Gene knockout of glycine transporter 1: characterization of the behavioral phenotype.

N-methyl-d-aspartate receptor (NMDAR) activation requires both the binding of glutamate to its recognition site and occupancy of the strychnine insensitive glycine modulatory site (GMS). Pharmacological studies suggest that the glycine transporter, GlyT1, maintains subsaturating concentrations of glycine at synaptic NMDARs. To characterize further the role of GlyT1, we generated mice in which the gene encoding GlyT1 was inactivated by homologous recombination through insertion of a PGK-Neo cassette in place of exons 2 and 3. Real-time quantitative PCR revealed no transcripts in newborn homozygous [GlyT1(-/-)] mice and a 50% reduction in heterozygous (HZ) [GlyT1(+/-)] mice as compared with WT littermates. The activity of Na(+)-dependent glycine transport in forebrain homogenates was similarly affected. Homozygous mice died within 12 h of birth. In acute hippocampal slices, exogenous glycine or d-serine (10 microM) enhanced NMDAR currents with Schaffer collateral stimulation in WT mice but not HZ mice, suggesting that the GMS was more occupied in the latter. The NMDAR/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ratio of the excitatory postsynaptic currents was significantly increased in the HZ mice. In the water maze, the HZ mice exhibited better spatial retention. Furthermore, HZ mice were less sensitive to an amphetamine disruption of prepulse inhibition than WT mice but were more sensitive to the effects of MK-801. Thus, reduced expression of GlyT1 enhances hippocampal NMDAR function and memory retention and protects against an amphetamine disruption of sensory gating, suggesting that drugs which inhibit GlyT1 might have both cognitive enhancing and antipsychotic effects.

Valproate attenuates hyperactive and perseverative behaviors in mutant mice with a dysregulated dopamine system.

BACKGROUND: Dopamine transporter (DAT) knockdown (KD) mice, with approximately 90% loss of expression of the DAT, allow for the examination of the behavioral consequences of a chronically dysregulated dopamine system. The DAT KD mice have hyperdopaminergic tone, are hyperactive, and show impaired response inhibition in a number of paradigms. We hypothesized that the DAT KD mice would also display deficits in prepulse inhibition (PPI) and would be perseverative in their locomotor behavior. METHODS: Basal levels of PPI and patterns of locomotor behavior were measured in two cohorts of DAT KD mice. In addition, measurements of locomotor behavior were recorded after pretreatment with 100 mg/kg valproate in both DAT KD and wildtype mice. RESULTS: The DAT KD mice were hyperactive and displayed perseverative motor behavior but had normal levels of PPI. The clinically effective antimania drug valproate significantly attenuated the hyperactivity and perseverative locomotor behavior in the DAT KD mice and had no effect in control mice. CONCLUSIONS: The DAT KD mice appear to provide a model of some aspects of manic behavior. With limited models of bipolar disorder, the DAT KD mice might provide a vehicle to screen for new psychiatric therapies to treat mania and its related symptoms.

Dopamine D1 rather than D2 receptor agonists disrupt prepulse inhibition of startle in mice.

Although substantial literature describes the modulation of prepulse inhibition (PPI) by dopamine (DA) in rats, few reports address the effects of dopaminergic manipulations on PPI in mice. We characterized the effects of subtype-specific DA agonists in the PPI paradigm to further delineate the specific influences of each DA receptor subtype on sensorimotor gating in mice. The mixed D1/D2 agonist apomorphine and the preferential D1-family agonists SKF82958 and dihydrexidine significantly disrupted PPI, with differing or no effects on startle. In contrast to findings in rats, the D2/D3 agonist quinpirole reduced startle but had no effect on PPI. Pergolide, which has affinity for D2/D3 and D1-like receptors, reduced both startle and PPI, but only at the higher, nonspecific doses. In addition, the D1-family receptor antagonist SCH23390 blocked the PPI-disruptive effects of apomorphine on PPI, but the D2-family receptor antagonist raclopride failed to alter the disruptive effect of apomorphine. These studies reveal potential species differences in the DA receptor modulation of PPI between rats and mice, where D1-family receptors may play a more prominent and independent role in the modulation of PPI in mice than in rats. Nevertheless, due to the limited selectivity of DA receptor agonists, further studies using specific receptor knockout mice are warranted to clarify the respective roles of specific DA receptor subtypes in modulating PPI in mice.

Differential effects of direct and indirect dopamine agonists on prepulse inhibition: a study in D1 and D2 receptor knock-out mice.

Stimulation of the dopamine (DA) system disrupts prepulse inhibition (PPI) of the acoustic startle response. On the basis of rat studies, it appeared that DA D2 receptors (D2Rs) rather than D1 receptors (D1Rs) regulate PPI, albeit possibly in synergism with D1Rs. To characterize the DA receptor modulation of PPI in another species, we tested DA D1R and D2R mutant mice with direct and indirect DA agonists and with the glutamate receptor antagonist, dizocilpine (MK-801). Neither the mixed D1/D2 agonist apomorphine (5 mg/kg) nor the more selective D1-like agonist SKF82958 (0.3 mg/kg) altered PPI in D1R knock-out mice, although both compounds disrupted PPI in D2R mutant and wild-type mice, suggesting that the D1R alone might modulate PPI in mice. However, amphetamine (10 mg/kg) significantly lowered PPI in each genotype of D1R mice, suggesting that the D1R is not necessary for the PPI-disruptive effect of the indirect agonist in mice. As reported previously, amphetamine (10 mg/kg) failed to disrupt PPI in D2R knock-out mice, supporting a unique role of the D2R in the modulation of PPI. Dizocilpine (0.3 mg/kg) induced similar PPI deficits in D1R and D2R mutant mice, confirming that the influences of the NMDA receptor on PPI are independent of D1Rs and D2Rs in rodents. Thus, both D1Rs and D2Rs modulate aspects of PPI in mice in a manner that differs from dopaminergic modulation in rats. These findings emphasize that further cross-species comparisons of the pharmacology of PPI are essential to understand the relevance of rodent PPI studies to the deficits in PPI observed in patients with schizophrenia.