Synaptic remodeling of GluA1 and GluA2 expression in the nucleus accumbens promotes susceptibility to cognitive deficits concomitant with downstream GSK3ß mediated neurotoxicity in female mice during abstinence from voluntary oral methamphetamine.

Stimulant-use disorders can present with long-term cognitive and mental health deficits. Little is known about the underlying molecular mechanisms perpetuating sex differences in cognitive and behavioral deficits in preclinical models of addiction to stimulants such as methamphetamine (MA). The current study investigated the neurochemical shifts underlying sex disparities in MA-induced working memory deficits and an addictive phenotype following abstinence from chronic MA abuse. We used our previously reported mouse model of voluntary oral methamphetamine administration (VOMA) consisting of an acquisition phase (days 1-14) characterized by escalating doses of MA and a binge phase (days 14-28) characterized by static doses. Female VOMA mice exhibited sustained MA consumption during the binge phase, demonstrating sex-specific vulnerabilities to the maintenance of MA addiction. The 8-arm radial maze was used to test spatial working memory performance following abstinence from VOMA. Results indicate working memory deficits correlated to higher MA consumption in females only. Hippocampal and accumbal tissue were collected and analyzed by immunoblotting. Female VOMA mice had decreased GluA1, but not GluA2, in the hippocampus, which may perpetuate synaptic destabilization and working memory deficits. Female-specific increases in GluA1 and p-GSK3ß expression in accumbal tissue suggest vulnerability toward abstinence-induced drug craving and heightened downstream neurotoxicity. Our study reveals female-specific neurochemical shifts in hippocampal and accumbal AMPA receptor signaling following abstinence from chronic MA consumption that may perpetuate female susceptibility to MA-induced cognitive deficits. These data demonstrate a novel molecular pathway that would exacerbate memory deficits and perpetuate an addictive phenotype in female populations following MA abuse.

Voluntary oral methamphetamine increases memory deficits and contextual sensitization during abstinence associated with decreased PKMζ and increased κOR in the hippocampus of female mice.

BACKGROUND: Female populations exhibit vulnerabilities to psychostimulant addiction, as well as cognitive dysfunction following bouts of abuse. AIMS: The goal for this study was to advance our understanding of the mechanisms that produce sex disparities in drug addiction. METHODS: We used an animal model for voluntary oral methamphetamine administration (VOMA) and focused on male and female mice that consumed 7.6-8.2 mg/kg of methamphetamine (MA) per day during the last 18 days of the paradigm. RESULTS: The VOMA-exposed female mice displayed increased locomotor activity in the drug-administration context compared to male mice, demonstrating sex-specific changes in contextual sensitization. During 2 weeks of forced abstinence, mice underwent further behavioral testing. We show that abstinence increased open-arm entries on the elevated plus maze in both sexes. There were no differences in immobility on the tail suspension test. In a hippocampal-dependent radial arm maze task, VOMA-treated female mice, but not male mice, showed working memory deficits. Hippocampal tissue was collected and analyzed using Western blotting. VOMA-exposed female mice exhibited increased kappa opioid receptor (κOR) expression in the hippocampus compared to male mice, suggesting a vulnerability toward abstinence-induced dysphoria. Female VOMA mice also exhibited a decrease in the memory protein marker, protein kinase M zeta (PKMζ), in the hippocampus. CONCLUSIONS: Our study reveals sex-specific effects following abstinence from chronic MA consumption on hippocampal κOR and PKMζ expression, suggesting that these neural changes in female mice may underlie spatial memory deficits and identify an increased susceptibility to dysregulated neural mechanisms. These data validate VOMA as a model sensitive to sex differences in behavior and hippocampal neurochemistry following chronic MA exposure.

The Insomnia-Addiction Positive Feedback Loop: Role of the Orexin System.

Significant sleep impairments often accompany substance use disorders (SUDs). Sleep disturbances in SUD patients are associated with poor clinical outcomes and treatment adherence, emphasizing the importance of normalizing sleep when treating SUDs. Orexins (hypocretins) are neuropeptides exclusively produced by neurons in the posterior hypothalamus that regulate various behavioral and physiological processes, including sleep-wakefulness and motivated drug taking. Given its dual role in sleep and addiction, the orexin system represents a promising therapeutic target for treating SUDs and their comorbid sleep deficits. Here, we review the literature on the role of the orexin system in sleep and drug addiction and discuss the therapeutic potential of orexin receptor antagonists for SUDs. We argue that orexin receptor antagonists may be effective therapeutics for treating addiction because they target orexin's regulation of sleep (top-down) and motivation (bottom-up) pathways.

PACAP27 mitigates an age-dependent hippocampal vulnerability to PGJ2-induced spatial learning deficits and neuroinflammation in mice.

