L-type calcium channel regulation of depression, anxiety and anhedonia-related behavioral phenotypes following chronic stress exposure.

Exposure to chronic and unpredictable stressors can precipitate mood-related disorders in humans, particularly in individuals with pre-existing mental health challenges. L-type calcium channels (LTCCs) have been implicated in numerous neuropsychiatric disorders, as LTCC encoding genes have been identified as candidate risk factors for neuropsychiatric illnesses. In these sets of experiments, we sought to examine the ability of LTCC blockade to alter depression, anxiety, and anhedonic-related behavioral responses to chronic unpredictable stress (CUS) exposure in female and male rats. Rats first underwent either 21 days of CUS or no exposure to chronic stressors, serving as home cage controls (HCC). Then rats were examined for anhedonia-related behavior, anxiety and depression-like behavioral responses as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and forced swim test (FST). CUS exposed females and males showed anhedonic and anxiogenic-like behavioral responses on the SPT and EPM, respectively, when compared to HCCs. In female and male rats, systemic administration of the LTCC blocker isradipine (0.4 mg/kg and 1.2 mg/kg, I.P.) attenuated the CUS-induced decrease in sucrose preference and reversed the CUS-induced decrease in open arm time. In the FST, systemic isradipine decreased immobility time across all groups, consistent with an antidepressant-like response. However, there were no significant differences in forced swim test immobility time between HCC and CUS exposed animals. Taken together, these data point to a role of LTCCs in the regulation of mood disorder-related behavioral phenotype responses to chronic stress exposure.

Impact of vanilla flavor on nicotine taste, choice, intake, and seeking behaviors.

RATIONALE: Flavors can alter the orosensory properties of tobacco products. Specifically, flavors can serve as an oral cue for smokeless tobacco products. OBJECTIVES: We aimed to investigate the impact of oral vanillin, the principal chemical of vanilla flavor in tobacco products, on nicotine's taste, and nicotine choice, intake, and seeking behaviors. METHODS: Experiments were performed in young adult Sprague Dawley rats. We employed a two-bottle free-choice test (2BC) to measure the preference for different concentrations of vanillin and its effect on nicotine preference. To explore the long-term effects of early exposure to sweetened vanillin, we utilized a combined 2BC and intraoral self-administration (IOSA) model. We assessed the nicotine taking and seeking behaviors in the presence or absence of vanillin. We performed a taste reactivity test (TRT) to quantify liking (ingestive) and disliking (aversive) taste responses to oral nicotine with or without vanillin. RESULTS: In 2BC, female rats preferred vanillin containing solutions more than their male counterparts. In IOSA, vanillin alone and in combination with nicotine led to greater IOSA compared to water. Female rats self-administered vanillin plus nicotine more than male rats. Vanillin increased motivation to nicotine taking, but only in females. In TRT, vanillin increased nicotine's ingestive responses but blocked aversive responses in both sexes. CONCLUSIONS: These results indicate that vanilla flavor can increase oral nicotine intake. It can also increase liking and decrease disliking of nicotine's taste. Furthermore, the impact of vanilla flavor on nicotine taste and nicotine choice, intake, and seeking behaviors is concentration and sex dependent.

Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.

The impact of racism on Black American mental health.

Black individuals in the USA experience disparities in mental health that lead to unfavorable health outcomes and increased morbidity from mental illness due to centuries of racism. We emphasize the need to understand the roots of racial injustice to achieve racial equity. Historical factors such as European imperialism, enslavement, the myth of Black inferiority, and scientific racial classification have all perpetuated disparities, leading to the current underestimation, misdiagnosis, and inadequate treatment of mental illness in Black populations. Many of the issues discussed herein apply to Black people globally; however, our focus is on Black Americans and the inequities that result from the current US mental health system. We discuss the limitations of using the DSM-5 classification system and common epidemiological surveys, which do not capture or call for a comprehensive analysis of the systems producing mental health issues, to understand mental illness among Black Americans.

Self-reported continuing professional development needs of medical laboratory professionals in Ghana.

