Biology subjects

Knackstedt, L. A.

Publications and source records attributed to Knackstedt, L. A..

5 recordsLinked to original sources

bioRxiv2026

Oxytocin modulates behavioral economic and dopaminergic measures of motivation to seek intravenous oxycodone in rats

The opioid epidemic persists despite available pharmacotherapies for opioid use disorder (OUD), motivating interest in treatments targeting the motivational and neurochemical substrates of opioid seeking. Peripherally administered oxytocin (OT) attenuates drug seeking and consumption across substances and modulates the mesolimbic dopamine system, yet its effects on opioid seeking and its underlying neurobiology remain poorly characterized. Here we investigated the effects of OT on behavioral and dopaminergic measures of opioid reinforcement using in vivo fiber photometry with the dopamine sensor, GRABDA2m, in the nucleus accumbens (NA) core of male and female rats. Daily OT (15 IU/kg, IP) administered 30 min prior to operant sessions increased demand elasticity for intravenous oxycodone self-administration in males but not females. Acute OT (15 and 45 IU/kg, IP) increased GRABDA2m dopamine signal in the NA core in females, and potentiated oxycodone-evoked dopamine release in both sexes. In a high-effort task, NA core dopamine increased prior to lever presses, and acute OT (15 IU/kg, IP) produced sex-divergent effects on phasic NA core dopamine release during lever pressing, increasing peak signal and area under the curve measures in males. Support vector machine classifiers determined that features of dopamine transients (e.g., mean peak, standard deviation of the amplitude, peak-valley range) before an active lever press distinguished between treatment and sex. Thus, the ability of chronic oxytocin to reduce the motivation to self-administer oxycodone in male rats is independent of oxycodone-induced NA dopamine release but rather may involve dopamine transmission during lever pressing under high effort conditions.

neuroscience↗

bioRxiv2023

Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking

Opioid-alcohol polysubstance use is prevalent and worsens treatment outcomes. Here we assessed whether co-consumption of oxycodone and alcohol would influence intake of one another, demand for oxycodone, and the neurocircuitry underlying cue-primed reinstatement of oxycodone-seeking. Male and female rats underwent oxycodone intravenous self-administration (IVSA) with access to either alcohol (20% v/v) and water or only water immediately after the IVSA session. Next, economic demand for intravenous oxycodone was assessed while access to alcohol and/or water continued. Control rats self-administered sucrose followed by access to alcohol and/or water. Rats underwent extinction training and brains were processed for c-fos mRNA expression immediately following a cue-primed reinstatement test. While both sexes decreased oxycodone intake if they had access to alcohol, and decreased alcohol intake if they had access to oxycodone, female oxycodone+alcohol rats exhibited decreased demand elasticity for intravenous oxycodone and increased cue-primed reinstatement while male rats did not. Spontaneous withdrawal signs were correlated with oxycodone intake while alcohol intake was correlated with anxiety-like behavior. Alcohol consumption increased the number of basolateral and central amygdala neurons activated during sucrose and oxycodone reinstatement and the number of ventral and dorsal striatum neurons engaged by sucrose reinstatement. Nucleus accumbens shell dopamine 1 receptor containing neurons displayed activation patterns consistent with oxycodone reinstatement. Thus, alcohol alters the motivation to seek oxycodone in a sex-dependent manner and alters the neural circuitry engaged by cue-primed reinstatement of sucrose and oxycodone-seeking.

neuroscience↗

bioRxiv2022

Resilience to anxiety and anhedonia after predator scent stress is accompanied by increased nucleus accumbens mGlu5 in female rats

