Ecological Factors of Telemental Healthcare Utilization Among Adolescents with Increased Substance Use During the COVID-19 Pandemic: The Moderating Effect of Gender.

Background: Adolescent substance use is often associated with concurrent mental health problems (e.g., depression, suicide attempts, parental emotional and physical abuse, not feeling close to people at school, and lower virtual connectedness) at multiple ecological levels. Objective: This study examined whether such risk factors among adolescents were associated with the use of telemental healthcare (TMHC) and whether gender moderated these associations. Methods: Data were drawn from the Adolescent Behaviors and Experiences Survey, collected by the U.S. Centers for Disease Control and Prevention from January to June 2021. A hierarchical multiple logistic regression analysis was conducted using a national sample of 1,460 students in Grades 9-12 in the United States who reported having used more alcohol and/or drugs during the pandemic than before it started. Results: The results showed that only 15.3% of students sought TMHC. Students reporting increased substance use during the pandemic were more likely to use TMHC if they experienced more severe mental health problems (e.g., suicide attempts) compared to other ecological factors, such as issues with their family, school, or community. Analysis of the moderating effect showed that the closer male students felt to people at school, the more likely they were to seek TMHC, whereas the opposite was true for female students. Conclusions: The findings highlighted that feeling close to people at school is an important aspect of understanding the help-seeking behavior of female and male adolescent substance users.

The Hepatocyte Growth Factor/c-Met Antagonist, Divalinal-Angiotensin IV, Blocks the Acquisition of Methamphetamine Dependent Conditioned Place Preference in Rats.

The use of methamphetamine (MA) is increasing in the U.S. and elsewhere around the world. MA's capacity to cause addiction significantly exceeds other psychostimulant drugs, and its use negatively impacts learning and memory. Recently, attempts have been made to interfere with the presumed mechanism(s) underlying the establishment of drug-induced memory consolidation. The majority of these studies have employed matrix metalloproteinase (MMP) inhibitors to disrupt MMP-induced extracellular matrix molecule dependent synaptic reconfiguration, or GABA receptor agonists. The present investigation utilized an angiotensin IV (AngIV) analogue, Divalinal-AngIV (divalinal), to disrupt acquisition of MA-induced dependence in rats as measured using the conditioned place preference paradigm. Results indicate that both acute and chronic intracerebroventricular infusion of divalinal prior to each daily subcutaneous injection of MA prevented acquisition. However, divalinal was unable to prevent MA-induced reinstatement after prior acquisition followed by extinction trials. These results indicate that prevention of MA dependence can be accomplished by blockade of the brain AT4 receptor subtype. On the other hand, once MA-induced memory consolidation is in place divalinal appears to be ineffective. Mechanistic studies indicated that divalinal is a potent inhibitor of the hepatocyte growth factor (HGF)/c-Met receptor system, and thus it appears that a functional HGF/c-Met system is required for the acquisition of MA-mediated conditioned place preference.

The role of the AT4 and cholinergic systems in the Nucleus Basalis Magnocellularis (NBM): effects on spatial memory.

The brain AT(4) and cholinergic systems play a pivotal role in learning and memory. Studies have investigated the nootropic and amnesic properties of both systems. The cholinergic system has received the most attention for its contribution to cognitive functioning. For example, one of the best known cognitive disorders, Alzheimer's disease (AD), is treated with cholinergic-directed drugs, and post-mortem studies of AD patient brains show neurodegenerative devastation in cholinergic areas of the brain. Studies suggest that potentiation of cholinergic transmission may be a mechanism by which the AngIV/AT(4) receptor system enhances cognition. Since the Nucleus Basalis Magnocellularis (Meynert in humans and primates) (NBM) is a main source of cholinergic innervation to cognitive areas of the brain, this site was chosen to investigate the role and interaction of the two systems. Rats were fitted with permanent bilateral cannulas targeting the NBM for drug administration. Divalinal-AngIV, an AT(4) receptor antagonist produced profound deficits in performance in the Circular water maze. Nicotine treatment reversed these impairments whereas carbachol did not. Similar to the AT(4) antagonist, scopolamine and mecamylamine prevented acquisition of the water maze. Based on these results, it appears that blocking any one of these systems results in impaired spatial learning, while activating the nicotinic receptor system counteracts the effects of AT(4) receptor blockade. These findings suggest a functional role for both the cholinergic and AT(4) receptor systems in spatial learning, and indicate for the first time a functional role for the AngIV/AT(4) receptor system in the NBM.