BACKGROUND: Because of the essential nature of the work of medical laboratory professionals, continuing development in knowledge and skills is indispensable. The study aimed at identifying and prioritizing the development and training needs of medical laboratory professionals in Ghana. This is expected to help in developing focused continuing professional development (CPD) that meets the needs of practitioners as well as the changing medical trends. METHODS: An online cross-sectional survey in February 2022 using a structured questionnaire was conducted. Respondents were asked questions that collected demographic and work-related data about them, their participation, preference, and challenges in being part of CPDs. Finally, a list of topics based on (i) quality management systems, (ii) technical competence, (iii) laboratory management, leadership, and coaching, (iv) pathophysiology, and (iv) data interpretation and research were asked with the option to rate them on a 3-point scale (most, moderate, and least) in order of importance. RESULTS: A total of 316 medical laboratory professionals participated in the study. Overall, the most frequently selected topics for training based on domains for CPD training and ranking as most important were (i) quality management systems, (mean = 80.59 ± 9.024; 95% CI = 73.04-88.13); (ii) pathophysiology, data interpretation, and research (mean = 78.0 ± 6.973; 95% CI = 73.97-82.03); (iii) technical competence (mean = 73.97 ± 10.65; 95% CI = 66.35-81.59); and (iv) laboratory management, leadership, and coaching (mean = 72.82 ± 9.719; 95% CI = 67.44-78.2). The factors affecting the choice of training needs included the medical laboratory professionals' current place of work, years in service, the reason for attending CPD activities, the period for attending the last CPD, being in a supervisory role, and the number of staff being supervised. Face-to-face presentations, training workshops, and hands-on workshops were the most preferred modes of CPD delivery with financial implications and workload/time constraints being the main challenges impeding CPD participation. CONCLUSION: The identified needs will help in developing CPD programs that address what medical laboratory professionals prioritize as training needs. Stakeholders should incorporate these training needs into future programs and address the challenges highlighted in this study to have more relevant training for medical laboratory professionals.

Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner .

Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice behaviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or consume freely available, less-preferred food. VTA administration of physostigmine (1 µg and 2 µg/side), a cholinesterase inhibitor, reduced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 µM, 10 µM, 30 µM/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 µM/side) coadministration with physostigmine (2 µg/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physostigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release. SIGNIFICANCE STATEMENT: Effort-choice impairments are observed in depressive disorders, which are often treatment resistant to currently available thymoleptics. The role of ventral tegmental area (VTA) acetylcholine muscarinic M5 receptors, in a preclinical model of effort-choice behavior, is examined. Using the selective negative allosteric modulator of the M5 receptor VU6000181, we show the role of VTA M5 receptors on effort-choice and regulation of dopamine release in the nucleus accumbens core. This study supports M5 receptors as therapeutic targets for depression.

High-resolution, respiratory-resolved coronary MRA using a Phyllotaxis-reordered variable-density 3D cones trajectory.

PURPOSE: To develop a respiratory-resolved motion-compensation method for free-breathing, high-resolution coronary magnetic resonance angiography (CMRA) using a 3D cones trajectory. METHODS: To achieve respiratory-resolved 0.98 mm resolution images in a clinically relevant scan time, we undersample the imaging data with a variable-density 3D cones trajectory. For retrospective motion compensation, translational estimates from 3D image-based navigators (3D iNAVs) are used to bin the imaging data into four phases from end-expiration to end-inspiration. To ensure pseudo-random undersampling within each respiratory phase, we devise a phyllotaxis readout ordering scheme mindful of eddy current artifacts in steady state free precession imaging. Following binning, residual 3D translational motion within each phase is computed using the 3D iNAVs and corrected for in the imaging data. The noise-like aliasing characteristic of the combined phyllotaxis and cones sampling pattern is leveraged in a compressed sensing reconstruction with spatial and temporal regularization to reduce aliasing in each of the respiratory phases. RESULTS: In initial studies of six subjects, respiratory motion compensation using the proposed method yields improved image quality compared to non-respiratory-resolved approaches with no motion correction and with 3D translational correction. Qualitative assessment by two cardiologists and quantitative evaluation with the image edge profile acutance metric indicate the superior sharpness of coronary segments reconstructed with the proposed method (P < 0.01). CONCLUSION: We have demonstrated a new method for free-breathing, high-resolution CMRA based on a variable-density 3D cones trajectory with modified phyllotaxis ordering and respiratory-resolved motion compensation with 3D iNAVs.

Chronic oral nicotine exposure decreases aversive taste of nicotine, increases nicotine withdrawal and reinstatement, but cherry flavor does not alter nicotine's effects in adolescent rats.

