Aversive Pathways Research Articles

Human α6β4 Nicotinic Acetylcholine Receptor: Heterologous Expression and Agonist Behavior Provide Insights into the Immediate Binding Site.

Study of α6β4 nicotinic acetylcholine receptors (nAChRs) as a pharmacological target has recently gained interest because of their involvement in analgesia, control of catecholamine secretion, dopaminergic pathways, and aversive pathways. However, an extensive characterization of the human α6β4 nAChRs has been vitiated by technical difficulties resulting in poor receptor expression. In 2020, Knowland and collaborators identified BARP (β-anchoring and regulatory protein), a previously known voltage-gated calcium channel suppressor, as a novel human α6β4 chaperone. Here, we establish that co-expression of human BARP with human α6β4 in Xenopus oocytes, resulted in the functional expression of human α6β4 receptors with acetylcholine-elicited currents that allow an in-depth characterization of the receptor using two electrode voltage-clamp electrophysiology together with diverse agonists and receptor mutations. We report: 1) an extended pharmacological characterization of the receptor, and 2) key residues for agonist-activity located in or near the first shell of the binding pocket. SIGNIFICANCE STATEMENT: The human α6β4 nicotinic acetylcholine receptor has attained increased interest because of its involvement in diverse physiological processes and diseases. Although recognized as a pharmacological target, development of specific agonists has been hampered by limited knowledge of its structural characteristics and by challenges in expressing the receptor. By including the chaperone β-anchoring and regulatory protein for enhanced expression and employing different ligands, we have studied the pharmacology of α6β4, providing insight into receptor residues and structural requirements for ligands important to consider for agonist-induced activation.

The unique pathways to coordinate specialty care for Black families navigating early psychosis: A preliminary report.

Aversive pathways to coordinated specialty care (CSC) for first episode psychosis have been linked to the extended duration of untreated psychosis, limited engagement, and treatment outcomes. Yet there has been very limited research that has solely explored the unique pathways to care among Black families in the U.S. This study utilized qualitative methods to explore the pathways to CSC among Black individuals experiencing their first episode of psychosis and their family members. Individuals who were or are enrolled in CSC programs and/or their family members were recruited to participate in semi-structured qualitative interviews. Qualitative interviews were used to characterize events and experiences prior to the initiation of CSC. All interviews were transcribed verbatim and analyzed using a qualitative descriptive approach. A total of 14 participants were recruited to complete semi-structured interviews. Findings revealed that during prodromal phase participants noticed changes in social functioning, identified prior childhood experiences that were viewed as traumatic, and sought very little help from formal sources. After the onset of psychosis, the majority of participants highlighted the importance of family members in the initiation of care, yet also expressed difficulties navigating services and engaging with clinical staff, contributing to further delays to the initiation of CSC. Finding from this study sheds light on understanding known disparities in utilization of services and potentially identifies areas that can be leveraged to improve the experiences for Black families seeking CSC.

First help-seeking attempt before and after psychosis onset: measures of delay and aversive pathways to care.

Delay in receiving effective treatment for psychosis adversely impacts outcomes. We investigated the timing of the first help-seeking attempt in individuals with recent onset non-affective psychosis by comparing those who sought help during the prodrome to those who sought help after psychosis onset across sociodemographic and clinical characteristics, overall functioning, and occurrence of aversive events during their pathways to care. Patients were admitted from February 1st, 2014 to January 31st, 2019 to the Program for Specialized Treatment Early in Psychosis (STEP) in New Haven, CT. Psychosis-onset date was ascertained using the Structured Interview for Psychosis-risk Syndromes. Key dates before and after psychosis onset, along with initiators and aversive events, were collected via semi-structured interview. Within 168 individuals, 82% had their first help-seeking episode after psychosis onset and did not differ in terms of sociodemographic characteristics from prodrome help seekers. When the first help-seeking episode started before (i.e., during prodrome) vs after psychosis onset it was mostly initiated by patients vs family members (Cramer's V = 0.23, p = 0.031) and led to a faster prescription of an antipsychotic once full-blown psychosis emerged (time to antipsychotic since psychosis onset = 21 vs 56days, p = 0.03). No difference in aversive events before STEP enrollment was detected across groups. Help seeking during the prodrome is associated with faster initiation of antipsychotic treatment and is more likely to be self-initiated, compared to help seeking after psychosis onset. Early detection efforts that target prodromal samples may improve the length and experience of pathways to care.

