Biology subjects

Gulley, J. M.

Publications and source records attributed to Gulley, J. M..

6 recordsLinked to original sources

bioRxiv2025

Ontogeny of catechol-o-methyltransferase expression in the rat prefrontal cortex: effects of methamphetamine exposure

Repeated use of methamphetamine (METH) is known to dysregulate the dopaminergic system and induce long-lasting changes in behavior, which may be influenced by sex and age of exposure. Catechol-o-methyltransferase (COMT) is an enzyme that is involved in the breakdown of catecholamines, and its role in dopamine clearance is thought to be especially important in the prefrontal cortex (PFC) where dopamine transporter (DAT) expression is relatively scarce. The first study in this report utilized a rat model to characterize the ontogeny of COMT protein expression in the PFC and nucleus accumbens (NAc) across adolescence, which is a developmental stage that has been shown to involve significant reorganization of dopaminergic innervation. Drug-naive male and female Sprague-Dawley rats were sacrificed on postnatal day (P) 29, 39, 49 or 69, and expression levels of COMT protein within the PFC and NAc were analyzed via Western blot. We found that COMT expression in the PFC increases across adolescence in a sex-dependent manner but does not significantly change in the NAc during this timeframe. A separate group of rats were injected daily from P40-48 (adolescence) or P70-78 (adulthood) with saline or 3.0 mg/kg METH and sacrificed on P49 or P79. While METH decreased COMT in adult rats of both sexes, METH increased COMT expression in the PFC of rats exposed in adolescence. The results of this work suggest that exposure to METH during adolescence uniquely effects dopamine clearance within the PFC, potentially contributing to differences in neurobiological outcomes from METH use.

neuroscience↗

bioRxiv2023

Timing of methamphetamine exposure during adolescence differentially influences parvalbumin and perineuronal net immunoreactivity in the medial prefrontal cortex of female, but not male, rats

Adolescence involves significant reorganization within the medial prefrontal cortex (mPFC), including modifications to inhibitory neurotransmission mediated through parvalbumin (PV) interneurons and their surrounding perineuronal nets (PNNs). These developmental changes, which result in increased PV neuron activity in adulthood, may be disrupted by drug use resulting in lasting changes in mPFC function and behavior. Methamphetamine (METH), which is a readily available drug used by some adolescents, increases PV neuron activity and could influence the activity-dependent maturational process of these neurons. In the present study, we used male and female Sprague Dawley rats to test the hypothesis that METH exposure influences PV and PNN expression in a sex- and age-specific manner. Rats were injected daily with saline or 3.0 mg/kg METH from early adolescence (EA; 30-38 days old), late adolescence (LA; 40-48 days old), or young adulthood (60-68 days old). One day following exposure, effects of METH on PV cell and PNN expression were assessed using immunofluorescent labeling within the mPFC. METH exposure did not alter male PV neurons or PNNs. Females exposed in early adolescence or adulthood had more PV expressing neurons while those exposed in later adolescence had fewer, suggesting distinct windows of vulnerability to changes induced by METH exposure. In addition, females exposed to METH had more PNNs and more intense PV neuron staining, further suggesting that METH exposure in adolescence uniquely influences development of inhibitory circuits in the female mPFC. This study indicates that the timing of METH exposure, even within adolescence, influences its neural effects in females.

neuroscience↗

bioRxiv2023

Effects of combined exposure to ethanol and delta-9-tetrahydrocannabinol during adolescence on synaptic plasticity in the prefrontal cortex of Long Evans rats

Significant exposure to alcohol or cannabis during adolescence can induce lasting disruptions of neuronal signaling in brain regions that are later to mature, such as the medial prefrontal cortex (mPFC). Considerably less is known about the effects of alcohol and cannabis co-use, despite its common occurrence. Here, we used male and female Long-Evans rats to investigate the effects of early-life exposure to ethanol, delta-9-tetrahydrocannabinol (THC), or their combination on high frequency stimulation (HFS)-induced plasticity in the prelimbic region of the mPFC. Animals were injected daily from postnatal days 30 to 45 with vehicle or THC (escalating doses, 3-20 mg/kg) and allowed to drink vehicle (0.1% saccharin) or 10% ethanol immediately after each injection. In vitro brain slice electrophysiology was then used to record population responses of layer V neurons following HFS in layer II/III after 3-4 weeks of abstinence. We found that THC exposure reduced body weight gains observed in ad libitum fed rats, and reduced intake of saccharin and ethanol. Compared to controls, there was a significant reduction in HFS-induced long-term depression (LTD) in rats exposed to either drug alone, and an absence of LTD in rats exposed to the drug combination. Bath application of indiplon or AR-A014418, which enhance GABAA receptor function or inhibit glycogen synthase kinase 3{beta} (GSK3{beta}), respectively, suggested the effects of ethanol, THC or their combination were due in part to lasting adaptations in GABA and GSK3{beta} signaling. These results suggest the potential for long-lasting adaptations in mPFC output following co-exposure to alcohol and THC.

