The Antagonism of Corticotropin-Releasing Factor Receptor-1 in Brain Suppress Stress-Induced Propofol Self-Administration in Rats

Propofol addiction has been detected in humans and rats, which may be facilitated by stress. Corticotropin-releasing factor acts through the corticotropin-releasing factor (CRF) receptor-1 (CRF1R) and CRF2 receptor-2 (CRF2R) and is a crucial candidate target for the interaction between stress and drug abuse, but its role on propofol addiction remains unknown. Tail clip stressful stimulation was performed in rats to test the stress on the establishment of the propofol self-administration behavioral model. Thereafter, the rats were pretreated before the testing session at the bilateral lateral ventricle with one of the doses of antalarmin (CRF1R antagonist, 100–500 ng/site), antisauvagine 30 (CRF2R antagonist, 100–500 ng/site), and RU486 (glucocorticoid receptor antagonist, 100–500 ng/site) or vehicle. The dopamine D1 receptor (D1R) in the nucleus accumbens (NAc) was detected to explore the underlying molecular mechanism. The sucrose self-administration establishment and maintenance, and locomotor activities were also examined to determine the specificity. We found that the establishment of propofol self-administration was promoted in the tail clip treated group (the stress group), which was inhibited by antalarmin at the dose of 100–500 ng/site but was not by antisauvagine 30 or RU486. Accordingly, the expression of D1R in the NAc was attenuated by antalarmin, dose-dependently. Moreover, pretreatments fail to change sucrose self-administration behavior or locomotor activities. This study supports the role of CRF1R in the brain in mediating the central reward processing through D1R in the NAc and provided a possibility that CRF1R antagonist may be a new therapeutic approach for the treatment of propofol addiction.

Animal Models in Psychiatry

Darwin made a compelling case that studies of animals could provide insights into the behavior of humans. Early studies by Pavlov and Harlow paved the way for further developments of animal models of psychiatric disorders. Seligman and Maier’s learned helplessness model continues to be employed in laboratory studies of stress and depression. It has become clear that no single animal model can possibly reproduce all of the critical facets of a mental disorder in humans. However, animal models do provide an essential element in attempts to understand the mechanisms that underlie mental disorders and to reveal molecular targets for the development of new drug therapies. Concerns have been raised about the reproducibility of laboratory experiments with inbred strains of laboratory mice and rats. Any animal model should be evaluated based upon a battery of behavioral tests and the parameters of stressful stimulation employed in experiments should be chosen with care.

Resilience

A consistent finding from research on animal models of depression and PTSD is that some animals are highly susceptible to the effects of stressful stimulation, while others show few obvious effects. A relatively new of line of research on resilience has emerged and has directed attention to those animals that are resistant to the effects of chronic or traumatic stressors. By tracking animals that are resistant to the behavioral effects of these stressful paradigms, one can then explore the molecular underpinnings of resilience in the brains of these same animals. Using chronic social defeat stress, some investigators have focused their attention on the ventral tegmental area, nucleus accumbens, and the prefrontal cortex. Other systems that have been studied include signaling molecules of the immune system and communication pathways between the immune system and the brain. A related line of research has addressed the possibility that prior exposure to stressors may inoculate animals to the deleterious effects of later stressor exposure.

Stress and Schizophrenia

Developing animal models of schizophrenia is challenging because of the uniquely human nature of some of the classic symptoms of the disorder (e.g., hallucinations, delusions, disordered thought). Several efforts have been guided by the neurodevelopmental hypothesis of schizophrenia and have included exposure of animals to stressful stimulation. Other animal models have involved prenatal exposure to maternal immune activation or drugs that disrupt neuronal development, followed by stress during adolescence or in early adulthood to unmask vulnerabilities. Neonatal hippocampal lesions have been employed in other animal models of schizophrenia. Another profitable approach has been to selectively breed laboratory mice or rats for their susceptibility to dopaminergic drugs. A more recent approach has been to develop laboratory mice with targeted alterations in risk genes for schizophrenia that were previously identified in clinical studies. In many cases, the effects of these risk genes are unmasked by exposure of animals to stressful stimulation during specific stages of postnatal development.

Comparative analysis of microRNA profiles between wild and cultured Haemaphysalis longicornis (Acari, Ixodidae) ticks

The miRNA profiles of a Haemaphysalis longicornis wild-type (HLWS) and of a Haemaphysalis longicornis cultured population (HLCS) were sequenced using the Illumina Hiseq 4000 platform combined with bioinformatics analysis and real-time polymerase chain reaction (RT-PCR). A total of 15.63 and 15.48 million raw reads were acquired for HLWS and HLCS, respectively. The data identified 1517 and 1327 known conserved miRNAs, respectively, of which 342 were differentially expressed between the two libraries. Thirty-six novel candidate miRNAs were predicted. To explain the functions of these novel miRNAs, Gene Ontology (GO) analysis was performed. Target gene function prediction identified a significant set of genes related to salivary gland development, pathogen-host interaction and regulation of the defence response to pathogens expressed by wild H. longicornis ticks. Cellular component biogenesis, the immune system process, and responses to stimuli were represented at high percentages in the two tick libraries. GO enrichment analysis showed that the percentages of most predicted functions of the target genes of miRNA were similar, as were certain specific categories of functional enhancements, and that these genes had different numbers and specific functions (e.g., auxiliary transport protein and electron carrier functions). This study provides novel findings showing that miRNA regulation affects the expression of immune genes, indicating a considerable influence of environment-induced stressful stimulation on immune homeostasis. Differences in the living environments of ticks can lead to differences in miRNAs between ticks and provide a basis and a convenient means to screen for genes encoding immune factors in ticks.