GFRAL-expressing neurons suppress food intake via aversive pathways

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α-like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre -expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non-meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

T242. THE TIMING OF FIRST HELP-SEEKING ATTEMPT IN FIRST EPISODE PSYCHOSIS CAN LEAD TO AVERSIVE PATHWAYS TO CARE. RESULTS FROM THE STEP-ED STUDY

BackgroundIn the U.S., individuals affected by a first episode psychosis endure 74 mean weeks of delay in receiving effective treatment. Facilitating their access to care has become a public health priority. This delay has proven to have adverse consequences both in short and long-term outcomes. Moreover, aversive pathways to care can imperil subsequent engagement with treatment. A better understanding of how a patient’s characteristics might influence interactions with healthcare systems could help tailor early detection interventions and target delays in treatments.By comparing the timing of the first help seeking attempt initiated in a sample of first episode psychosis participants of an early detection campaign, we aim to investigate if people starting to seek help before psychosis will have shorter delays to care, and if an earlier help-seeking attempt correlates with a lower rate of adverse pathways to care (e.g. police involvement, involuntary admissions).MethodsParticipants were recruited starting February 1st, 2014 to January 31st, 2019, to STEP, a Coordinated Specialty Care Program in New Haven, CT. Based on the date of the first help-seeking episode, demographic, clinical, and socioeconomic data were used to compare participants who had their first help-seeking attempt before or after psychosis onset (psychosis onset defined using the POPS criteria at the SIPS Interview). Chi-square test was used to compare categorical variables; non-parametric or Student’s t test was used to compare the continuous variables.ResultsThe sample comprised 168 subjects, the majority of which were male, African American, young adults (mean age was 22.4, SD=3.8), with a median time from psychosis onset to first antipsychotic of 52 days [IQ range, 15 – 196], and had their first help-seeking attempt after psychosis onset (70%). Between the two groups there was no difference in sociodemographic characteristics, in psychosis diagnosis, and in the global assessment of functioning (at baseline and 12 months prior).Help-seeking attempts made before psychosis onset were mostly initiated by the patients themselves, while attempts made after onset had the family as the prime initiator.Once the first help-seeking attempt was initiated, it took longer to get prescribed an antipsychotic for subjects seeking help before onset compared to those who sought help after (median 245 days [5 – 1400] vs. 1 day [0 – 999], p<0.0001). By contrast, it took less time for those who sought help before POPS to have their first antipsychotic prescribed once they became psychotic (median 21 days [0 – 445] vs. 56 days [0 – 1153], p=0.03). However, both groups had no significant difference in delay to STEP (p=0.30).Help-seekers after psychosis onset had a trend of longer patient side delay (defined as the time interval from when patients noticed a change-patient’s term for psychotic symptoms- to the day they sought help) compared to participants seeking help before onset (median 75 days [0 – 3928] vs. 14 days [0 – 1093], p=0.09).Compared to those who had their first help seeking episode before psychosis onset, the group who sought help after onset had more contacts with the police (64 vs 10), more involuntary admissions (40 vs 6), and same median number of nights spent in a psychiatric hospital six months before STEP enrollment (n=14).DiscussionTiming of first help seeking in early psychosis can be crucial in shaping the individual experience of care. Longer delays in receiving the appropriate treatment and aversive pathways might be associated with help seeking which started only after psychosis onset, compared to first help seeking started before psychosis onset. Tailored interventions are needed to improve psychosis detection and referral of first episodes to specialized services.

SUN-269 Activation of GFRAL Neurons Decreases Food Intake via Aversive Pathways

Growth and differentiation factor 15 (GDF15), an anorexigenic peptide that represents a promising candidate for anti-obesity treatment, acts via GDNF Family Receptor Alpha Like (GFRAL), which is expressed almost exclusively on a subset of neurons in the area postrema (AP). To determine the function and mechanisms of action for GFRAL neurons, we generated Gfralcre and conditional GfralCreERT mice. Although their chemogenetic (DREADD-mediated) activation promoted FOS in a variety of brainstem, hypothalamic, and limbic nuclei, GFRAL neurons projected only to the nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN), where they innervated and activated aversive/anorexigenic GCRP-expressing cells. Tetanus-toxin-mediated silencing of PBN CGRP neurons abrogated the aversive and anorexic effects of GDF15. Furthermore, while non-gastrointestinal (GI) stimuli (e.g., GDF15 and LPS, but not feeding or gut peptide mimetics) activated GFRAL neurons, chemogenetically activating these cells decreased gastric emptying, suppressed feeding, and promoted a conditioned taste aversion. These findings suggest that GFRAL neurons link non-GI anorexigenic signals to the control of gut physiology and to the aversive suppression of food intake. Additionally, because the chemogenetic activation of GFRAL neurons suppressed food intake more strongly than GDF15 in lean mice, additional modes of activating GFRAL neurons may augment the anorectic potential of GDF15.

Projection-Specific Potentiation of Ventral Pallidal Glutamatergic Outputs after Abstinence from Cocaine.