Endocrine regulation of cognition and neuroplasticity: our pursuit to unveil the complex interaction between hormones, the brain, and behaviour.

Gonadal and stress hormones modulate neuroplasticity and behaviour. This review focuses on our findings over the past decade on the effects of estrogens and androgens on hippocampal neurogenesis, hippocampus-dependent learning and memory and the effects of reproductive experience in the rodent. Evidence suggests that acute estradiol initially enhances and subsequently suppresses cell proliferation in the dentate gyrus of adult female rodents. Repeated exposure to estradiol modulates hippocampal neurogenesis and cell death in adult female, but not male, rodents while, testosterone and dihydrotestosterone upregulate hippocampal neurogenesis in adult male rodents. Estradiol dose-dependently affects different brain regions involved in working memory (prefrontal cortex, hippocampus), reference memory (hippocampus) and conditioned place preference (amygdala). Pregnancy and motherhood differentially regulate adult hippocampal neurogenesis and spatial working memory in the dam after weaning. These studies and others demonstrate that the female brain responds to steroid hormones differently than the male brain. It is of the upmost importance to investigate the effects on neuroplasticity and behaviour in both the male and the female, particularly when modelling diseases that exhibit sex differences in incidence, etiology or treatment.

Central pressor actions of aminopeptidase-resistant angiotensin II analogs: challenging the angiotensin III hypothesis.

UNLABELLED: Intracerebroventricular administration of angiotensins causes pronounced pressor and dipsogenic responses. The suggestion that angiotensin III rather than angiotensin II is the active peptide in the brain spawned what we call The Angiotensin III. HYPOTHESIS: To test this hypothesis, 5 angiotensin II analogs containing zero or one position substitutions conferring resistance to aminopeptidases were administered intracerebroventricularly to determine their pressor and dipsogenic efficacies. Two aminopeptidase-resistant analogs caused significantly greater pressor responses than angiotensin II, whereas 3 analogs caused pressor responses similar to angiotensin II. Latency to cause a pressor response for 4 of the 5 aminopeptidase-resistant angiotensin II analogs was the same as for angiotensin II. There was no detectable formation of (125)I-angiotensin III from 1 of the intracerebroventricularly administered analogs, (125)I- N-Methyl-l-Asp(1)-angiotensin II, indicating its aminopeptidase resistance. Latency to drink also did not differ between the angiotensins. After the initial dipsogenic response, water was removed until 25 minutes after angiotensin administration to avoid interfering with the pressor response. The dipsogenic stimulus was sustained 25 minutes after intracerebroventricular injection of angiotensin II and its aminopeptidase-resistant analogs. Comparison of angiotensin III and angiotensin II showed equivalent pressor responses with similar latencies and durations. The latency to drink was similar for angiotensin III and angiotensin II. However, there was no dipsogenic response to angiotensin III 25 minutes after intracerebroventricular injection. These data do not support The Angiotensin III Hypothesis and suggest that conversion of exogenously applied angiotensin II to angiotensin III is not necessary to cause brain-mediated pressor or dipsogenic responses.

Roles of brain angiotensins II and III in thirst and sodium appetite.

