• Early-life ketamine exposure attenuates the preference for ethanol in adolescent Sprague-Dawley rats

      Franco, Daniela; Zamudio, Jennifer; Blevins, Kennedy M; Núñez-Larios, Eric A; Ricoy, Ulises M; Iñiguez, Sergio D; Zavala, Arturo R; Univ Arizona, Dept Neurosci (ELSEVIER, 2020-07-01)
      Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces quick and effective antidepressant results in depressed juvenile and adult individuals. The long-term consequences of using ketamine in juvenile populations are not well known, particularly as it affects vulnerability to drugs of abuse later in life, given that ketamine is also a drug of abuse. Thus, the current study examined whether early-life ketamine administration produces long-term changes in the sensitivity to the rewarding effects of ethanol, as measured using the conditioned place preference (CPP) paradigm. On postnatal day (PD) 21, juvenile male and female rats were pretreated with ketamine (0.0 or 20 mg/kg) for 10 consecutive days (i.e., PD 21-30) and then evaluated for ethanol-induced CPP (0.0, 0.125, 0.5, or 2.0 g/kg) from PD 32 - 39. Results revealed that early-life ketamine administration attenuated the rewarding properties of ethanol in male rats, as ketamine pretreated rats failed to exhibit ethanol-induced CPP at any dose compared to saline pretreated rats, which showed an increased preference towards the ethanol-paired compartment in a dose-dependent manner. In females, ethanol-induced CPP was generally less robust compared to males, but ketamine pretreatment resulted in a rightward shift in the dose-response curve, given that ketamine pretreated rats needed a higher dose of ethanol compared to saline pretreated rats to exhibit ethanol-induced CPP. When considered together, the findings suggest that early use of ketamine does not appear to enhance the vulnerability to ethanol later in life, but in contrast, it may attenuate the rewarding effects of ethanol.
    • Social context-dependent singing alters molecular markers of dopaminergic and glutamatergic signaling in finch basal ganglia Area X

      So, Lisa Y; Munger, Stephanie J; Miller, Julie E; Univ Arizona, Program Neurosci; Univ Arizona, Dept Neurosci; Univ Arizona, Dept Speech Language & Hearing Sci (ELSEVIER SCIENCE BV, 2019-03-15)
      Dopamine (DA) is an important neuromodulator of motor control across species. In zebra finches, DA levels vary in song nucleus Area X depending upon social context. DA levels are high and song output is less variable when a male finch sings to a female (female directed, FD) compared to when he is singing by himself (undirected, UD). DA modulates glutamatergic input onto cortico-striatal synapses in Area X via N-methyl-d-aspartate (NMDA) and DA receptor mechanisms, but the relationship to UD vs. FD song output is unclear. Here, we investigate the expression of molecular markers of dopaminergic and glutamatergic synaptic transmission (tyrosine hydroxylase - TH, alpha-synuclein - α-syn) and plasticity (NMDA 2B receptor - GRIN2B) following singing (UD vs. FD) and non-singing states to understand the molecular mechanisms driving differences in song output. We identified relationships between protein levels for these biomarkers in Area X based on singing state and the amount of song, measured as the number of motifs and time spent singing. UD song amount drove increases in TH, α-syn, and NMDA 2B receptor protein levels. By contrast, the amount of FD song did not alter TH and NMDA 2B receptor expression. Levels of α-syn showed differential expression patterns based on UD vs. FD song, consistent with its role in modulating synaptic transmission. We propose a molecular pathway model to explain how social context and amount of song are important drivers of molecular changes required for synaptic transmission and plasticity.
    • Social context-dependent singing alters molecular markers of synaptic plasticity signaling in finch basal ganglia Area X

      So, Lisa Y.; Miller, Julie E.; Univ Arizona, Dept Neurosci; Univ Arizona, Dept Speech Language & Hearing Sci (Elsevier BV, 2021-02)
      Vocal communication is a crucial skill required throughout life. However, there is a critical gap in our understanding of the underlying molecular brain mechanisms, thereby motivating our use of the zebra finch songbird model. Adult male zebra finches show differences in neural activity patterns in song-dedicated brain nuclei when they sing in two distinct social contexts: a male singing by himself (undirected, UD) and a male singing to a female (female-directed, FD). In our prior work, we showed that in song-dedicated basal ganglia Area X, protein levels of a N-methyl-D-aspartate receptor subtype 2B (NMDAR2B) increased with more UD song and decreased with more FD song. We hypothesized that molecules downstream of this receptor would show differential protein expression levels in Area X between UD and FD song. Specifically, we investigated calcium/calmodulin dependent protein kinase II beta (CaMKIIB), homer scaffold protein 1 (HOMER1), serine/threonine protein kinase (Akt), and mechanistic target of rapamycin kinase (mTOR) following singing and non-singing states in Area X. We show relationships between social context and protein levels. HOMER1 protein levels decreased with time spent singing FD song, and mTOR protein levels decreased with the amount of and time spent singing FD song. For both HOMER1 and mTOR, there were no differences with the amount of UD song. With time spent singing UD, CaMKIIB protein levels trended in a U-shaped curve whereas Akt protein levels trended down. Both molecules showed no change with FD song. Our results support differential involvement of molecules in synaptic plasticity pathways between UD and FD song behaviors.
    • Use of home cage wheel running to assess the behavioural effects of administering a mu/delta opioid receptor heterodimer antagonist for spontaneous morphine withdrawal in the rat

      Morgan, Michael M; Peecher, Danielle L; Streicher, John M; Univ Arizona, Coll Med, Dept Pharmacol (ELSEVIER, 2020-10-06)
      Opioid abuse is a major health problem. The objective of the present study was to evaluate the potentially disruptive side effects and therapeutic potential of a novel antagonist (D24M) of the mu-/delta-opioid receptor (MOR/DOR) heterodimer in male rats. Administration of high doses of D24M (1 & 10 nmol) into the lateral ventricle did not disrupt home cage wheel running. Repeated twice daily administration of increasing doses of morphine (5-20 mg/kg) over 5 days depressed wheel running and induced antinociceptive tolerance measured with the hot plate test. Administration of D24M had no effect on morphine tolerance, but tended to prolong morphine antinociception in non-tolerant rats. Spontaneous morphine withdrawal was evident as a decrease in body weight, a reduction in wheel running and an increase in sleep during the normally active dark phase of the circadian cycle, and an increase in wheel running and wakefulness in the normally inactive light phase. Administration of D24M during the dark phase on the third day of withdrawal had no effect on wheel running. These data provide additional evidence for the clinical relevance of home cage wheel running as a method to assess spontaneous opioid withdrawal in rats. These data also demonstrate that blocking the MOR/DOR heterodimer does not produce disruptive side effects or block the antinociceptive effects of morphine. Although administration of D24M had no effect on morphine withdrawal, additional studies are needed to evaluate withdrawal to continuous morphine administration and other opioids in rats with persistent pain.