Lasting Differential Effects on Plasticity Induced by Prenatal Stress in Dorsal and Ventral Hippocampus

Early life adversaries have a profound impact on the developing brain structure and functions that persist long after the original traumatic experience has vanished. One of the extensively studied brain structures in relation to early life stress has been the hippocampus because of its unique association with cognitive processes of the brain. While the entire hippocampus shares the same intrinsic organization, it assumes different functions in its dorsal and ventral sectors (DH and VH, resp.), based on different connectivity with other brain structures. In the present review, we summarize the differences between DH and VH and discuss functional and structural effects of prenatal stress in the two sectors, with the realization that much is yet to be explored in understanding the opposite reactivity of the DH and VH to stressful stimulation.

Characterization of tyramine β-hydroxylase, an enzyme upregulated by stress in Periplaneta americana

Octopamine (OA) is an important neuroactive substance that modulates several physiological functions and behaviors of various invertebrate species. This biogenic monoamine, structurally related to noradrenaline, acts as a neurotransmitter, a neuromodulator, or a neurohormone in insects. The tyramine β-hydroxylase (TBH) catalyzes the last step in OA biosynthesis and thus plays a key role in the regulation of synthesis and secretion of OA in neurons. The aim of this study was to characterize TBH in the cockroach Periplaneta americana and to get a better understanding of its regulation under stress conditions in this insect. First of all, five full-length cDNAs encoding TBH isoforms were cloned from the nerve cord of the physiological model P. americana. PaTBH transcripts were found mainly expressed in nervous tissues and in octopaminergic dorsal unpaired median neurons. In addition, a new ELISA assay was developed so as to allow determination of both OA level and TBH activity in stressed cockroaches. Mechanical stressful stimulation led to a significant increase in TBH activity after 1 and 24 h, with a higher induction after 1 h than after 24 h. Thus, TBH could be considered as a promising biomarker of stress in insects rather than OA.

Activation of 5-HT1A receptors in the medullary raphe reduces cardiovascular changes elicited by acute psychological and inflammatory stresses in rabbits

The present strategy for the prevention of excessive sympathetic neural traffic to the heart relies on the use of beta-blockers, drugs that act at the heart end of the brain-heart axis. In the present study, we attempted to suppress cardiac sympathetic nerve activity by affecting the relevant cardiomotoneurons in the brain using the selective serotonin-1A (5-HT1A) receptor agonist 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT). In conscious, unrestrained rabbits, instrumented for recordings of heart rate, arterial pressure, or cardiac output, we provoked increases in cardiac sympathetic activity by psychological (loud sound, pinprick, and air jet) or inflammatory (0.5 μg/kg iv lipopolysaccharide) stresses. Pinprick and air-jet stresses elicited transient increases in heart rate (+50 ± 7 and +38 ± 4 beats/min, respectively) and in mean arterial pressure (+16 ± 2 and +15 ± 3 mmHg, respectively). Lipopolysaccharide injection caused sustained increases in heart rate (from 210 ± 3 to 268 ± 10 beats/min) and in arterial pressure (from 74 ± 3 to 92 ± 4 mmHg). Systemically administered 8-OH-DPAT (0.004–0.1 mg/kg) substantially attenuated these responses in a dose-dependent manner. Drug effects were prevented by a selective 5-HT1A receptor antagonist, WAY-100635 (0.1 mg/kg iv). Similarly to systemic administration, microinjection of 8-OH-DPAT (500 nl of 10 mM solution) into the medullary raphe-parapyramidal region caused antitachycardic effects during stressful stimulation and during lipopolysaccharide-elicited tachycardia. This is the first demonstration that activation of 5-HT1A receptors in the medullary raphe-parapyramidal area causes suppression of neurally mediated cardiovascular changes during acute psychological and immune stresses.

Regulation of ventilation and oxygen consumption by delta- and mu-opioid receptor agonists

To study the effect of endorphins on metabolic rate and on the relationship between O2 consumption (VO2) and ventilation, we administered enkephalin analogues (relatively selective delta-receptor agonists) and a morphiceptin analogue (a highly selective mu-receptor agonist) intracisternally in nine unanesthetized chronically instrumented adult dogs. Both delta- and mu-agonists decreased VO2 by 40–60%. delta-Agonists induced a dose-dependent decrease in mean instantaneous minute ventilation (VT/TT) associated with periodic breathing. The decrease in VT/TT started and resolved prior to the decrease and returned to baseline of VO2, respectively. In contrast, the mu-agonists induced an increase in VT/TT associated with rapid shallow breathing. Arterial PCO2 increased and arterial PO2 decreased after both delta- and mu-agonists. Low doses of intracisternal naloxone (0.002–2.0 micrograms/kg) reversed the opioid effect on VT/TT but not on VO2; higher doses of naloxone (5–25 micrograms/kg) reversed both. Naloxone administered alone had no effect on VT/TT or VO2. These data suggest that 1) both delta- and mu-agonists induce alveolar hypoventilation despite a decrease in VO2, 2) this hypoventilation results from a decrease in VT/TT after delta-agonists but an increase in dead space ventilation after mu-agonists, and 3) endorphins do not modulate ventilation and metabolic rate tonically, but we speculate that they may do so in response to stressful stimulation.