José Vicente Negrete-Díaz

Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+ -calmodulin at mossy fiber-CA3 synapses.

J. Neurochem. (2012) 122, 891–899.

Neonatal ventral hippocampus lesion induces increase in no levels which is attenuated by subchronic haloperidol treatment

Haloperidol is a potent dopamine receptor antagonist and used to treat psychotic disorders, such as schizophrenia. Recent clinical and preclinical studies demonstrated the overactivity of the nitric oxide (NO) system in schizophrenia. Neonatal ventral hippocampal (nVH) lesions in rats have been widely used as a neurodevelopmental model that mimics schizophrenia‐like behaviors. Here, we investigate first whether the nVH lesion causes changes in NO levels in different limbic brain regions in young adults, postnatal day (PD) 81, and second, whether haloperidol treatment from PD60 to PD81 reverses these changes, by determining the accumulation of nitrites. The results show that NO levels at the level of the prefrontal cortex, occipital cortex, and cerebellum are higher in the nVH lesion animals, and that the haloperidol, in part, attenuates these altered NO levels. The NO levels observed in the nVH lesion animals with and without haloperidol treatment may be relevant to behaviors observed in schizophrenia. Synapse 64:941–947, 2010.

Electroencephalographic activity in neonatal ventral hippocampus lesion in adult rats

A neonatal ventral hippocampal lesion (NVHL) in rats has been commonly used as a neurodevelopmental model to mimic schizophrenia‐like behaviors. Recently, we reported that NVHL resulted in dendritic retraction and spine loss in pyramidal neurons of the prefrontal cortex (PFC). In addition, the hippocampus and PFC are important structures in the regulation of the electroencephalographic (EEG) activity. Patients with PFC lesions show deficits in the EEG activity. This study aimed to determine whether the EEG activity was altered in NVHL rats. In addition, we also analyzed the locomotor activity induced by a novel environment and exploratory behavior using the hole‐board test. Consistent with the behavioral findings, the EEG analysis of the cortical regions showed that the NVHL rats displayed a lower power in cortical bands. At 1–8 Hz, 9–14 Hz, and 15–30 Hz bands, our findings showed a decrease in the absolute power of the parietal and occipital cortices recordings. In addition, the NVHL rats also showed a reduction in the exploratory behavior tested using the hole‐board test. In conclusion, this study demonstrated that the EEG activity was reduced in adult NVHL rats and suggests that this may play a role in the behavioral changes observed in this neurodevelopmental model of schizophrenia. Synapse, 2012.

Kainate receptor-mediated depression of glutamatergic transmission involving protein kinase A in the lateral amygdala.

J. Neurochem. (2012) 121, 36–43.

Non-canonical Mechanisms of Presynaptic Kainate Receptors Controlling Glutamate Release

A metabotropic modus operandi for kainate receptors (KARs) was first discovered in 1998 modulating GABA release. These receptors have been also found to modulate glutamate release at different synapses in several brain regions. Mechanistically, a general biphasic mechanism for modulating glutamate release by presynaptic KARs with metabotropic actions has emerged, with low KA concentrations invoking an increase in glutamate release, whereas higher concentrations of KA mediate a decrease in the release of this neurotransmitter. The molecular mechanisms underpinning the opposite modulation of glutamate release are distinct, with a G-protein-independent, adenylate cyclase (AC)- and protein kinase A (PKA)-dependent mechanism mediating the facilitation of glutamate release, while a G-protein dependent mechanism (with or without protein kinase recruitment) is involved in the decrease of neurotransmitter release. In the present review, we revisit the mechanisms underlying the non-canonical modus operandi of KARs effecting the bimodal control of glutamatergic transmission in different brain regions, and address the possible functions that this modulation may support.

Excitatory amino acids in neurological and neurodegenerative disorders.

This book covers the biochemistry of amino acid metabolism in the context of health and disease.

Nitric oxide in neonatal ventral hippocampus lesion rats

Dear Dr. Flores: In a recent Letter to the Editor published in this journal, Bernstein and coworkers performed a valuable integration of results obtained in his laboratory (Bernstein et al., 1999), our laboratory (Negrete-Diaz et al., 2010) and others about the role of nitric oxide (NO) in the pathophysiology of schizophrenia, and summarized them in a very comprehensive review (Bernstein et al., 2005). Using the same animal model of schizophrenia, adult rats with a neonatal ventral hippocampus (nVH) lesion, Bernstein and coworkers and our group found an alteration of the nitrergic system (an increase in the number of cortical neurons expressing neuronal nitric oxide synthase (nNOS) and NADPH diaphorase and increased production of NO respectively, in the prefrontal cortex of adult animals with nVH-lesions). Therefore, both works are complementary to each other and reinforce our view of the role of the nitrergic system in the pathophysiology of schizophrenia. The results are also consistent with postmortem studies in humans with schizophrenia, because the chronic treatment with haloperidol may produce a decrease in the expression of nNOS (see Bernstein et al., 2005 for review), and our results show that subchronic doses of the typical neuroleptic haloperidol (0.5 mg /kg) administrated to nVH-lesion animals result in a decrease of higher NO activity (NegreteDiaz et al., 2010). This suggests that haloperidol exerts in part its therapeutic effect through its action on the activity of NO. It is interesting to note that compared to other models, the animal model of the nVH lesion is one of the best characterized, having been published to date in around a hundred works (see Tseng et al., 2009 for review). This is a neurodevelopmental model in which the behavioral changes mimic some of the symptoms of schizophrenia and are clearly observable after puberty. In summary, we believe that our findings support the integration of the results of previous works and facilitate our understanding of the role of NO in the pathophysiology of schizophrenia, as described by Bernstein and coworkers quite clearly in his letter to the editor of this journal (Bernstein et al., 2010).

Addictive Drugs and Synaptic Plasticity

The term addiction, derived from a Latin word meaning ‘‘bound to’’ or ‘‘enslaved by,’’ was initially not linked to substance use. However, over the past several hundred years, addiction became associated with excessive alcohol and then drug use, such that by the late 1980s it was largely synonymous with compulsive drug use (O’Brien et al., 2006). The core features of addiction are manifest in the continued performance of the behavior despite adverse consequences, compulsive engagement or diminished control over the behavior, and an appetitive urge or craving state prior to the behavioral engagement representing core elements (Holden, 2010).