Biology subjects

Pina, M. M.

Publications and source records attributed to Pina, M. M..

8 recordsLinked to original sources

bioRxiv2026

The role of serotonin in the orbitofrontal cortex in alcohol consumption

Binge alcohol drinking is a public health concern that can dramatically increase the risk for development of alcohol use disorder (AUD). Continued alcohol drinking in the face of negative consequences is another key feature of AUD. A better understanding of the neural circuitry that regulates these behaviors could provide insight as to novel treatments for AUD. Serotonin is a neurotransmitter that has been implicated in alcohol consumption in both human studies and animal models. The orbitofrontal cortex (OFC) is a brain region that both receives serotonergic input from the dorsal raphe and has been implicated in AUD. However, how volitional alcohol consumption impacts serotonin signaling within the OFC and how this contributes to alcohol related behaviors is unknown. Here, we show that a history of alcohol consumption alters the ability of 5-HT to hyperpolarize OFC pyramidal neurons in mice and monkeys. Consistent with this, a history of binge alcohol consumption decreases the expression of the 5-HT1A but not 5-HT2A receptor in the OFC from mice. Next, we show that deletion of the 5-HT1A receptor from the OFC increased alcohol intake and preference in male, but not female mice. Finally, we found that 5-HT1A receptor deletion led to increased quinine-adulterated alcohol intake, a measure of aversion-resistant drinking, in both male and female mice. Altogether, we identified serotonin signaling in the OFC as key target for modulation of binge and compulsive alcohol consumption.

neuroscience↗

bioRxiv2022

Sex-specific regulation of binge drinking and affective behaviors by subcortical serotonin 5HT2c receptors

Serotonin 5HT2c receptors have been implicated in the pathophysiology of both mood disorders and alcohol use disorder, but the circuits mediating the effects of systemic pharmacological manipulations of this receptor on behavior have not been identified. Binge alcohol consumption induces discrete social and arousal disturbances in human populations, which are thought to promote increased drinking. However, whether models of binge drinking in rodents can induce these same long-term negative behavioral symptoms is unknown. In this study, we employed multiple anatomical, physiological, and behavioral approaches to identify two populations of neurons expressing serotonin 5HT2c receptors, one in the lateral habenula (LHb5HT2c) and one in the bed nucleus of the stria terminalis (BNST5HT2c), that display coordinated in-vivo responses to social, arousal, and alcohol-related stimuli and are physiologically modulated by binge alcohol consumption in a sex-specific manner. Critically, these physiological changes were associated with sex-specific behavioral disturbances that closely mirror social and arousal symptoms observed in humans during abstinence from binge drinking. Specifically, we observed that one week of abstinence from three weeks of binge alcohol drinking induced social recognition deficits in females and potentiated acoustic startle responses in males. While both populations of neurons (BNST and LHb) and the 5HT2c receptor itself contribute to the sex-specific effects of alcohol on social and arousal behaviors to some degree, the primary causal mechanism underlying these phenomena appears to be excessive activation of LHb5HT2c neurons. These findings may have implications for the development of sex-specific treatments for mood and alcohol use disorders targeting the brains serotonin system.

neuroscience↗

bioRxiv2019

Extended Amygdala Kappa Opioid Receptor Signaling Gates Alcohol-induced Stress Impairments in Mice

"The authors have withdrawn their manuscript because they identified errors in the methods and data reporting that make the results and conclusions unreliable. The published version of this preprint has already been retracted. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author."

neuroscience↗

bioRxiv2019

Kappa Opioid Receptor and Dynorphin Signaling in the Central Amygdala Regulates Alcohol Intake

Excessive alcohol drinking has been shown to modify brain circuitry to predispose individuals for future alcohol abuse. Previous studies have implicated the central nucleus of the amygdala (CeA) as an important site for mediating the somatic symptoms of withdrawal and for regulating alcohol intake. In addition, recent work has established a role for both the Kappa Opioid Receptor (KOR) and its endogenous ligand dynorphin in mediating these processes. However, it is unclear whether these effects are due to dynorphin or KOR arising from within the CeA itself or other input brain regions. To directly examine the role of preprodynorphin (PDYN) and KOR expression in CeA neurons, we performed region-specific conditional knockout of these genes and assessed the effects on the Drinking in the Dark (DID) and Intermittent Access (IA) paradigms. We then examined the effects of DID on PDYN and KOR modulation of CeA circuit physiology. Conditional gene knockout resulted in sex-specific responses wherein PDYN knockout decreased alcohol drinking in both male and female mice, whereas KOR knockout decreased drinking in males only. We also found that neither PDYN nor KOR knockout protected against anxiety caused by alcohol drinking. Lastly, a history of alcohol drinking did not alter synaptic transmission in PDYN neurons in the CeA of either sex, but excitability of PDYN neurons was increased in male mice only. Taken together, our findings indicate that PDYN and KOR signaling in the CeA plays an important role in regulating excessive alcohol consumption and highlight the need for future studies to examine how this is mediated through downstream effector regions.

