Rate of onset of dopamine transporter inhibitors assessed with intracranial self-stimulation and in vivo dopamine photometry in rats

Baird, Tyson R; Karin, Kimberly N.; Marsh, Samuel; Carroll, F. Ivy; Medina-Contreras, J M L; Negus, S. Stevens; Eltit, José M.

doi:10.1007/s00213-023-06340-8

Cited by 2 publications

(3 citation statements)

References 51 publications

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“…Our result is similar to the prior finding that both α-PBT and α-PVP facilitate ICSS responses. , In general, a reduced ICSS threshold is considered to indicate greater brain reward and reinforcing properties of addictive drugs, which are key for addiction in humans . The involvement of DA in BSR is well documented. , For instance, drugs that reduce DA release or block the activation of DA receptors produce effects indicative of a higher brain reward threshold, i.e., attenuated BSR function . Additionally, ICSS itself elevates DA release in the NAc, as is the case with addictive drugs that increase DA neurotransmission. , In contrast, DA antagonists attenuate ICSS responses, along with other drugs that decrease DA levels .…”

Section: Discussionsupporting

confidence: 89%

“…26 The involvement of DA in BSR is well documented. 26,45 For instance, drugs that reduce DA release or block the activation of DA receptors produce effects indicative of a higher brain reward threshold, i.e., attenuated BSR function. 46 Additionally, ICSS itself elevates DA release in the NAc, as is the case with addictive drugs that increase DA neurotransmission.…”

Section: Discussionmentioning

confidence: 99%

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Effects of the Synthetic Cathinone α-Pyrrolidinobutiothiophenone (α-PBT) on Discriminative Stimulus Effects and Intracranial Self-Stimulation Thresholds in Male Rats

Jang,

Lee,

Yun

et al. 2024

ACS Chem. Neurosci.

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Recently, the abuse of synthetic cathinones is increasing among young people. α-Pyrrolidinobutiothiophenone (α-PBT), a synthetic cathinone, is a designer drug that is freely traded online with no legal restrictions. Moreover, there is currently no scientific basis for legal regulation. Here, we examined the addictive properties of α-PBT using a drug discrimination (DD) task. We also investigated the role of α-PBT in brain stimulation reward (BSR) using an intracranial self-stimulation (ICSS) paradigm in rats. Initially, the rats were trained to discriminate between cocaine and saline. After the discrimination training criteria were met, we determined the dose–effect curves of cocaine and conducted generalization tests with α-PBT and α-pyrrolidinopentiothiophenone (α-PVT) using a cumulative dosing protocol. In a separate set of studies, we examined the dopaminergic mechanisms underlying the function of α-PBT as an interoceptive stimulus (17.8 mg/kg) by intraperitoneally injecting either the dopamine (DA) D1 antagonist SCH23390 (0.06 and 0.12 mg/kg) or the D2 antagonist eticlopride (0.05 and 0.1 mg/kg) 15 min before DD testing. Brain reward function was measured using an ICSS procedure to examine the effects of α-PBT on ICSS threshold under the frequency-rate procedure. Our results showed that α-PBT functioned as a discriminative cue similar to cocaine in rats. More importantly, SCH23390 abolished the effects of α-PBT as an interoceptive stimulus in a dose-dependent manner in rats trained to press a lever to receive cocaine. Similarly, eticlopride dose-dependently attenuated the effect of α-PBT used as a discriminative cue. Additionally, cumulative α-PBT administration dose-dependently lowered ICSS thresholds compared with those in saline-treated rats. Furthermore, α-PBT-induced potentiation of BSR was abolished by pretreatment with both SCH23390 and eticlopride. Taken together, our results suggest that α-PBT can function as a cocaine-like discriminative cue via the activation of D1 and D2 receptors. α-PBT also appears to influence BSR by reducing the brain reward threshold via changes in D1 and D2 receptors. The present study suggests that α-PBT could have addictive properties through DA D1 and D2 receptors and thus poses a threat to humans.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Effects of the Synthetic Cathinone α-Pyrrolidinobutiothiophenone (α-PBT) on Discriminative Stimulus Effects and Intracranial Self-Stimulation Thresholds in Male Rats

Jang,

Lee,

Yun

et al. 2024

ACS Chem. Neurosci.

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“…Decades of work with established techniques (microdialysis, voltammetry, electrophysiology) have elucidated the kinetics of electrically-and cue-evoked DA signaling and firing patterns of DA neurons in vivo in response to acute, experimenteradministered or repeated self-administration of alcohol and other drugs of abuse [26][27][28][29][30]. Investigators recently have built on this work by assessing DA responses using dLight during alcohol self-administration [31], and in response to stimulants [32][33][34][35] and opioids [33,36,37]. While FSCV studies in slices [38,39] and in vivo [30,40] have noted the presence of spontaneous DA signals, it has never been possible to assess these events in awake and behaving animals on such a rapid time scale as with dLight.…”

Section: Introductionmentioning

confidence: 99%

Kappa Opioid Receptors Negatively Regulate Real Time Spontaneous Dopamine Signals by Reducing Release and Increasing Uptake

Wallace,

Holleran,

Slinkard

et al. 2024

Preprint

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The role of the dynorphin/kappa opioid receptor (KOR) system in dopamine (DA) regulation has been extensively investigated. KOR activation reduces extracellular DA concentrations and increases DA transporter (DAT) activity and trafficking to the membrane. To explore KOR influences on real-time DA fluctuations, we used the photosensor dLight1.2 with fiber photometry in the nucleus accumbens (NAc) core of freely moving male and female C57BL/6 mice. First, we established that the rise and fall of spontaneous DA signals were due to DA release and reuptake, respectively. Then mice were systemically administered the KOR agonist U50,488H (U50), with or without pretreatment with the KOR antagonist aticaprant (ATIC). U50 reduced both the amplitude and width of spontaneous signals in males, but only reduced width in females. Further, the slope of the correlation between amplitude and width was increased in both sexes, suggesting that DA uptake rates were increased. U50 also reduced the frequency of signals in both males and females. All effects of KOR activation were stronger in males. Overall, KORs exerted significant inhibitory control over spontaneous DA signaling, acting through at least three mechanisms - inhibiting DA release, promoting DAT-mediated uptake, and reducing the frequency of signals.

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Rate of onset of dopamine transporter inhibitors assessed with intracranial self-stimulation and in vivo dopamine photometry in rats

Cited by 2 publications

References 51 publications

Effects of the Synthetic Cathinone α-Pyrrolidinobutiothiophenone (α-PBT) on Discriminative Stimulus Effects and Intracranial Self-Stimulation Thresholds in Male Rats

Effects of the Synthetic Cathinone α-Pyrrolidinobutiothiophenone (α-PBT) on Discriminative Stimulus Effects and Intracranial Self-Stimulation Thresholds in Male Rats

Kappa Opioid Receptors Negatively Regulate Real Time Spontaneous Dopamine Signals by Reducing Release and Increasing Uptake

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