BACKGROUND: Inflammation in the brain is mediated by the cyclooxygenase pathway, which leads to the production of prostaglandins. Prostaglandin (PG) D2, the most abundant PG in the brain, increases under pathological conditions and is spontaneously metabolized to PGJ2. PGJ2 is highly neurotoxic, with the potential to transition neuroinflammation into a chronic state and contribute to neurodegeneration as seen in many neurological diseases. Conversely, PACAP27 is a lipophilic peptide that raises intracellular cAMP and is an anti-inflammatory agent. The aim of our study was to investigate the therapeutic potential of PACAP27 to counter the behavioral and neurotoxic effects of PGJ2 observed in aged subjects. METHODS: PGJ2 was injected bilaterally into the hippocampal CA1 region of 53-week-old and 12-week-old C57BL/6N male mice, once per week over 3 weeks (three total infusions) and included co-infusions of PACAP27 within respective treatment groups. Our behavioral assessments looked at spatial learning and memory performance on the 8-arm radial maze, followed by histological analyses of fixed hippocampal tissue using Fluoro-Jade C and fluorescent immunohistochemistry focused on IBA-1 microglia. RESULTS: Aged mice treated with PGJ2 exhibited spatial learning and long-term memory deficits, as well as neurodegeneration in CA3 pyramidal neurons. Aged mice that received co-infusions of PACAP27 exhibited remediated learning and memory performance and decreased neurodegeneration in CA3 pyramidal neurons. Moreover, microglial activation in the CA3 region was also reduced in aged mice cotreated with PACAP27. CONCLUSIONS: Our data show that PGJ2 can produce a retrograde spread of damage not observed in PGJ2-treated young mice, leading to age-dependent neurodegeneration of hippocampal neurons producing learning and memory deficits. PACAP27 can remediate the behavioral and neurodegenerative effects that PGJ2 produces in aged subjects. Targeting specific neurotoxic prostaglandins, such as PGJ2, offers great promise as a new therapeutic strategy downstream of cyclooxygenases, to combat the neuronal deficits induced by chronic inflammation.

Contextual fear memory modulates PSD95 phosphorylation, AMPAr subunits, PKMζ and PI3K differentially between adult and juvenile rats.

It is well known that young organisms do not maintain memories as long as adults, but the mechanisms for this ontogenetic difference are undetermined. Previous work has revealed that the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAr) subunits are trafficked into the synaptic membrane following memory retrieval in adults. Additionally, phosphorylated PSD-95-pS295 promotes AMPAr stabilization at the synapse. We investigated these plasticity related proteins as potential mediators in the differential contextual stress memory retrieval capabilities observed between adult and juvenile rats. Rats were assigned to either pedestal stress (1 h) or no stress control (home cage). Each animal was placed alone in an open field for 5 min at the base of a 6 × 6 sq inch pedestal (4ft high). Stress subjects were then placed on this pedestal for 1hr and control subjects were placed in their home cage following initial exploration. Each animal was returned to the open field for 5 min either 1d or 7d following initial exposure. Freezing postures were quantified during the memory retrieval test. The 1d test shows adult (P90) and juvenile (P26) stressed rats increase their freezing time compared to controls. However, the 7d memory retrieval test shows P90 stress rats but not P26 stress rats freeze while in the fear context. Twenty minutes after the memory retrieval test, hippocampi and amygdala were micro-dissected and prepared for western blot analysis. Our results show that 1d fear memory retrieval induced an upregulation of PSD-95 and pS295 in the adult amygdala but not in the juvenile. However, the juvenile animals upregulated PKMζ, PI3K and GluA2/3, GluA1-S845 in the dorsal hippocampus (DH), but the adults did not. Following the 7d memory retrieval test, adults upregulated GluA2 in the amygdala but not the juveniles. In the DH, adults increased PSD-95 and pS295 but not the juveniles. The adults appear to preferentially increase amygdala-driven processing at 1d and increase DH-driven context specific processing at 7d. These data identify molecular processes that may underlie the reduced fear-memory retrieval capability of juveniles. Together these data provide a potential molecular target that could be beneficial in treatment of anxiety disorders and PTSD.

Chronic voluntary oral methamphetamine induces deficits in spatial learning and hippocampal protein kinase Mzeta with enhanced astrogliosis and cyclooxygenase-2 levels.

Methamphetamine (MA) is an addictive drug with neurotoxic effects on the brain producing cognitive impairment and increasing the risk for neurodegenerative disease. Research has focused largely on examining the neurochemical and behavioral deficits induced by injecting relatively high doses of MA [30 mg/kg of body weight (bw)] identifying the upper limits of MA-induced neurotoxicity. Accordingly, we have developed an appetitive mouse model of voluntary oral MA administration (VOMA) based on the consumption of a palatable sweetened oatmeal mash containing a known amount of MA. This VOMA model is useful for determining the lower limits necessary to produce neurotoxicity in the short-term and long-term as it progresses over time. We show that mice consumed on average 1.743 mg/kg bw/hour during 3 hours, and an average of 5.23 mg/kg bw/day over 28 consecutive days on a VOMA schedule. Since this consumption rate is much lower than the neurotoxic doses typically injected, we assessed the effects of long-term chronic VOMA on both spatial memory performance and on the levels of neurotoxicity in the hippocampus. Following 28 days of VOMA, mice exhibited a significant deficit in short-term spatial working memory and spatial reference learning on the radial 8-arm maze (RAM) compared to controls. This was accompanied by a significant decrease in memory markers protein kinase Mzeta (PKMζ), calcium impermeable AMPA receptor subunit GluA2, and the post-synaptic density 95 (PSD-95) protein in the hippocampus. Compared to controls, the VOMA paradigm also induced decreases in hippocampal levels of dopamine transporter (DAT) and tyrosine hydroxylase (TH), as well as increases in dopamine 1 receptor (D1R), glial fibrillary acidic protein (GFAP) and cyclooxygenase-2 (COX-2), with a decrease in prostaglandins E2 (PGE2) and D2 (PGD2). These results demonstrate that chronic VOMA reaching 146 mg/kg bw/28d induces significant hippocampal neurotoxicity. Future studies will evaluate the progression of this neurotoxic state.