Although e-cigarette use among youth is recognized as an epidemic, there is limited understanding regarding nicotine's orosensory and chronic use effects in youth, and how fruit e-cigarette flavorings may influence nicotine's effects. We aimed to characterize the orosensory and chronic use effects of nicotine in adolescent rats. We also determined the acute and chronic effects of benzaldehyde, a cherry/berry/almond flavoring, on nicotine's taste, consumption, withdrawal, and reinstatement. Rats were examined for their acute taste responses to the different nicotine concentrations. The effects of chronic exposure on nicotine's taste, withdrawal, and reinstatement were also determined. In addition, impact of benzaldehyde on these nicotine use behaviors was evaluated. While taste responses to low nicotine concentrations did not differ from water, high nicotine concentrations induced aversion. Aversive responses to nicotine that were observed in naïve animals vanished after chronic nicotine exposure, indicating the development of tolerance to nicotine's aversive taste. Additionally, nicotine abstinence after chronic exposure induced withdrawal. Following abstinence, animals reinstated nicotine use. Further, animals showed higher preference to nicotine after reinstatement, compared to preference values before nicotine withdrawal. Benzaldehyde did not alter nicotine's taste reactivity, withdrawal, and reinstatement experiments. Some sex differences were found in benzaldehyde's taste response and choice behavior experiments.

L-type calcium channel regulation of dopamine activity in the ventral tegmental area to nucleus accumbens pathway: Implications for substance use, mood disorders and co-morbidities.

L-type calcium channels (LTCCs), including the Cav1.2 and Cav1.3 LTCC subtypes, are important regulators of calcium entry into neurons, which mediates neurotransmitter release and synaptic plasticity. Cav1.2 and Cav1.3 are encoded by the CACNA1C and CACNA1D genes, respectively. These genes are implicated in substance use disorders and depression in humans, as demonstrated by genetic-wide association studies (GWAS). Pre-clinical models have also revealed a critical role of LTCCs on drug and mood related behavior, including the co-morbidity of substance use and mood disorders. Moreover, LTCCs have been shown to regulate the neuronal firing of dopamine (DA) neurons as well as drug and stress-induced plasticity within the ventral tegmental area (VTA) to nucleus accumbens (NAc) pathway. Thus, LTCCs are interesting targets for the treatment of neuropsychiatric diseases. In this review, we provide a brief introduction to voltage-gated calcium channels, specifically focusing on the LTCCs. We place particular emphasis on the ability of LTCCs to regulate DA neuronal activity and downstream signaling in the VTA to NAc pathway, and how such processes mediate substance use and mood disorder-related behavioral responses. We also discuss the bi-directional control of VTA LTCCs on drug and mood-related behaviors in pre-clinical models, with implications for co-morbid psychiatric diagnosis. We conclude with a section on the clinical implications of LTCC blockers, many which are already FDA approved as cardiac medications. Thus, pre-clinical and clinical work should examine the potential of LTCC blockers to be repurposed for neuropsychiatric illness. This article is part of the Special Issue on 'L-type calcium channel mechanisms in neuropsychiatric disorders'.

Animal Models to Investigate the Impact of Flavors on Nicotine Addiction and Dependence.

BACKGROUND: Tobacco use in humans is a long-standing public health concern. Flavors are common additives in tobacco and alternative tobacco products, added to mask nicotine's harsh orosensory effects and increase the appeal of these products. Animal models are integral for investigating nicotine use and addiction and are helpful for understanding the effects of flavor additives on the use of nicotine delivery products. OBJECTIVE: This review focuses on preclinical models to evaluate the contribution of flavor additives to nicotine addiction. MATERIALS AND METHODS: An electronic literature search was conducted by authors up to May 2022. Original articles were selected. RESULTS: The behavioral models of rodents described here capture multiple dimensions of human flavored nicotine use behaviors, including advantages and disadvantages. CONCLUSION: The consensus of the literature search was that human research on nicotine use behavior has not caught up with fast-changing product innovations, marketing practices, and federal regulations. Animal models are therefore needed to investigate mechanisms underlying nicotine use and addiction. This review provides a comprehensive overvie.

Cholinergic and dopaminergic-mediated motivated behavior in healthy states and in substance use and mood disorders.