The current study examined the effects of intracerebroventricular (icv) infused aminopeptidase-resistant analogs of angiotensin II (AngII) and angiotensin III (AngIII) on thirst and sodium appetite. The analogs, [D-Asp1D-Arg2]AngII and [D-Arg1]AngIII, were further protected from degradation by pretreatment with the aminopeptidase A inhibitor, EC33, or the aminopeptidase N inhibitor, PC18. Prior to icv infusions, rats were sodium depleted with furosemide, followed by the angiotensin-converting enzyme inhibitor captopril, to block endogenous angiotensin formation. Both angiotensin analogs, at either of the two doses, were capable of eliciting fluid intakes of water and 0.3 M NaCl. Water and saline intakes were increased to a similar extent by 125 and 1250 pmol of [D-Asp1D-Arg2]AngII. [D-Arg1]AngIII produced a dose-dependent increase in water intake, whereas saline intake was equivalently increased by the 125 and 1250 pmol infusions. Pretreatment with EC33 or PC18 decreased water and saline intakes in response to [D-Asp1D-Arg2]AngII, while pretreatment with PC18 altered the time course of the [D-Arg1]AngIII-induced water and saline intakes. The ability of both inhibitors to decrease, but not completely block, AngII analog-induced intakes, coupled with the altered time course of the responses induced by the AngIII analog in the presence of PC18, supports the hypothesis that both AngII and AngIII are active ligands in brain angiotensin-mediated thirst and sodium appetite. However, these results do not resolve the primary question of whether conversion of AngII to AngIII is a prerequisite to dipsogenic and salt appetite responses in the brain.

Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats.

The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogs d-Asp(1)ANG II and d-Arg(1)ANG III in alert freely moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A inhibitor EC33 or the aminopeptidase N inhibitor PC18. The results indicate that the maximum elevations in mean arterial pressure (MAP) were very similar for each of these compounds across the dose range 1, 10, and 100 pmol/min during a 5-min infusion period. However, d-Asp(1)ANG II revealed significantly extended durations of pressor effects before return to base level MAP. Pretreatment intracerebroventricular infusion with EC33 blocked the pressor activity induced by the subsequent infusion of d-Asp(1)ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion of d-Arg(1)ANG III. In contrast, pretreatment infusion with PC18 extended the duration of the d-Asp(1)ANG II pressor effect by about two to three times and the duration of d-Arg(1)ANG III's effect by approximately 10 to 15 times. Pretreatment with the specific AT(1) receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT(1) receptor subtype. These results suggest that the brain AT(1) receptor may be designed to preferentially respond to ANG III, and ANG III's importance as a centrally active ligand has been underestimated.

Salt appetite of adrenalectomized rats after a lesion of the SFO.

Circumventricular organs such as the subfornical organ (SFO) may mediate the effects of circulating angiotensin (ANG) II on salt appetite under conditions of sodium depletion in the rat. We studied the effects of an electrolytic lesion of SFO on salt appetite after adrenalectomy (ADX) in Long-Evans rats. The SFO lesion had no effect on saline intake, but it did abolish water intake after acute peripheral treatments with 2 mg/kg of captopril or a 10 mg/kg of furosemide. These findings contrast with other recent data from this laboratory demonstrating large reductions in salt appetite in adrenal-intact rats with lesions of either SFO or the organum vasculosum laminae terminalis during acute iv infusions of ANG II. Thus, the SFO may contribute to the salt appetite response to circulating ANG II, but it is not essential for the response to adrenalectomy.

Forebrain circumventricular organs mediate salt appetite induced by intravenous angiotensin II in rats.

Two circumventricular organs, the subfornical organ (SFO) and organum vasculosum laminae terminalis (OVLT), may mediate salt appetite in response to acute intravenous infusions of angiotensin (ANG) II. Fluid intakes and mean arterial pressures were measured in rats with sham lesions or electrolytic lesions of the SFO or OVLT during an intravenous infusion of 30 ng/min ANG II. Beginning 21 h before the 90-min infusion, the rats were depleted of sodium with furosemide and given a total of 300 mg/kg captopril in 75 ml/kg water in three spaced gavages to block the usual salt appetite and to hydrate the rats. No other food or fluids were available for ingestion. Sham-lesioned rats drank 9.3+/-1.2 ml if 0.3 M NaCl alone was available and drank 8.9+/-1.6 ml of saline and 3.7+/-1.6 ml of water if both were available. Either SFO or OVLT lesions reduced the intakes of saline to <5 ml in both conditions and of water to <1 ml. Mean arterial pressure did not differ among the groups and was maintained above 100 mmHg after the depletion and captopril treatments because of the large doses of water. Thus, a full expression of salt appetite in response to an acute intravenous infusion of ANG II requires the integrity of both the SFO and OVLT.