neuroscience↗

bioRxiv2019

Ethanol-induced conditioned place preference and aversion differentially alter plasticity in the bed nucleus of stria terminalis

Contextual cues associated with drugs of abuse, such as ethanol, can trigger craving and drug seeking behavior. Pavlovian procedures, such as place conditioning, have been widely used to study the rewarding/aversive properties of drugs and the association between environmental cues and drug seeking. Previous research has shown that ethanol as an unconditioned stimulus can induce a strong conditioned place preference (CPP) or aversion (CPA) in rodents. However, the neural mechanisms underlying ethanol induced reward and aversion have not been thoroughly investigated. The bed nucleus of the stria terminalis (BNST), an integral part of the extended amygdala, is engaged by both rewarding and aversive stimuli and plays a role in ethanol seeking behavior. Here, we used ex-vivo slice physiology to probe learning-induced synaptic plasticity in the BNST following ethanol-induced CPP and CPA. Male DBA/2J mice (2-3 months old) were conditioned using previously reported ethanol-induced CPP/CPA procedures. Ethanol-induced CPP was associated with increased neuronal excitability in the ventral BNST (vBNST). Conversely, ethanol-induced CPA resulted in a significant decrease in spontaneous glutamatergic transmission without alterations in GABAergic signaling. Ethanol-CPA also led to significant increase in paired pulse ratio at excitatory synapses, suggestive of a decrease in presynaptic glutamate release. Collectively, these data demonstrate that the vBNST is involved in the modulation of contextual learning associated with both the rewarding and the aversive properties of ethanol in mice.

neuroscience↗

bioRxiv2018

Male and female mice demonstrate divergent cellular responses in the bed nucleus of stria terminalis (BNST) following morphine withdrawal

The United States is experiencing an opioid epidemic of significant proportions, imposing enormous fiscal and societal costs. While prescription opioid analgesics are essential for treating pain, the cessation of these drugs can induce a withdrawal syndrome, and thus opioid use often persists to alleviate or avoid these symptoms. Therefore, it is essential to understand the neurobiology underlying this critical window of withdrawal from opioid analgesics to prevent continued usage. To model this, we administered a low dose of morphine, and precipitated withdrawal with naloxone to investigate the behavioral and cellular responses in C57BL/6J male and female mice. Following 3 days of administration, both male and female mice sensitized to the repeated bouts of withdrawal, as evidenced by their composite global withdrawal score. Female mice exhibited increased withdrawal symptoms on some individual measures, but did not show characteristic weight loss observed in male mice. Because of its role in mediating withdrawal-associated behaviors, we examined neuronal excitability and inhibitory synaptic transmission in the bed nucleus of the stria terminalis (BNST) 24 hours following the final precipitated withdrawal. In male mice, morphine withdrawal increased spontaneous GABAergic signaling compared to controls. In contrast, morphine withdrawal decreased spontaneous GABAergic signaling, and increased BNST projection neuron excitability in female mice. Intriguingly, these opposing GABAergic effects were dependent on within slice excitability. Our findings suggest that male and female mice manifest divergent cellular responses in the BNST following morphine withdrawal, and alterations in BNST inhibitory signaling may be a significant factor contributing to the expression of behaviors following opioid withdrawal.

neuroscience↗

bioRxiv2018

Predator odor increases glutamatergic synaptic transmission in the prelimbic cortex via corticotropin-releasing factor receptor 1 signaling

The authors have withdrawn their manuscript because the University of North Carolina at Chapel Hill conducted a research misconduct proceeding and concluded that research misconduct occurred involving results presented in this preprint. Hence, the results and conclusions of the preprint article are no longer reliable. The published version of this preprint (Neuropsychopharmacology, doi: 10.1038/s41386-018-0279-2) is being retracted as well. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

neuroscience↗

bioRxiv2018

Stress-induced alterations of norepinephrine release in the bed nucleus of the stria terminalis of mice

Stress can drive adaptive changes to maintain survival during threatening stimuli. Chronic stress exposure, however, may result in pathological adaptations. A key neurotransmitter involved in stress signaling is norepinephrine. Previous studies show that stress elevates norepinephrine levels in the bed nucleus of the stria terminalis (BNST), a critical node regulating anxiety and upstream of stress responses. Here, we use mice expressing channelrhodopsin in norepinephrine neurons to selectively activate terminals in the BNST, and measure norepinephrine release with fast-scan cyclic voltammetry. Mice exposed to a single restraint session show an identical norepinephrine release profile compared to that of unexposed mice. Mice experiencing five days of restraint stress, however, show elevated noradrenergic release across multiple stimulation parameters, and reduced sensitivity to the 2-adrenergic receptor antagonist idazoxan. These data are the first to examine norepinephrine release in the BNST to tonic and phasic stimulation frequencies, and confirm that repeated stress alters autoreceptor sensitivity.\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/335653_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (28K):\norg.highwire.dtl.DTLVardef@75ef4aorg.highwire.dtl.DTLVardef@b0fd27org.highwire.dtl.DTLVardef@1bc3afborg.highwire.dtl.DTLVardef@c469f1_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