. These findings indicate that a1 receptor-mediated PPI disruption occurs exclusively through stimulation of central receptors and is dissociable from alterations in baseline startle or autonomic effects.