Biology subjects

Varga, A. G.

Publications and source records attributed to Varga, A. G..

4 recordsLinked to original sources

bioRxiv2026

Disruption of opioid and mesolimbic dopamine dynamics and behavior upon intranasal delivery of opioids in mice

The endogenous opioid system, consisting of mu, delta, and kappa opioid receptors, along with naturally occurring peptides, is central for regulating reward processing, mood, motivation, and social attachment. Endogenous opioids, as well as opioid drugs that are administered clinically or are misused/abused, are potent modulators of several neurotransmitter systems in the brain, including dopamine (DA). Since the opioid system is dysregulated in neuropsychiatric conditions, and opioids are prevalently misused/abused to achieve altered affective and cognitive states, the understanding of the mechanisms of action of opioids is highly significant. Unfortunately, there is no pre-clinical approach for understanding the actions of intranasally (IN) administered opioids, a common route of administration by both individuals with opioid use disorder and a route used clinically to achieve reversal of opioid overdose. Here we combined reliable and precise delivery of opioids into the nasal cavity of mice together with measures of opioid and DA dynamics in the nucleus accumbens (NAc) with fiber photometry, or, with measures of behaviors known impacted by opioids following other routes of administration, including respiration, to demonstrate the outcomes of IN opioids in mice. We uncovered a prompt and prolonged increase in mesolimbic DA by both IN morphine and fentanyl and the restoration of DA to baseline levels by subsequent IN opioid receptor antagonism with naloxone. Simultaneously, IN morphine and fentanyl each resulted in a short-lasting increase in NAc opioid dynamics. Next, in separate mice, we found that IN opioids elicit rapid canonical opioid-induced behaviors, including respiratory depression, which were rapidly reversed by IN naloxone. Overall, this work establishes a sensitive approach for evaluating the neural circuitry underlying opioid use disorder in a manner which recapitulates IN opioid use with ecological validity. Moreover, our findings point towards a likely important role for mesolimbic DA in mediating opioid overdose reversal.

neuroscience↗

bioRxiv2026

Glutamate co-release from catecholaminergic neurons shapes breathing and is inhibited during opioid-induced respiratory depression

Breathing is controlled by a distributed brainstem network that includes multiple catecholaminergic nuclei. The locus coeruleus (LC), the brains primary source of noradrenaline (NA), projects to several respiratory centers, including the Kolliker-Fuse (KF) nucleus in the pons. While LC neurons are predominantly noradrenergic (NAergic), many co-release glutamate, which may contribute to the state-dependent modulation of breathing, particularly during opioid exposure. Here, we examined how opioids affect NAergic and glutamatergic signaling in the LC-KF circuit using optogenetics and whole-cell patch clamp recordings in mouse brain slices. Optogenetic activation of LC terminals evoked glutamatergic excitatory postsynaptic currents (EPSCs) in KF neurons that were presynaptically inhibited by the opioid receptor agonist Met-enkephalin. Additionally, [~]36% of glutamate-responsive KF neurons exhibited postsynaptic opioid inhibition via GIRK currents, while KF neurons receiving excitatory NAergic input showed minimal opioid sensitivity. To assess the behavioral role of glutamate release from all catecholaminergic neurons, we compared breathing in awake VGluT2fl/fl::TH-Cre mice (lacking VGluT2 in tyrosine hydroxylase-positive neurons) to control littermates and TH-Cre hemizygous mice using whole-body plethysmography. The conditional VGluT2 knockout mice exhibited prolonged inspiratory duration, increased tidal volume, and reduced respiratory rate during baseline breathing, with state-dependent differences emerging during hypercapnia. Systemic morphine administration diminished these genotype differences, and machine learning analysis using dynamic time warping confirmed that genotype-specific breathing patterns were distinguishable at baseline, but not after morphine. These findings demonstrate that glutamate co-release from catecholaminergic neurons modulates respiratory patterning in a state-dependent manner and is selectively vulnerable to opioid inhibition.

neuroscience↗

bioRxiv2025

Opposing control of the respiratory brainstem on multiple timescales achieved by transmitter co-release from the locus coeruleus

The locus coeruleus (LC) provides widespread noradrenergic (NAergic) modulation throughout the brain to influence a wide range of functions, including breathing. Although both anatomical and physiological evidence supports the involvement of the LC in both the upstream integration and the downstream modulation of breathing, the circuitry behind the latter is unknown. Here, we show that NAergic LC neurons send projections to the K[o]lliker-Fuse nucleus (KF), a critical site in the control of breathing. Long duration activation of NAergic LC neuron terminals in pontine slices induces persistent inhibitory and excitatory NA currents or increases firing rate in postsynaptic KF neurons. Short stimulation on the other hand leads to the VGluT2-dependent release of glutamate that may be co-released with NA in a monosynaptic circuit. Together these results demonstrate that LC neurons can exert flexible, opposing effects on different timescales via glutamatergic and NAergic signaling onto a key respiratory brainstem nucleus.

neuroscience↗

bioRxiv2024

Sniffing is initiated by the actions of dopamine on ventral striatum neurons

Sniffing is a motivated behavior displayed by nearly all terrestrial vertebrates. While sniffing is associated with acquiring and processing odors, sniffing is also intertwined with affective and motivated states. The neuromodulatory systems which influence the display of sniffing are unclear. Here, we report that dopamine release into the ventral striatum is coupled with bouts of sniffing and that stimulation of dopaminergic terminals in these regions drives increases in respiratory rate to initiate sniffing whereas inhibition of these terminals reduces respiratory rate. Both the firing of individual neurons and the activity of post-synaptic D1 and D2 receptor-expressing neurons in the ventral striatum are also coupled with sniffing and local antagonism of D1 and D2 receptors squelches sniffing. Together, these results support a model whereby sniffing can be initiated by dopamines actions upon ventral striatum neurons. The nature of sniffing being integral to both olfaction and motivated behaviors implicates this circuit in a wide array of functions.

neuroscience↗