Acetylcholine is an important neuromodulator of the mesolimbic dopamine (DA) system, which itself is a mediator of motivated behavior. Motivated behavior can be described by two primary components, termed directional and activational motivation, both of which can be examined and dissociated using effort-choice tasks. The directional component refers to motivated behavior directed towards reinforcing stimuli and away from aversive stimuli. Behaviors characterized by increased vigor, persistence, and work output are considered to reflect activational components of motivation. Disruption of DA signaling has been shown to decrease activational components of motivation, while leaving directional features intact. Facilitation of DA release promotes the activational aspects of motivated behavior. In this review, we discuss cholinergic and DA regulation of motivated behaviors. We place emphasis on effort-choice processes and the ability of effort-choice tasks to examine and dissociate changes of motivated behavior in the context of substance use and mood disorders. Furthermore, we consider how altered cholinergic transmission impacts motivated behavior across disease states, and the possible role of cholinergic dysregulation in the etiology of these illnesses. Finally, we suggest that treatments targeting cholinergic activity may be useful in ameliorating motivational disruptions associated with substance use and comorbid substance use and mood disorders.

Evaluation of Flavor Effects on Oral Nicotine Liking and/or Disliking Using the Taste Reactivity Test in Rats.

INTRODUCTION: Tobacco product flavors may change the sensory properties of nicotine, such as taste and olfactory cues, which may alter nicotine reward and aversion and nicotine taking behavior. The hedonic or aversive value of a taste stimulus can be evaluated by examining affective orofacial movements in rodents. AIMS AND METHODS: We characterized taste responses to various oral nicotine concentrations using the taste reactivity test in rats. We also evaluated the impact of menthol and benzaldehyde (cherry, almond) flavorants on both ingestive and aversive responses to oral nicotine. Adult Sprague-Dawley rats (n = 5-10 per sex per group) were implanted with intraoral catheters and received 20 infusions (200 µl/ea). Nicotine (1-100 µg/mL) was evaluated in taste reactivity test to determine taste responses to nicotine. Later, the effects of menthol (50 µg/mL) and benzaldehyde (100 µg/mL) on the taste responses to nicotine were determined. RESULTS: Nicotine at low concentrations (3 µg/mL in males, 1 µg/mL in females) elicited significantly greater ingestive responses compared with water, whereas higher nicotine concentrations (≥30 µg/mL in males, ≥10 µg/mL in females) elicited significant aversive reactions. Thus, intraoral nicotine induced both hedonic and aversive responses in a concentration- and sex-dependent manner. Females were more sensitive to nicotine's concentration. The addition of menthol or benzaldehyde significantly increased the hedonic responses to nicotine, and significantly decreased the aversive nicotine responses. CONCLUSIONS: Oral nicotine induces both hedonic and aversive taste responses, which may represent liking and disliking. Menthol and benzaldehyde can alter the orosensory experience of nicotine, which may influence nicotine's abuse liability. IMPLICATIONS: Our work represents a model to study impact of flavors on oral nicotine liking and disliking responses in rats. Moreover, our findings show that menthol and benzaldehyde alter the orosensory experience of nicotine, suggesting that both could influence nicotine's abuse liability.

An ongoing saga of nicotine complexity and dopamine heterogeneity: Nicotine activation and inhibition mediating reward and anxiety.

In this issue of Neuron, Nguyen and colleagues (Nguyen et al., 2021) investigate nicotine's effects on diverse midbrain dopamine neurons. Their findings provide new understanding of the functional role of ventral tegmental area (VTA) dopamine neurons and reveal topographically distinct, pathway-specific, and opposite dopaminergic responses to nicotine that likely mediate reward and anxiety, respectively.

Combined Infusion and Stimulation with Fast-Scan Cyclic Voltammetry (CIS-FSCV) to Assess Ventral Tegmental Area Receptor Regulation of Phasic Dopamine.

Phasic dopamine (DA) release from the ventral tegmental area (VTA) to the nucleus accumbens plays a pivotal role in reward processing and reinforcement learning. Understanding how the diverse neuronal inputs into the VTA control phasic DA release can provide a better picture of the circuitry that controls reward processing and reinforcement learning. Here, we describe a method that combines intra-VTA cannula infusions of pharmacological agonists and antagonists with stimulation-evoked phasic DA release (combined infusion and stimulation, or CIS) as measured by in vivo fast-scan cyclic voltammetry (FSCV). Using CIS-FSCV in anesthetized rats, a phasic DA response can be evoked by electrically stimulating the VTA with a bipolar electrode fitted with a cannula while recording in the nucleus accumbens core. Pharmacological agonists or antagonists can be infused directly at the stimulation site to investigate specific VTA receptors' roles in driving phasic DA release. A major benefit of CIS-FSCV is that VTA receptor function can be studied in vivo, building on in vitro studies.

Examining the role of muscarinic M5 receptors in VTA cholinergic modulation of depressive-like and anxiety-related behaviors in rats.