The ventral pallidum (VP) is a central node in the reward system that is strongly implicated in reward and addiction. Although the majority of VP neurons are GABAergic and encode reward, recent studies revealed a novel glutamatergic neuronal population in the VP [VP neurons expressing the vesicular glutamate transporter 2 (VPVGluT2)], whose activation generates aversion. Withdrawal from drugs has been shown to induce drastic synaptic changes in neuronal populations associated with reward, such as the ventral tegmental area (VTA) or nucleus accumbens neurons, but less is known about cocaine-induced synaptic changes in neurons classically linked with aversion. Here, we demonstrate that VPVGluT2 neurons contact different targets with different intensities, and that cocaine conditioned place preference (CPP) training followed by abstinence selectively potentiates their synapses on targets that encode aversion. Using whole-cell patch-clamp recordings combined with optogenetics in male and female transgenic mice, we show that VPVGluT2 neurons preferentially contact aversion-related neurons, such as lateral habenula neurons and VTA GABAergic neurons, with minor input to reward-related neurons, such as VTA dopamine and VP GABA neurons. Moreover, after cocaine CPP and abstinence, the VPVGluT2 input to the aversion-related structures is potentiated, whereas the input to the reward-related structures is depressed. Thus, cocaine CPP followed by abstinence may allow VPVGluT2 neurons to recruit aversion-related targets more readily and therefore be part of the mechanism underlying the aversive symptoms seen after withdrawal.SIGNIFICANCE STATEMENT The biggest problem in drug addiction is the high propensity to relapse. One central driver for relapse events is the negative aversive symptoms experienced by addicts during withdrawal. In this work, we propose a possible mechanism for the intensification of aversive feelings after withdrawal that involves the glutamatergic neurons of the ventral pallidum. We show not only that these neurons are most strongly connected to aversive targets, such as the lateral habenula, but also that, after abstinence, their synapses on aversive targets are strengthened, whereas the synapses on other rewarding targets are weakened. These data illustrate how after abstinence from cocaine, aversive pathways change in a manner that may contribute to relapse.

Risk of involuntary admission among first-generation ethnic minority groups with early psychosis: a retrospective cohort study using health administrative data.

Ethnic minority groups often have more complex and aversive pathways to mental health care. However, large population-based studies are lacking, particularly regarding involuntary hospitalisation. We sought to examine the risk of involuntary admission among first-generation ethnic minority groups with early psychosis in Ontario, Canada. Using health administrative data, we constructed a retrospective cohort (2009-2013) of people with first-onset non-affective psychotic disorder aged 16-35 years. This cohort was linked to immigration data to ascertain migrant status and country of birth. We identified the first involuntary admission within 2 years and compared the risk of involuntary admission for first-generation migrant groups to the general population. To control for the role of migrant status, we restricted the sample to first-generation migrants and examined differences by country of birth, comparing risk of involuntary admission among ethnic minority groups to a European reference. We further explored the role of migrant class by adjusting for immigrant vs refugee status within the migrant cohort. We also explored effect modification of migrant class by ethnic minority group. We identified 15 844 incident cases of psychotic disorder, of whom 19% (n = 3049) were first-generation migrants. Risk of involuntary admission was higher than the general population in five of seven ethnic minority groups. African and Caribbean migrants had the highest risk of involuntary admission (African: risk ratio (RR) = 1.52, 95% CI = 1.34-1.73; Caribbean: RR = 1.58, 95% CI = 1.37-1.82), and were the only groups where the elevated risk persisted when compared to the European reference group within the migrant cohort (African: RR = 1.24, 95% CI = 1.04-1.48; Caribbean: RR = 1.29, 95% CI = 1.07-1.56). Refugee status was independently associated with involuntary admission (RR = 1.16, 95% CI = 1.02-1.32); however, this risk varied by ethnic minority group, with Caribbean refugees having an elevated risk of involuntary admission compared with Caribbean immigrants (RR = 1.72, 95% CI = 1.15-2.58). Our findings are consistent with the international literature showing increased rates of involuntary admission among some ethnic minority groups with early psychosis. Interventions aimed at improving pathways to care could be targeted at these groups to reduce disparities.

Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction.

Quantitative assessment of TRPM5-dependent oral aversiveness of pharmaceuticals using a mouse brief-access taste aversion assay

Many orally administered pharmaceuticals are regarded by humans as aversive, most often described as 'bitter'. Taste aversiveness often leads to patient noncompliance and reduced treatment effectiveness. 'Bitter' taste is mediated by T2R G-protein coupled receptors through a peripheral signaling pathway critically dependent upon function of the TRPM5 ion channel. The brief-access taste aversion (BATA) assay operationally defines aversive taste as suppression of the rate at which a rodent licks from sipper tubes that deliver tastant solutions or suspensions. We have used a mouse BATA assay for rapid quantification of oral aversiveness from a set of 20 active pharmaceutical ingredients (APIs). Robust lick-rate dose-response functions were obtained from both C57BL/6J wild type (WT) and C57BL/6J/TRPM5-/- (TRPM5 knockout) mouse strains, generating reliable determinations of potency and relative maximal oral aversiveness for each API. A subset of APIs was also evaluated in a human bitterness assessment test; effective concentrations for half-maximum responses (EC50s) from both the human test and WT mouse BATA were equivalent. Relative to WT potencies, EC50s from TRPM5 knockout mice were right-shifted more than 10-fold for most APIs. However, APIs were identified for which EC50s were essentially identical in both mouse strains, indicating a TRPM5-independent alternative aversive pathway. Our results suggest the BATA assay will facilitate formulation strategies and taste assessment of late development-phase APIs.

Pathways to Care for African Americans With Early Psychosis

Pathways to Care for African Americans With Early Psychosis