Despite the higher prevalence of post-traumatic stress disorder (PTSD) in women, the majority of preclinical neuroscience research has been conducted utilizing male subjects. We have found that male rats exposed to the predator scent 2,4,5-trimethyl-3-thiazoline (TMT) show heterogenous development of long-term anxiety-like behavior and conditioned fear to the TMT environment. Stress-Resilient males exhibit increased mGlu5 mRNA expression in the basolateral amygdala (BLA) and prefrontal cortex. Here we sought to determine whether the same behavioral and genetic responses would be observed in female rats exposed to TMT. Sprague-Dawley rats were exposed to TMT for ten minutes, while Controls were exposed to an unscented environment. Anxiety and anhedonia were assessed 7-14 days later with elevated plus maze (EPM), acoustic startle response (ASR), light/dark box, and sucrose preference test. TMT-exposed females spent less time in the EPM open arms and exhibited greater startle amplitude, and reduced sucrose intake compared to Controls. Median split analyses conducted on EPM and sucrose intake yielded phenotypes that displayed behavior in the light/dark box consistent with EPM and sucrose testing. Unlike male Susceptible rats, female Susceptible rats showed no freezing when re-exposed to the TMT context, nor did Resilient female rats present elevated BLA mGlu5 mRNA levels. Instead, Susceptible females had greater BLA mGlu5 than Resilient or Control rats. This work indicates that, as in humans, rats exhibit sex-dependent responses to stress. This translational animal model may provide insight into how females are uniquely affected by PTSD.

neuroscience↗

bioRxiv2020

Ceftriaxone and mGlu2/3 interactions in the nucleus accumbens core affect the reinstatement of cocaine-seeking in male and female rats

RationaleThe beta-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine-seeking. While the restoration of nucleus accumbens core (NA core) GLT-1 expression is necessary for ceftriaxone to attenuate reinstatement, AAV-mediated GLT-1 overexpression is not sufficient to attenuate reinstatement and does not prevent glutamate efflux during reinstatement. AimsHere, we test the hypothesis that ceftriaxone attenuates reinstatement through interactions with glutamate autoreceptors mGlu2 and mGlu3 in the NA core. MethodsMale and female rats self-administered cocaine for 12 days followed by 2-3 weeks of extinction training. During the last 6-10 days of extinction, rats received ceftriaxone (200 mg/kg IP) or vehicle. In experiment 1, rats were killed, and NA core tissue was biotinylated for assessment of total and surface expression of mGlu2 and mGlu3 via western blotting. In experiment 2, we tested the hypothesis that mGlu2/3 signaling is necessary for ceftriaxone to attenuate cue- and cocaine-primed reinstatement by administering bilateral intra-NA core infusion of mGlu2/3 antagonist LY341495 or vehicle immediately prior to reinstatement testing. ResultsmGlu2 expression was reduced by cocaine and restored by ceftriaxone. There were no effects of cocaine or ceftriaxone on mGlu3 expression. We observed no effects of estrus on expression of either protein. The antagonism of mGlu2/3 in the NA core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement. ConclusionsThese results indicate that ceftriaxones effects depend on mGlu2/3 function and possibly mGlu2 receptor expression. Future work will test this hypothesis by manipulating mGlu2 expression in pathways that project to the NA core.

neuroscience↗

bioRxiv2020

Role of prefrontal cortex projections to the nucleus accumbens core in mediating the effects of ceftriaxone on cued cocaine relapse

Ceftriaxone is an antibiotic that reliably attenuates the reinstatement of cocaine-seeking after extinction while preventing the nucleus accumbens (NA) core glutamate efflux that drives reinstatement. However, when rats undergo abstinence without extinction, ceftriaxone attenuates context-primed relapse but NA core glutamate efflux still increases. Here we sought to determine if the same would occur when relapse is prompted by both context and discrete cues (context+cues) after cocaine abstinence. Male rats self-administered intravenous cocaine for 2 hr/day for 2 weeks. Cocaine delivery was accompanied by drug-associated cues (light+tone). Rats were then placed into abstinence with daily handling but no extinction training for two weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a context+cue relapse test, microdialysis procedures were conducted. Rats were perfused at the end of the test for later Fos analysis. A separate cohort of rats was infused with the retrograde tracer cholera toxin B in the NA core and underwent the same self-administration and relapse procedures. Ceftriaxone increased baseline glutamate and attenuated both context+cue-primed relapse and NA core glutamate efflux during this test. Ceftriaxone reduced Fos expression in regions sending projections to the NA core (prefrontal cortex, basolateral amygdala, ventral tegmental area) and specifically reduced Fos in prelimbic cortex and not infralimbic cortex neurons projecting to the NA core. Thus, when relapse is primed by drug-associated cues and context, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core-projecting neurons.

neuroscience↗