Acetylcholine is implicated in mood disorders including depression and anxiety. Increased cholinergic tone in humans and rodents produces pro-depressive and anxiogenic-like effects. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate these responses in male rats, as measured by the sucrose preference test (SPT), elevated plus maze (EPM), and the forced swim test (FST). However, these effects have not been examined in females, and the VTA muscarinic receptor subtype(s) mediating the pro-depressive and anxiogenic-like behavioral effects of increased cholinergic tone are unknown. We first examined the behavioral effects of increased VTA cholinergic tone in male and female rats, and then determined whether VTA muscarinic M5 receptors were mediating these effects. VTA infusion of the acetylcholinesterase inhibitor physostigmine (0.5 µg, 1 µg and 2 µg/side) in males and females produced anhedonic-like, anxiogenic, pro-depressive-like responses on the SPT, EPM, and FST. In females, VTA administration of the muscarinic M5 selective negative allosteric modulator VU6000181 (0.68 ng, 2.3 ng, 6.8 ng/side for a 3 µM, 10 µM, 30 µM/side infusion) did not alter SPT, EPM nor FST behavior. However, in males intra-VTA infusion of VU6000181 alone reduced time spent immobile on the FST. Furthermore, co-infusion of VU6000181 with physostigmine, in male and female rats, attenuated the pro-depressive and anxiogenic-like behavioral responses induced by VTA physostigmine alone, in the SPT, EPM, and FST. Together, these data reveal a critical role of VTA M5 receptors in mediating the anhedonic, anxiogenic, and depressive-like behavioral effects of increased cholinergic tone in the VTA.

Cholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence.

Drug relapse after periods of abstinence is a common feature of substance abuse. Moreover, anxiety and other mood disorders are often co-morbid with substance abuse. Cholinergic receptors in the ventral tegmental area (VTA) are known to mediate drug-seeking and anxiety-related behavior in rodent models. However, it is unclear if overlapping VTA cholinergic mechanisms mediate drug relapse and anxiety-related behaviors associated with drug abstinence. We examined the effects of VTA cholinergic receptor blockade on cue-induced cocaine seeking and anxiety during cocaine abstinence. Male Sprague-Dawley rats were trained to self-administer intravenous cocaine (~0.5 mg/kg/infusion, FR1 schedule) for 10 days, followed by 14 days of forced abstinence. VTA infusion of the non-selective nicotinic acetylcholine receptor antagonist mecamylamine (0, 10, and 30 µg/side) or the non-selective muscarinic receptor antagonist scopolamine (0, 2.4 and 24 µg /side) significantly decreased cue-induced cocaine seeking. In cocaine naïve rats, VTA mecamylamine or scopolamine also led to dose-dependent increases in open arm time in the elevated plus maze (EPM). In contrast, rats that received I.V. cocaine, compared to received I.V. saline rats, displayed an anxiogenic response on day 14 of abstinence as reflected by decreased open arm time in the EPM. Furthermore, low doses of VTA mecamylamine (10 µg /side) or scopolamine (2.4 µg /side), that did not alter EPM behavior in cocaine naive rats, were sufficient to reverse the anxiogenic effects of cocaine abstinence. Together, these data point to an overlapping role of VTA cholinergic mechanisms to regulate relapse and mood disorder-related responses during cocaine abstinence.

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse.

Tobacco-related morbidity and mortality continue to be a significant public health concern. Unfortunately, current FDA-approved smoking cessation pharmacotherapies have limited efficacy and are associated with high rates of relapse. Therefore, a better understanding of the neurobiological and neurophysiological mechanisms that promote smoking relapse is needed to develop novel smoking cessation medications. Here, we review preclinical studies focused on identifying the neurotransmitter and neuromodulator systems that mediate nicotine relapse, often modeled in laboratory animals using the reinstatement paradigm, as well as the plasticity-dependent neurophysiological mechanisms that facilitate nicotine reinstatement. Particular emphasis is placed on how these neuroadaptations relate to smoking relapse in humans. We also highlight a number of important gaps in our understanding of the neural mechanisms underlying nicotine reinstatement and critical future directions, which may lead toward the development of novel, target pharmacotherapies for smoking cessation.

Whole-heart coronary MR angiography using a 3D cones phyllotaxis trajectory.

