Neurochemical changes in LPA1 receptor deficient mice--a putative model of schizophrenia.

LPA1 is a Gi-coupled seven transmembrane receptor with high affinity for the ligand lysophosphatidic acid. We have investigated the effect of targeted deletion at the lpa1 locus on evoked release of amino acids from hippocampal slices, using in vitro superfusion techniques, and evoked 5-HT efflux from the dorsal raphe nucleus, using in vitro fast cyclic voltammetry. Superfusion of hippocampal slices revealed that basal levels of tyrosine, aspartate and glutamate release were significantly increased while K+ -evoked release of glutamate and GABA were significantly decreased in lpa1(-/-) mice. Fast cyclic voltammetry measurements in the dorsal raphe nucleus demonstrated significant decreases in electrically evoked 5-HT efflux in lpa1(-/-) mice. In summary, these data demonstrate that the lpa1 mutation produces a number of changes in neurotransmitters that have been associated with a schizophrenic-like pathology.

The effect of clozapine on extracellular dopamine levels in the shell subregion of the rat nucleus accumbens is reversed following chronic administration: comparison with a selective 5-HT(2C) receptor antagonist.

The clinical onset of both the therapeutic and side effects of antipsychotic drugs can take days/weeks to develop. Therefore, it is likely that adaptive changes in neurotransmission of key systems may only manifest upon chronic administration. Thus, using in vivo microdialysis we have evaluated the acute and chronic (21 days) effects of the atypical antipsychotic clozapine on nucleus accumbens (NAcc) dopamine (DA) output in the rat. Clozapine (10 mg/kg p.o.) produced an acute 60% increase in extracellular levels of DA in the shell but not the core subregion of the NAcc. This clozapine-induced effect was also apparent on day 8 (59% increase) of chronic administration. However, on day 22 (following 21 days chronic administration), clozapine-induced a significant decrease in extracellular DA levels (44% decrease). Since clozapine possesses significant affinity for the 5-HT(2C) receptor these clozapine-induced effects were compared to those of SB-243213, a selective 5-HT(2C) receptor antagonist. SB-243213 (10 mg/kg p.o.) had no effect on NAcc DA levels either acutely or following 21 days chronic administration. These data demonstrate that the atypical neuroleptic clozapine is more effective at eliciting changes in the shell vs the core subregion of the NAcc. In contrast, chronic treatment produces a time-dependent reduction in clozapine-induced DA efflux in the shell subregion. This selective temporal change in dopaminergic neurotransmission may be associated with the delayed therapeutic onset of antipsychotic activity. However, since SB-243213 had no effect on DA levels in the NAcc, it is likely that 5-HT(2C) receptor antagonism alone is not the mechanism by which clozapine exerts is actions.

BACE1 (beta-secretase) transgenic and knockout mice: identification of neurochemical deficits and behavioral changes.

BACE1 is a key enzyme in the generation of Abeta, the major component of senile plaques in the brains of Alzheimer's disease patients. We have generated transgenic mice expressing human BACE1 with the Cam Kinase II promoter driving neuronal-specific expression. The transgene contains the full-length coding sequence of human BACE1 preceding an internal ribosome entry site element followed by a LacZ reporter gene. These animals exhibit a bold, exploratory behavior and show elevated 5-hydroxytryptamine turnover. We have also generated a knockout mouse in which LacZ replaces the first exon of murine BACE1. Interestingly these animals show a contrasting behavior, being timid and less exploratory. Despite these clear differences both mouse lines are viable and fertile with no changes in morbidity. These results suggest an unexpected role for BACE1 in neurotransmission, perhaps through changes in amyloid precursor protein processing and Abeta levels.

Gradient of dopamine responsiveness to dopamine receptor agonists in subregions of the rat nucleus accumbens.

The present study sought to investigate the possibility that the degree of selectivity of dopamine D3/D2 receptor agonists such as quinelorane, 7-hydroxy-2-dipropylaminotetralin (7-OH-DPAT), quinpirole and apomorphine on dopamine D3 over D2 receptor subtypes can be assessed by measuring dopamine transmission in the shell vs. core compartments of the nucleus accumbens by using microdialysis in freely moving rats. Significant reductions in dialysate dopamine levels compared to vehicle-treated animals were observed in the shell of the nucleus accumbens with 3, 10 and 30 microg/kg quinelorane, 100 microg/kg 7-OH DPAT, 25 and 100 microg/kg quinpirole, and 100 microg/kg apomorphine. In the core subregion, significant reductions in dopamine were seen at 10 and 30 microg/kg quinelorane, 25 and 100 microg/kg 7-OH-DPAT, 100 microg/kg quinpirole and 100 microg/kg apomorphine. However, a significant shell/core dichotomy could only be observed in response to the lowest dose of quinelorane (3 microg/kg) with the shell being hyper-responsive compared with the core. The present findings suggest that quinelorane is one of the most selective dopamine D3 receptor agonists based on its ability to target the shell subregion of the nucleus accumbens.

Intraventricular 5,7-dihydroxytryptamine lesions disrupt acquisition of working memory task rules but not performance once learned.

The serotonergic system is implicated in learning and memory and its disorder, e.g. after 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") abuse. This study examined the effects of widespread depletion of serotonin (5-HT) using intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) on the learning of a working memory task in the dark agouti (DA) rat. The lesion impaired acquisition but not later performance of a nonspatial working memory rule, as measured using nonmatch to sample object recognition in the Y-maze. The lesion had a marginal effect on choice completion times over the course of testing. However, nonspecific effects did not provide a good account of the reduction in choice accuracy as this persisted when completion times were taken into account statistically. Similarly, in a second experiment, the same lesioned rats were slowed in the acquisition of spatial alternation in the T-maze. However, in the open field, there were no comparably long-lasting effects of the serotonergic depletion on line crossings and defecation, only a transient reduction in activity on the first day.Together, these data suggest that the serotonergic system is important in the acquisition of working memory tasks in the rat and that this outcome was unlikely to be the result of nonspecific effects of the lesion.