Biology subjects

Freels, T. G.

Publications and source records attributed to Freels, T. G..

6 recordsLinked to original sources

bioRxiv2023

Sex differences in adolescent cannabis vapor self-administration mediate enduring effects on behavioral flexibility and prefrontal microglia activation in rats

Cannabis is the most used illicit drug in the United States. With many states passing legislation to permit its recreational use, there is concern that cannabis use among adolescents could increase dramatically in the coming years. Historically, it has been difficult to model real-world cannabis use to investigate the causal relationship between cannabis use in adolescence and behavioral and neurobiological effects in adulthood. To this end, we used a novel volitional vapor administration model to investigate long-term effects of cannabis use during adolescence on the medial prefrontal cortex (mPFC) and mPFC-dependent behaviors in male and female rats. Adolescent (35-55 day old) female rats had significantly higher rates of responding for vaporized {Delta}9-tetrahydrocannabinol (THC)-dominant cannabis extract (CANTHC) compared to adolescent males. In adulthood (70-110 day old), female, but not male, CANTHC rats also took more trials to reach criterion and made more regressive errors in an automated attentional set-shifting task compared to vehicle rats. Similar set-shifting deficits were observed in males when they were exposed to a non-contingent CANTHC vapor dosing regimen that approximated CANTHC self-administration rates in females. No differences were observed in effort-based decision making in either sex. In the mPFC, female (but not male) CANTHC rats displayed more reactive microglia with no significant changes in myelin basic protein expression or dendritic spine density. Together, these data reveal important sex differences in rates of cannabis vapor self-administration in adolescence that confer enduring alterations to mPFC structure and function. Importantly, female-specific deficits in behavioral flexibility appear to be driven by elevated rates of CANTHC self-administration as opposed to a sex difference in the effects of CANTHC vapor per se.

neuroscience↗

bioRxiv2020

Chronic Effects of Indirect and Direct Cannabinoid Receptor Agonists on Addiction-Related Behaviors and Dopamine Release

The cannabinoid system is being researched as a potential pharmaceutical target for a multitude of disorders. The present study examined the effect of indirect and direct cannabinoid agonists on mesolimbic dopamine release and related behaviors in C57BL/6J (B6) mice. The indirect cannabinoid agonist N-arachidonoyl serotonin (AA-5-HT) indirectly agonizes the cannabinoid system by preventing the metabolism of endocannabinoids through fatty acid amide hydrolase (FAAH) inhibition while also inhibiting transient receptor potential vanilloid type 1 (TRPV1) channels. Effects of AA-5-HT were compared with the direct cannabinoid receptor type 1 (CB1R) agonist arachidonoyl-2-chloroethylamide (ACEA). In Experiment 1, mice were pretreated with 7 daily injections of AA-5-HT, ACEA, or vehicle prior to assessments of locomotor activity using open field (OF) testing and phasic dopamine release using in vivo fixed potential amperometry. Chronic exposure to AA-5-HT did not alter locomotor activity or mesolimbic dopamine functioning. Chronic exposure to ACEA did not alter locomotor activity but did decrease phasic dopamine release while increasing the dopaminergic response to cocaine. In Experiment 2, mice underwent AA-5-HT, ACEA, or vehicle conditioned place preference (CPP) then saccharin preference testing, a measure commonly associated with anhedonia. Mice did not develop a CPP or aversion for AA-5-HT or ACEA, and repeated exposure to AA-5-HT or ACEA did not alter saccharin preference. Altogether, the findings suggest that neither of these drugs induce behaviors that are classically associated with abuse liability in mice; however, direct CB1R agonism may play more of a role in mediating mesolimbic dopamine functioning than indirect cannabinoid agonism.

neuroscience↗

bioRxiv2020

Impact of Cannabinoid Type 1 Receptor Modulation on Risky Decision-Making

Recent changes in policy regarding cannabis in the U.S. have been accompanied by an increase in the prevalence of cannabis use and a reduction in the perceived harms associated with consumption. However, little is understood regarding the effects of cannabinoids on cognitive processes. Given that deficient risk-taking is commonly observed in individuals suffering from substance use disorders (SUDs), we assessed the impact of manipulating cannabinoid type 1 receptors (CB1Rs; the primary target for {Delta}9-tetrahydrocannabinol in the brain) on punishment-based risk-taking using the risky decision-making task (RDT) in male Long-Evans rats. The RDT measures preference for small, safe rewards over large, risky rewards associated with an escalating chance of foot shock. Systemic bidirectional CB1R manipulation with a CB1R agonist, CB1R antagonist, and FAAH inhibitor (which increases overall endocannabinoid tone) did not alter overt risk-taking in the RDT. Interestingly, direct CB1R agonism, but not indirect CB1R stimulation or CB1R blockade, resulted in reduction in latency to make risky choices while not altering safe choice latency. Our findings suggest that CB1R activation expedites engagement in punishment based risk-taking without affecting overall preference for risky vs. safe options. This indicates that risk preference and rate of deliberation for risk-taking are influenced by distinct neural substrates, an important consideration for development of precise treatments targeting the aberrant risk-taking typical of SUD symptomology.

animal behavior and cognition↗

bioRxiv2020

Maternal cannabis vapor exposure causes long-term alterations in emotional reactivity, social behavior, and behavioral flexibility in offspring.