PURPOSE: To develop a 3D cones steady-state free precession sequence with improved robustness to respiratory motion while mitigating eddy current artifacts for free-breathing whole-heart coronary magnetic resonance angiography. METHOD: The proposed sequence collects cone interleaves using a phyllotaxis pattern, which allows for more distributed k-space sampling for each heartbeat compared to a typical sequential collection pattern. A Fibonacci number of segments is chosen to minimize eddy current effects with the trade-off of an increased number of acquisition heartbeats. For verification, phyllotaxis-cones is compared to sequential-cones through simulations, phantom studies, and in vivo coronary scans with 8 subjects using 2D image-based navigators for retrospective motion correction. RESULTS: Simulated point spread functions and moving phantom results show less coherent motion artifacts for phyllotaxis-cones compared to sequential-cones. Assessment of the right and left coronary arteries using reader scores and the image edge profile acutance vessel sharpness metric indicate superior image quality and sharpness for phyllotaxis-cones. CONCLUSION: Phyllotaxis 3D cones results in improved qualitative image scores and coronary vessel sharpness for free-breathing whole-heart coronary magnetic resonance angiography compared to standard sequential ordering when using a steady-state free precession sequence.

The L-type calcium channel blocker, isradipine, attenuates cue-induced cocaine-seeking by enhancing dopaminergic activity in the ventral tegmental area to nucleus accumbens pathway.

Previous preclinical and clinical investigations have focused on the L-type calcium channel (LTCC) as a potential therapeutic target for substance abuse. While some clinical studies have examined the ability of LTCC blockers to alter cocaine's subjective effects, very few LTCC studies have examined cocaine relapse. Here, we examined whether ventral tegmental area (VTA)-specific or systemic administration of the LTCC inhibitor, isradipine, altered cocaine-seeking behavior in a rat model. Male Sprague-Dawley rats first received 10 days of cocaine self-administration training (2 h sessions), where active lever depression resulted in delivery of a ∼0.5 mg/kg cocaine infusion paired with a tone + light cue. Rats then underwent 10 days of forced abstinence, without access to cocaine or cocaine cues. Rats were then returned to the opertant chamber for the cue-induced cocaine-seeking test, where active lever depression in the original training context resulted in tone + light cue presentation. We found VTA specific or systemic isradipine administration robustly attenuated cocaine-seeking, without altering cocaine-taking nor natural reward seeking. Dopamine (DA) signaling in the nucleus accumbens (NAc) core is necessary and sufficient for cue-induced drug-seeking. Surprisingly in our study, isradipine enhanced tonic and phasic DA signaling in cocaine abstinent rats, with no change in sucrose abstinent nor naïve rats. Strikingly, isradipine's behavioral effects were dependent upon NAc core DA receptor activation. Together, our findings reveal a novel mechanism by which the FDA-approved drug, isradipine, could act to decrease cocaine relapse.

Evaluating oral flavorant effects on nicotine self-administration behavior and phasic dopamine signaling.

Understanding how tobacco product flavor additives, such as flavorants in electronic cigarettes, influence smoking behavior and addiction is critical for informing public health policy decisions regarding tobacco product regulation. Here, we developed a combined intraoral (i.o.) and intravenous (i.v.) self-administration paradigm in rats to determine how flavorants influence self-administration behavior. By combining i.o. flavorant delivery with fast scan cyclic voltammetry (FSCV) or i.v. nicotine self-administration in adult, male rats, we examined whether flavors alter phasic dopamine (DA) signaling and nicotine self-administration. Oral administration of 10% sucrose or 0.32% saccharin, but not 0.005% menthol, increased phasic DA release in the nucleus accumbens (NAc). Oral sucrose or saccharin, when combined with i.v. nicotine delivery, also led to increased self-administration behavior. Specifically, combined i.o. sucrose and i.v. nicotine decreased responding compared to sucrose alone, and increased responding compared to nicotine alone. In contrast, i.o. flavorants did not alter motivational breakpoint in a progressive ratio task. Oral menthol, which did not alter i.v. nicotine administration, reversed oral nicotine aversion (50 and 100 mg/L) in a two-bottle choice test. Here, we demonstrate that i.o. appetitive flavorants that increase phasic DA signaling also increase self-administration behavior when combined with i.v. nicotine delivery. Additionally, oral menthol effects were specific to oral nicotine, and were not observed with i.v. nicotine-mediated reinforcement. Together, these preclinical findings have important implications regarding menthol and sweet flavorant additive effects on tobacco product use and can be used to inform policy decisions on tobacco product flavorant regulation.