neuroscience↗

bioRxiv2023

Effects of combined use of alcohol and delta-9-tetrahydrocannibinol on working memory in Long Evans rats

The increase in social acceptance and legalization of cannabis over the last several years is likely to increase the prevalence of its co-use with alcohol. In spite of this, the potential for effects unique to co-use of these drugs, especially in moderate doses, has been studied relatively infrequently. We addressed this in the current study using a laboratory rat model of voluntary drug intake. Periadolescent male and female Long-Evans rats were allowed to orally self-administer ethanol, {Delta}9-tetrahydrocannibinol (THC), both drugs, or their vehicle controls from postnatal day (P) 30 to P47. They were subsequently trained and tested on an instrumental behavior task that assesses attention, working memory and behavioral flexibility. Similar to previous work, consumption of THC reduced both ethanol and saccharin intake in both sexes. Blood samples taken 14h following the final self-administration session revealed that females had higher levels of the THC metabolite THC-COOH. There were modest effects of THC on our delayed matching to position (DMTP) task, with females exhibiting reduced performance compared to their control group or male, drug using counterparts. However, there were no significant effects of co-use of ethanol or THC on DMTP performance, and drug effects were also not apparent in the reversal learning phase of the task when non-matching to position was required as the correct response. These findings are consistent with other published studies in rodent models showing that use of these drugs in low to moderate doses does not significantly impact memory or behavioral flexibility following a protracted abstinence period.

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bioRxiv2020

Effects of the GluN2B antagonist, Ro 25-6981, on extinction consolidation following adolescent- or adult-onset methamphetamine self-administration in male and female rats

Previous work suggests adolescent rats have deficient extinction consolidation relative to adults. Although the mechanisms underlying this age difference are currently unknown, studies in adult rats have implicated GluN2B-containing NMDA receptor function in extinction consolidation of drug-associated memory. Importantly, GluN2B neurotransmission emerges during adolescent development, and drugs of abuse during adolescence may delay the development of extinction consolidation by disrupting the ontogeny of GluN2B function. Here, we trained Sprague-Dawley rats of both sexes to self-administer methamphetamine (METH, 0.1 mg/kg/infusion i.v.) beginning during adolescence [postnatal (P) day 41] or adulthood (P91). Rats were given short access (2 h) to self-administer METH in seven daily sessions followed by fourteen sessions with long access (6 h). Subsequently, rats underwent four daily 30-min extinction sessions with immediate post-session injections of either a GluN2B antagonist (Ro25-6981; 6 mg/kg, i.p.) or a vehicle solution. After four daily 2-h extinction sessions, a priming injection (1 mg/kg METH, i.p.) was given prior to a final 2-h reinstatement session. During LgA, adolescent-onset rats earn more METH than adult-onset rats and display greater drug-loading behavior. Rats reduced their drug-seeking behavior across extinction sessions, with no significant group differences. Rats reinstated drug-seeking following the METH priming injection, with females displaying greater reinstatement than males. These results do not support our a priori hypothesis that adolescent-onset METH use disrupts the ontogeny of GluN2B transmission and contributes to age-of-onset differences in extinction of METH-seeking. However, our findings suggest that age-of-onset contributes to excessive METH-taking, while sex confers vulnerability to relapse to METH-seeking.

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bioRxiv2019

Extended access self-administration of methamphetamine is associated with age- and sex-dependent differences in drug taking behavior and recognition memory deficits in rats

Individuals who begin drug use during early adolescence experience more adverse consequences compared to those initiating later, especially if they are female. The mechanisms for these age and gender differences remain obscure, but studies in rodents suggest that psychostimulants may disrupt the normal ontogeny of dopamine and glutamate systems in the prefrontal cortex (PFC). Here, we studied Sprague-Dawley rats of both sexes who began methamphetamine (METH, i.v.) self-administration (SA) in adolescence (postnatal [P] day 41) or adulthood (P91). Rats received seven daily 2-h SA sessions with METH or saccharin as the reinforcer, followed by 14 daily long access (LgA; 6 h) sessions. After 7 and 14 days of abstinence, novel object (OR) or object-in-place (OiP) recognition was assessed. PFC and nucleus accumbens were collected 7 days after the final cognitive test and NMDA receptor subunits and dopamine D1 receptor expression was measured. We found that during LgA sessions, adolescent-onset rats escalated METH intake more rapidly than adult-onset rats, with adolescent-onset females earning the most infusions. Adolescent-onset rats exhibited modest deficits in OiP compared to adult-onset rats, but there was no sex difference in this effect and no groups differed in OR. We found no group differences in D1 and NMDA receptor expression, suggesting no long-lasting alteration of ontogenetic expression profiles. Our findings suggest that adolescent-onset drug use is more likely to lead to compulsive-like patterns of drug-taking and subsequent dysfunction of PFC-dependent cognition.

neuroscience↗