The use of cannabis during pregnancy is a growing public health concern. As more states implement legislation permitting recreational cannabis use, there is an urgent need to better understand its impact on fetal neurodevelopment and its long-term effects in exposed offspring. Studies examining effects of prenatal cannabis exposure typically employ injections of synthetic cannabinoids or isolated cannabis constituents that may not accurately model cannabis use in human populations. To address this limitation, we have developed a novel e-cigarette technology-based system to deliver vaporized cannabis extracts to pregnant Long Evans rats. We used this model to determine effects of prenatal cannabis exposure on emotional, social, and cognitive endpoints of male and female offspring during early development and into adulthood. Dams were exposed to cannabis vapor (CANTHC: 400 mg/ml), vehicle vapor (VEH), or no vapor (AIR) twice daily during mating and gestation. Offspring exposed to CANTHC and VEH showed reduced weight gain relative to AIR offspring prior to weaning. CANTHC offspring made more isolation-induced ultrasonic vocalizations (USVs) on postnatal day 6 (P6) relative to VEH-exposed offspring, which is indicative of increased emotional reactivity. Male CANTHC offspring engaged in fewer social investigation behaviors than VEH-exposed male offspring during a social play test on P26. In adulthood, CANTHC-exposed offspring spent less time exploring the open arms of the elevated plus maze and exhibited dose-dependent deficits in behavioral flexibility in an attentional set-shifting task relative to AIR controls. These data collectively indicate that prenatal cannabis exposure causes enduring effects on the behavioral profile of offspring.

neuroscience↗

bioRxiv2019

Vaporized cannabis extracts have reinforcing properties and support conditioned drug-seeking behavior in rats

Recent trends in cannabis legalization have increased the necessity to better understand the effects of cannabis use. Animal models involving traditional cannabinoid self-administration approaches have been notoriously difficult to establish and differences in the drug employed and its route of administration have limited the translational value of preclinical studies. To address this challenge in the field, we have developed a novel method of cannabis self-administration using response-contingent delivery of vaporized {Delta}9-tetrahydrocannabinol-rich (CANTHC) or cannabidiol-rich (CANCBD) complete cannabis extracts. Male Sprague Dawley rats were trained to nosepoke for discrete puffs of CANTHC, CANCBD, or vehicle (VEH) in daily one-hour sessions. Cannabis vapor reinforcement resulted in strong discrimination between active and inactive operanda. CANTHC maintained higher response rates under fixed ratio schedules and higher break points under progressive ratio schedules compared to CANCBD or VEH, and the number of vapor deliveries positively correlated with plasma THC concentrations. Moreover, metabolic phenotyping studies revealed alterations in locomotor activity, energy expenditure, and daily food intake that are consistent with effects in human cannabis users. Furthermore, both cannabis regimens produced ecologically relevant brain concentrations of THC and CBD and CANTHC administration decreased hippocampal CB1 receptor binding. Removal of CANTHC reinforcement (but not CANCBD) resulted in a robust extinction burst and an increase in cue-induced cannabis-seeking behavior relative to VEH. These data indicate that volitional exposure to THC-rich cannabis vapor has bona fide reinforcing properties and collectively support the utility of the vapor self-administration model for the preclinical assessment of volitional cannabis intake and cannabis-seeking behaviors.

neuroscience↗

bioRxiv2019

Risky Decision-Making Predicts Dopamine Release Dynamics in Nucleus Accumbens Shell

The risky decision-making task (RDT) measures risk-taking in a rat model by assessing preference between a small, safe reward and a large reward with increasing risk of punishment (mild foot shock). It is well-established that dopaminergic drugs modulate risk-taking; however, little is known about how differences in baseline phasic dopamine signaling drive individual differences in risk preference. Here, we used in vivo fixed potential amperometry in male Long-Evans rats to test if phasic nucleus accumbens shell (NACs) dopamine dynamics are associated with risk-taking. We observed a positive correlation between medial forebrain bundle-evoked dopamine release in the NACs and risky decision-making, suggesting that risk-taking is associated with elevated dopamine sensitivity. Moreover, \"risk-taking\" subjects were found to demonstrate greater phasic dopamine release than \"risk-averse\" subjects. Risky decision-making also predicted enhanced sensitivity to nomifensine, a dopamine reuptake inhibitor, quantified as elevated latency for dopamine to clear from the synapse. Importantly, this hyperdopaminergic phenotype was selective for risky decision-making, as delay discounting performance was not predictive of phasic dopamine release or dopamine supply. These data identify phasic NACs dopamine release as a possible therapeutic target for alleviating the excessive risk-taking observed across multiple forms of psychopathology.\n\nSignificance StatementExcessive risky decision-making is a hallmark of addiction, promoting ongoing drug seeking despite the risk of social, financial, and physical consequences. However, punishment-driven risk-taking is understudied in preclinical models. Here, we examined the relationship between individual differences in risk-taking and dopamine release properties in the rat nucleus accumbens shell, a brain region associated with motivation and decision-making. We observed that high risk taking predicted elevated phasic dopamine release and sensitivity to the dopamine transporter blocker nomifensine. This hypersensitive dopamine system was not observed in rats with high impulsive choice, another behavior associated with substance use disorder. This provides critical information about neurobiological factors underlying a form of decision-making that promotes vulnerability to substance abuse.

neuroscience↗