International Congress on Schizophrenia Research S248Posters (Monday) molecular pathways affected in the cortex of subjects with MRDS and supports the notion that studying sub-groups within the syndrome of schizophrenia is worthwhile. ; or a combination of FS+RS). At adulthood, animals were tested for anxiety responses, cognitive function, and locomotor response to amphetamine. We also evaluated the activity of dopamine (DA) neurons in the ventral tegmental area (VTA) using in vivo electrophysiology. M102. PREFRONTAL CORTEX DYSFUNCTIONIn another experiment, we evaluated if a lesion within the plPFC in rats at PD25 induced by infusing ibotenic acid into the plPFC would increase the vulnerability to FS exposure during adolescence in the DA system activity. Results: All stressors induced anxiety-like responses in the elevated plusmaze. FS and FS+RS also disrupted cognitive function as assessed by the novel-object recognition test. Only animals exposed to the combination of FS+RS showed amphetamine-induced hyperlocomotion and increased VTA DA population activity. Interestingly, the increased DA population activity was confined to the lateral VTA, which project to associative striatal regions analogous to those found to be hyper-responsive in SZ patients. Unlike intact rats, animals with a plPFC lesion exposed only to the FS during adolescence showed a DA hyper-responsivity. However, these animals displayed a more widespread increase in DA neuron activity, with significant differences in both medial and lateral VTA. Given that the medial and central parts of the VTA send projections to the mPFC and amygdala and these projections play a role in emotional states, an increased DA activity in these VTA regions may reflect a mechanism related to a disruption of the plPFC control of amygdala reactivity to stress. Conclusion: Our results are in agreement with studies showing long-lasting changes induced by stressful events during adolescence. The impact on DA system activity, however, seems to depend on higher-level multiple stressors. Furthermore, a failure of the plPFC to regulate the impact of stress, which may be present in at-risk individuals, increases the vulnerability to stress consequences. Thus, predisposition to stress hyper-responsivity, or exposure to substantial stressors, during adolescence can initiate a cascade of events that result in a SZ-like profile in adults. Support: NIH-MH57440.

Animal models of psychiatric disorders have been highly effective in advancing the field, identifying circuits related to pathophysiology, and identifying novel therapeutic targets. In this review, we show how animal models, particularly those based on development, have provided essential information regarding circuits involved in disorders, disease progression, and novel targets for intervention and potentially prevention. Nonetheless, in recent years there has been a pushback, largely driven by the US National Institute of Mental Health (NIMH), to shift away from animal models and instead focus on circuits in normal subjects. This has been driven primarily from a lack of discovery of new effective therapeutic targets, and the failure of targets based on preclinical research to show efficacy. We discuss why animal models of complex disorders, when strongly cross-validated by clinical research, are essential to understand disease etiology as well as pathophysiology, and direct new drug discovery. Issues related to shortcomings in clinical trial design that confound translation from animal models as well as the failure to take patient pharmacological history into account are proposed to be a source of the failure of what are likely effective compounds from showing promise in clinical trials.

Schizophrenia is a complex disorder that involves several neurotransmitters such as dopamine, glutamate, and GABA. More recently, the endocannabinoid system has also been associated with this disorder. Although initially described as present mostly in the periphery, cannabinoid type-2 (CB2) receptors are now proposed to play a role in several brain processes related to schizophrenia, such as modulation of dopaminergic neurotransmission, microglial activation, and neuroplastic changes induced by stress. Here, we reviewed studies describing the involvement of the CB2 receptor in these processes and their association with the pathophysiology of schizophrenia. Taken together, these pieces of evidence indicate that CB2 receptor may emerge as a new target for the development of antipsychotic drugs.

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Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages.