Sex differences in μ-opioid regulation of coerulear-cortical transmission

Stress-induced activation of locus coeruleus (LC)-norepinephrine (NE) projections to the prefrontal cortex are thought to promote cognitive responses to stressors. LC activation by stressors is modulated by endogenous opioids that restrain LC activation and facilitate a return to baseline activity upon stress termination. Sex differences in this opioid influence could be a basis for sex differences in stress vulnerability. Consistent with this, we recently demonstrated that μ-opioid receptor (MOR) expression is decreased in the female rat LC compared to the male LC, and this was associated with sexually distinct consequences of activating MOR in the LC on cognitive flexibility. Given that the LC-NE system affects cognitive flexibility through its projections to the medial prefrontal cortex (mPFC), the present study quantified and compared the effects of LC-MOR activation on mPFC neural activity in male and female rats. Local field potential (LFPs) were recorded from the mPFC of freely behaving male and female rats before and following local LC microinjection of the MOR agonist, DAMGO, or vehicle. Intra-LC DAMGO altered the LFP power spectrum selectively in male but not female rats, resulting in a time-dependent increase in the power in delta and alpha frequency bands. LC microinfusion of ACSF had no effect on either sex. Together, the results are consistent with previous evidence for decreased MOR function in the female rat LC and demonstrate that this translates to a diminished effect on cortical activity that can account for sex differences in cognitive consequences. Decreased LC-MOR function in females could contribute to greater stress-induced activation of the LC and increased vulnerability of females to hyperarousal symptoms of stress-related neuropsychiatric pathologies

Sex Differences in μ-Opioid Receptor Regulation of the Rat Locus Coeruleus and Their Cognitive Consequences

Stress-related neuropsychiatric pathologies are more prevalent in females compared with males. An important component of the stress response is activation of the locus coeruleus (LC)-norepinephrine system. Because LC activation is tempered by endogenous opioid release during stress, the magnitude of opioid regulation of the LC could determine stress vulnerability. Here we report convergent evidence for decreased μ-opioid receptor (MOR) function in the female rat LC. The selective MOR agonist, DAMGO (10 pg), completely inhibited LC discharge of male but not female rats and DAMGO (30 pg) produced no further inhibition of female LC neurons. Consistent with a decreased maximum DAMGO response, MOR protein and mRNA expression were decreased in female compared with male LC. These molecular and cellular sex differences were associated with sexually distinct effects of LC-MOR activation on cognitive processing in an operant strategy-shifting task. Although DAMGO (10 pg intra-LC) increased the number of trials to reach criterion for both sexes, it increased the duration to complete the task and the total number of errors selectively in males. Specifically, DAMGO increased premature responses, regressive errors, and random errors in males and perseverative errors in females. The sexually distinct cognitive consequences of activating LC-MOR may contribute to sex differences in opioid abuse patterns and may guide sex-specific therapies. Finally, given evidence that endogenous opioids restrain stress-induced LC activation and promote recovery of activity to pre-stress levels, decreased MOR function in the female LC could contribute to LC-NE overactivity that underlies the hyperarousal symptoms of stress-related psychiatric diseases

Inducible cAMP Early Repressor Regulates Corticosterone Suppression after Tricyclic Antidepressant Treatment

The cAMP-response element binding protein (CREB) is involved in antidepressant action, but the role of related CRE-binding transcription factors in the behavioral and endocrine responses to antidepressants is unclear. Alternative transcription of the cAMP response element-modulator (CREM) gene yields activator and repressor isoforms, including the strong repressor induciblecAMPearly repressor (ICER). ICER is highly expressed in hypothalamic tissues and upregulated after electroconvulsive seizure. Thus, ICER may be a novel mediator of antidepressant action at endocrine and/or behavioral levels. Here we establish that both subchronic and chronic desipramine (DMI) treatments upregulate hypothalamic ICER expression in wild-type mice. Behavioral responses to DMI in the forced swim and tail suspension tests are unchanged in mice lacking ICER. However, the ability of DMI to suppress an acute corticosterone response after swim stress is compromised in ICER-deficient mice, suggesting that increased hypothalamic ICER mRNA after DMI treatment may be required for suppression of corticosterone release. To investigate the mechanism underlying this response, we measured corticotropin releasing factor (CRF), an upstream modulator of corticosterone release. Using real-time quantitative PCR, we establish that hypothalamic CRF expression is significantly reduced after swim exposure in DMI-treated wild-type mice, however DMI is unable to blunt hypothalamic CRF expression in ICER-deficient mice. Furthermore, we demonstrate that ICER is enriched in CRF-expressing neurons in the paraventricular nucleus of the hypothalamus. These data indicate that ICER is required for DMI to reduce stress-induced corticosterone release through regulation of hypothalamic CRF expression, revealing a novel role for ICER in antidepressant regulation of the hypothalamic–pituitary adrenal axis

Altered locus coeruleus–norepinephrine function following single prolonged stress