Nonexistence of global solutions of abstract wave equations with high energies.

We consider an undamped second order in time evolution equation. For any positive value of the initial energy, we give sufficient conditions to conclude nonexistence of global solutions. The analysis is based on a differential inequality. The success of our result is based in a detailed analysis which is different from the ones commonly used to prove blow-up. Several examples are given improving known results in the literature.

Estradiol rapidly increases GluA2-mushroom spines and decreases GluA2-filopodia spines in hippocampus CA1.

Hippocampal dendritic spine density rapidly increases following estradiol (E2 ) treatment, but the types of spines and trafficking of synaptic markers have received little investigation. We assessed rapid effects of E2 over time on the density of four spine types (stubby, filopodial, long thin, and mushroom) and trafficking of AMPA receptor subunit GluA2 and PSD95 on tertiary, apical dendrites in CA1. Castrated male rats received 20 µg kg-1 of E2 or vehicle and were sacrificed 30 or 120 min later. Images of Golgi-Cox impregnated and PSD95/GluA2 stained dendrites were captured under the confocal microscope and quantified with IMARIS-XT. Stubby and filopodial spine densities did not change following treatment. Long-thin spines significantly decreased at 30 min while mushroom spines significantly increased at 120 min. GluA2, PSD95, and GluA2/PSD95 colocalization levels in stubby or long thin spines did not change, but filopodial spines had significantly reduced GluA2 levels at 30 min. Mushroom spines showed significantly increased levels for GluA2, PSD95 and GluA2/PSD95 colocalization at 120 min. Because GluA2 is important for memory consolidation, current results present novel data suggesting that trafficking of GluA2 to mushroom spines provides one mechanism contributing to estradiol's ability to enhance learning and memory by the PI3 signaling pathway.

Intentos suicidas en el área de salud del Policlínico Universitario José Martí Pérez / Suicidal attempts in the health area of José Martí Pérez University Polyclinic

Se efectuó un estudio descriptivo y transversal de 19 pacientes con intento suicida, pertenecientes al área de salud del Policlínico Universitario José Martí Pérez de Santiago de Cuba, desde julio del 2008 hasta igual mes del 2009, con vistas a determinar la conducta de estos y trazar estrategias de trabajo ante dicha situación. En la serie, ese acto predominó en las personas de 10-20 años, sexo masculino, raza mestiza, nivel de escolaridad universitario y desocupación laboral. Entre los métodos para suicidarse, los más empleados fueron la ingestión de psicofármacos y la autoagresión(AU)

A descriptive and cross-sectional study of 19 patients with suicide attempt, belonging to the health area of José Martí Pérez University Polyclinic from Santiago de Cuba was carried out from July, 2008 to the same month of 2009, aimed at determining their behaviour and to establish work strategies in this situation. People in the age group from 10-20, male sex, mestiza race, university school level and unemployment prevailed in the series. Among the methods of suicide, those mostly used were psycho-drugs ingestion and the self-aggression(AU)

Intentos suicidas en el área de salud del Policlínico Universitario José Martí Pérez / Suicidal attempts in the health area of José Martí Pérez University Polyclinic

Se efectuó un estudio descriptivo y transversal de 19 pacientes con intento suicida, pertenecientes al área de salud del Policlínico Universitario José Martí Pérez de Santiago de Cuba, desde julio del 2008 hasta igual mes del 2009, con vistas a determinar la conducta de estos y trazar estrategias de trabajo ante dicha situación. En la serie, ese acto predominó en las personas de 10-20 años, sexo masculino, raza mestiza, nivel de escolaridad universitario y desocupación laboral. Entre los métodos para suicidarse, los más empleados fueron la ingestión de psicofármacos y la autoagresión.

A descriptive and cross-sectional study of 19 patients with suicide attempt, belonging to the health area of José Martí Pérez University Polyclinic from Santiago de Cuba was carried out from July, 2008 to the same month of 2009, aimed at determining their behaviour and to establish work strategies in this situation. People in the age group from 10-20, male sex, mestiza race, university school level and unemployment prevailed in the series. Among the methods of suicide, those mostly used were psycho-drugs ingestion and the self-aggression.