Fos-like immunoreactivity and thirst following hyperosmotic loading in rats with subdiaphragmatic vagotomy.

If receptors in the gut relay information about increases in local osmolality to the brain via the vagus nerve, then vagotomy should diminish this signaling and reduce both thirst and brain Fos-like immunoreactivity (Fos-ir). Water intake in response to hypertonic saline (i.p. or i.g., 1 M NaCl, 1% BW; i.g., 0.6 M NaCl, 0.5% BW) was reduced during 120 min in rats with subdiaphragmatic vagotomy (VGX) compared to sham-VGX rats. Brain Fos-ir was examined in response to both i.g. loads. After the smaller load, VGX greatly reduced Fos-ir in the supraoptic nucleus (SON) and the magnocellular and parvocellular areas of the paraventricular nucleus (PVN). Fos-ir in the subfornical organ (SFO) and nucleus of the solitary tract (NTS) was not affected. After the larger load, VGX significantly reduced Fos-ir in the parvocellular PVN and in the NTS, but not in the other regions. Thus, decreased water intake by VGX rats was accompanied by decreased Fos-ir in the parvocellular PVN after the same treatments, indicating a role for the abdominal vagus in thirst in response to signaling from gut osmoreceptors. The decreased water intake in the VGX group was not reflected as a decrease in Fos-ir in the SFO. Absorption of the larger i.g. load may have activated Fos-ir through more rapidly increasing systemic osmolality, thereby obscuring a role for the vagus at this dose in the SON and magnocellular PVN.

Validity of single-site and multi-site models for estimating body composition of women using near-infrared interactance.

The purpose of this study was to develop a multi-site near-infrared (NIR) model (Model I) and compare its predictive accuracy to single-site models (IIA and IIB). In Model I, the sum of two optical density (OD) measures (Σ2OD), age, body weight, height, and physical activity level were used as potential predictors of body density (Db ). In Model IIA, the variables used in the manufacturer's NIR equation (biceps OD1 and OD2 , body weight, height, gender, and physical activity level) were the potential predictors. This model was modified by including age as an additional potential predictor in Model IIB. We also examined the test-retest reliability and interrelationships of OD measures taken at 10 anatomical sites, as well as the validity of the manufacturer's NIR equation, for estimating body composition of women. The subjects, 148 women between 20 and 72 years, were hydrostatically weighed to determine criterion Db . The Futrex-5000 was used to measure OD1 and OD2 at 10 anatomical sites. Only two sites (pectoral OD2 and biceps OD2 ) contributed significantly to the variance in Db . Thus, the sum of these two ODs (Σ2OD), was used as a potential predictor in the multi-site model. Test-retest reliability was high, with intraclass correlation coefficients ≥0.85 for many of the OD measurements. Intercorrelations of ODs ranged from 0.22 to 0.91. In the multi-site model (I), ΣOD, body weight, age, and height were significant predictors, accounting for 85.7% of the variance in Db . The SEE was 0.0076 g/ml or 3.3% BF. In the manufacturer's model (IIA), biceps OD2 , body weight, and height accounted for 76.3% of the variance in Db , and the SEE was 0.0094 g/ml (4.1% BF). When age was included as a predictor (Model IIB), the R2 increased (86.0%) and the SEE (0.0073 g/ml or 3.1% BF) decreased substantially. Cross-validation of the three equations yielded r2 s ranging between 0.688 (Model IIA) and 0.748 (Model I) and slightly larger SEEs (0.0094-0.001048 g/ml). There were no significant differences between average criterion Db and predicted Db for each equation. The manufacturer's equation programmed in the Futrex-5000 yielded a lower r2 (0.55), higher SEE (5.61% BF), and significantly underestimated criterion % BF by an average of 3% BF. Either the multi-site (model I) or single-site (Model IIB) equations is recommended to estimate body composition of this population. © 1992 Wiley-Liss, Inc.