Data from preclinical and clinical studies have implicated the norepinephrine system in the development and maintenance of post‐traumatic stress disorder. The primary source of norepinephrine in the forebrain is the locus coeruleus ( LC ); however, LC activity cannot be directly measured in humans, and previous research has often relied upon peripheral measures of norepinephrine to infer changes in central LC –norepinephrine function. To directly assess LC –norepinephrine function, we measured single‐unit activity of LC neurons in a validated rat model of post‐traumatic stress disorder – single prolonged stress ( SPS ). We also examined tyrosine hydroxylase mRNA levels in the LC of SPS and control rats as an index of norepinephrine utilisation. For electrophysiological recordings, 92 LC neurons were identified from 19 rats ( SPS , 12; control, 7), and spontaneous and evoked responses to a noxious event (paw compression) were recorded. Baseline and restraint stress‐evoked tyrosine hydroxylase mRNA expression levels were measured in SPS and control rats ( n  = 16 per group) in a separate experiment. SPS rats showed lower spontaneous activity but higher evoked responses, leading to an enhanced signal‐to‐noise ratio of LC neurons, accompanied by impaired recovery from post‐stimulus inhibition. In concert, tyrosine hydroxylase mRNA expression in the LC of SPS rats tended to be lower at baseline, but was exaggerated following restraint stress. These data demonstrate persistent changes in LC function following stress/trauma in a rat model of post‐traumatic stress, as measured by differences in both the electrophysiological properties of LC neurons and tyrosine hydroxylase mRNA transcription. Single unit activity of LC neurons and TH mRNA levels were measured in the S ingle P rolonged S tress model of P ost‐traumatic stress disorder. SPS decreased rates of spontaneous discharge, exaggerated phasic responses of LC neurons and augmented stress‐enhanced TH mRNA expression. These data demonstrate sustained LC ‐ NE system abnormalities in SPS , providing an opportunity to study the interaction between LC ‐ NE system, and other PTSD ‐like physiological and behavioral changes seen in this model.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/97273/1/ejn12095.pd

Narcotic discrimination in pigeons: Antagonism by naltrexone

In pigeons trained to discriminate between morphine (10 mg/kg) and saline, both morphine and ethylketazocine produced dose-related morphine-appropriate responding. The maximum effect produced by meperidine, however, was only 60% of that produced by morphine or ethylketazocine. Naltrexone (0.1-1.0 mg/kg) produced dose-related shifts to the right in the dose-response curves for the discriminative stimulus and rate-decreasing effects of morphine and ethylketazocine without affecting the response produced by meperidine. Thus, in contrast to the effects observed in other species, morphine and ethylketazocine produce similar discriminative effects in the pigeon. In addition, the morphine-like discriminative effects and the rate-decreasing effects of meperidine in the pigeon are not mediated by the naltrexone-sensitive mechanisms which mediate these effects of morphine or ethylketazocine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24677/1/0000096.pd

Corticotropin-releasing factor receptors in GtoPdb v.2023.1

Corticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [34]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone, a 41 amino-acid peptide, urocortin 1, 40 amino-acids, urocortin 2, 38 amino-acids and urocortin 3, 38 amino-acids. CRF1 and CRF2 receptors are activated non-selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0-CRF or [125I]Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF1 receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF2 receptors are selectively antagonized by antisauvagine and astressin 2B

Corticotropin-releasing factor receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

Corticotropin-releasing factor (CRF, nomenclature as agreed by the NC-IUPHAR subcommittee on Corticotropin-releasing Factor Receptors [30]) receptors are activated by the endogenous peptides corticotrophin-releasing hormone, a 41 amino-acid peptide, urocortin 1, 40 amino-acids, urocortin 2, 38 amino-acids and urocortin 3, 38 amino-acids. CRF1 and CRF2 receptors are activated non-selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0-CRF or [125I]Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF1 receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF2 receptors are selectively antagonized by antisauvagine and astressin 2B

Prediction of drug sensitivity in individuals with atypical serum cholinesterase based on in vitro biochemical studies

Vmax and Km values with twenty-five "atypical" and thirty-seven "usual" cholinesterase human sera were determined for the cholinesterase substrates procaine, tetracaine, benzoylcholine, o-nitro-phenylbutyrate, [alpha]-naphthylacetate and aspirin. Aspirin was demonstrated to be a substrate for serum cholinesterase. For each of these substrates the ratio of Vmax substrate to Vmax benzoylcholine was found to be similar with atypical and usual cholinesterase sera. Therefore, we concluded that the respective turnover numbers for atypical and usual cholinesterase were the same. Both atypical and usual cholinesterase sera had turnover numbers of 255 min-1 for procaine, 74 min-1 for tetracaine, 7200 min-1 for aspirin in the presence of 50 mM CaCl2 36,000 min-1 for [alpha]-naphthylacetate, and 48,000 min-1 for o-nitrophenylbutyrate, at 25[deg] in 0.1 M Tris-Cl buffer, pH 7.4. A comparison of Km values for atypical and usual cholinesterase indicated that the positively charged substrates, as well as aspirin in the presence of CaCl2, showed a lower affinity with atypical than with usual cholinesterase, while neutral esters had nearly the same Km for atypical and usual cholinesterase. These results imply that individuals with atypical cholinesterase will hydrolyze therapeutic doses of positively charged substrates and aspirin at reduced rates, but neutral substrates should be hydrolyzed at normal rates.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24348/1/0000615.pd