Prenatal treatment with methylazoxymethanol acetate as a neurodevelopmental disruption model of schizophrenia in mice.

Methylazoxymethanol (MAM)-treated pregnant rat at gestation day (GD) 17 has been shown to be a valuable developmental animal model for schizophrenia. Yet, this model remains to be established in mice. In the present study, we examined behavioral, cytoarchitectural, and neurochemical changes in the offspring of MAM-treated mice and validated the model's face, construct and predictive validities. We found that in contrast to a single injection of MAM to dams at GD 15, 16 or 17, its daily administration from GD 15 to 17 led to deficits in prepulse inhibition (PPI) of startle in the post-pubertal offspring. In addition, we observed behavioral deficits in working memory and social interactions, as well as an increase in locomotor activity induced by the NMDA antagonist MK-801 in GD15-17 MAM offspring. These animals also showed a reduction in the volume of the prefrontal cortex (PFC) and hippocampus, neuroanatomical changes such as discontinuities and heterotopias in the hippocampus, and an increase of DA level and DOPAC/DA ratio in the medial PFC. Atypical antipsychotic drugs clozapine, risperidone, and aripiprazole, but not the typical drug haloperidol, reversed the deficit in PPI and social withdrawal in the offspring of MAM-treated dams. In contrast, MK-801-induced hyperactivity in MAM mice was reversed by both and typical or atypical antipsychotic drugs. Taken together, the treatment of pregnant mice with MAM during GD 15-17 offers a new approach to study neurobiological mechanisms involved in the pathogenesis of schizophrenia.

Psychostimulants, antidepressants and neurokinin-1 receptor antagonists ('motor disinhibitors') have overlapping, but distinct, effects on monoamine transmission: the involvement of L-type Ca2+ channels and implications for the treatment of ADHD.

Both psychostimulants and antidepressants target monoamine transporters and, as a consequence, augment monoamine transmission. These two groups of drugs also increase motor activity in preclinical behavioural screens for antidepressants. Substance P-preferring receptor (NK1R) antagonists similarly increase both motor activity in these tests and monoamine transmission in the brain. In this article, the neurochemical and behavioural responses to these three groups of drugs are compared. It becomes evident that NK1R antagonists represent a distinct class of compounds ('motor disinhibitors') that differ substantially from both psychostimulants and antidepressants, especially during states of heightened arousal or stress. Also, all three groups of drugs influence the activation of voltage-gated Ca(v)1.2 and Ca(v)1.3 L-type channels (LTCCs) in the brain, albeit in different ways. This article discusses evidence that points to disruption of these functional interactions between NK1R and LTCCs as a contributing factor in the cognitive and behavioural abnormalities that are prominent features of Attention Deficit Hyperactivity Disorder (ADHD). Arising from this is the interesting possibility that the hyperactivity and impulsivity (as in ADHD) and psychomotor retardation (as in depression) reflect opposite poles of a behavioural continuum. A better understanding of this pharmacological network could help explain why psychostimulants augment motor behaviour during stress (e.g., in preclinical screens for antidepressants) and yet reduce locomotor activity and impulsivity in ADHD. This article is part of the Special Issue entitled 'CNS Stimulants'.