Ecologically recorded sleep patterns, stress, and lifestyle behaviors in college students prior to and during the COVID-19 pandemic.

Objective: Beginning in the spring of 2020, college students adapted to a myriad of COVID-19 pandemic-related stressors including personal and family health concerns, social isolation and future uncertainty that affect sleep behavior. We investigated how the pandemic affected ecologically recorded sleep patterns, self-reported stress and lifestyle behaviors in three semester-differentiated cohorts of college students enrolled in a psychology of sleep course. Methods: Students (N = 117) used the SleepScore biomotion sensor system to track sleep patterns and responded to behavior questions during the spring 2018, fall 2020, and spring 2022 semesters. Results: When compared to students in the spring 2018 pre-pandemic semester, students who underwent remote/hybrid learning in the fall 2020 semester displayed improved objective measures of sleep quality that were accompanied by increased deep sleep, fewer disruptions, and decreased time awake during the night, while self-reported stress ratings were unchanged. During pandemic semesters, students also reported decreased time studying, increased napping and screen use and higher ratings of bedroom comfort. Conclusions: Pandemic initiated remote learning and social restrictions may have allowed for healthier sleeping environments that likely contributed to better sleep health and stress resiliency in college students.

The phosphodiesterase inhibitor isobutylmethylxanthine attenuates behavioral sensitization to cocaine.

The factors influencing sensitization to cocaine are complex and likely include both cellular and neural systems factors. Upregulation of the striatal dopamine cAMP-signaling pathway and enhanced accumbens adenosine tone are two mechanisms that have been proposed to underlie the development of cocaine sensitization. Isobutylmethylxanthine (IBMX) is a nonspecific inhibitor of phosphodiesterase (PDE) that may enhance the intracellular cAMP levels. However, IBMX may inhibit the PDE-mediated production of adenosine. In this study, intracerebroventricular IBMX did not affect the acute hyperlocomotor response to cocaine, but when coadministered with cocaine for 7 consecutive days, attenuated development of behavioral sensitization. These results suggest that IBMX inhibition of PDE-mediated adenosine production is a stronger influence on cocaine sensitization than inhibition of intracellular PDE-mediated cAMP metabolism.

Use of personal EEG monitors in a behavioral neuroscience course to investigate natural setting sleep patterns and the factors affecting them in college students.

Sleep is often a topic of avid interest to college students, yet it is one that does not yield itself well to hands-on, interactive learning modules. Supplementing classroom learning with interactive "real world" laboratory activities provides students with a deeper understanding of behavior and its neural control. The project described here was designed to supplement the teaching of EEGs, sleep and circadian rhythms and involved students in the empirical process from hypothesizing about the factors that affect sleep, to personal data collection, data analysis and writing in the style of a peer-reviewed manuscript. Students enrolled in Behavioral Neuroscience at Connecticut College were provided with a home-based personal EEG monitor used to collect sleep data in their natural sleep setting. Participants recorded sleep data with the use of the ZEO® Personal Sleep Coach system and completed a nightly sleep journal questionnaire for seven nights. The ZEO® system uses EEG patterns to define sleep stages including wakefulness, light, deep and REM sleep. The journal included questions about factors known to affect sleep such as stress, caffeine, academic activity, exercise and alcohol. A class data set was compiled and used by students to perform univariate correlations examining the relationships between ZEO® variables and sleep journal variables. The data set allowed students to choose specific variables to investigate, analyze and write a peer-reviewed style manuscript. Significant class-wide correlations were found between specific sleep stages and behavioral variables suggesting that the ZEO® system is sophisticated yet inexpensive enough to be used as an effective tool in the classroom setting. Overall student feedback on the exercise was positive with many students indicating that it significantly enhanced their understanding of sleep architecture and made them keenly aware of the factors that affect quality of sleep.

Regulation of dynamin 2 and G protein-coupled receptor kinase 2 in rat nucleus accumbens during acute and repeated cocaine administration.

Exposure to cocaine causes many neuroadaptations including alterations in several neurotransmitter receptors and transporters. This study investigated potential mechanisms of cocaine-induced receptor and transporter regulation by measuring levels of two proteins involved in receptor and transporter trafficking, dynamin 2 and G protein-coupled receptor kinase 2 (GRK2). Male Fischer rats received three daily injections of cocaine, 15 mg/kg, in a binge-pattern (at 1 h intervals) for 1, 3, or 14 days. Brain regions of interest were collected 30 min after the last injection and proteins measured by Western blot. Acute binge-pattern cocaine administration produced a significant increase in both dynamin 2- and GRK2-immunoreactivity (227% and 358% of control) in the nucleus accumbens and GKR2 (150% of control) in the caudate putamen. Tolerance to this effect occurred, as levels of both proteins returned to baseline after 3 days of cocaine. In contrast, dynamin 2 and GRK2 were significantly decreased in the nucleus accumbens after chronic cocaine. This pattern of regulation was unique to the nucleus accumbens and not seen in the frontal cortex or substantia nigra. Pretreatment with either the dopamine (DA) D1 receptor antagonist SCH 23390 or D2 receptor antagonist eticlopride prior to acute cocaine blocked the upregulation of dynamin 2 and GRK2 in the nucleus accumbens. However, only eticlopride was effective in attenuating the decrease in these proteins following chronic cocaine exposure. These results demonstrate that two proteins involved in receptor and transporter trafficking are selectively regulated in the nucleus accumbens following acute versus chronic cocaine exposure, and dopamine receptor activation is required for this regulation.

Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat.

Chronic administration of cocaine has been shown to attenuate the functional capacity of delta opioid receptors to inhibit adenylyl cyclase activity. Abuse and withdrawal from cocaine in humans is associated with increases in anxiety and depression. Since recent research supports the role of delta opioid receptors in anxiety- and depression-like behaviors in rodents, we hypothesized that functional desensitization of delta opioid receptors contributes to anxiety- and depression-like behavioral phenotypes following short-term withdrawal from chronic administration of cocaine. To test this hypothesis, delta opioid receptor signaling and behaviors were evaluated 24h after 14days of binge-pattern cocaine administration (15mg/kg three times daily at 1h intervals) in male Sprague-Dawley rats. Results showed that the inhibition of adenylyl cyclase by delta opioid receptor agonists was attenuated in the frontal cortex, nucleus accumbens and caudate putamen 24h after cessation of cocaine administration. One day withdrawal from chronic administration of cocaine resulted in increased anxiety- and depression-like behaviors as measured by the elevated plus maze and the forced swim test respectively, and no change in locomotor activity. The anxiety- and depression-like behaviors were dose-dependently reduced by acute administration of the selective delta opioid receptor agonist, SNC80. These results demonstrate that early withdrawal from cocaine resulted in increased anxiety and depression, which accompanies the desensitization of delta opioid receptor function. Furthermore, cocaine-induced anxiety- and depression-like behaviors were reversible by the delta opioid receptor agonist SNC80.

A role for mu opioid receptors in cocaine-induced activity, sensitization, and reward in the rat.

RATIONALE: Considerable evidence suggests that the endogenous opioid system plays a role in mediating the behavioral effects of psychostimulants. Opioidergic drugs have been shown to have profound effects on cocaine-induced behavioral sensitization and conditioned reward. However, the role specifically of the mu opioid receptor in this regard is unclear as most previous pharmacological studies have used nonselective opioid receptor ligands. OBJECTIVES: The objective of this series of experiments was to elucidate the role of mu opioid receptors in the behavioral effects of cocaine in the rat. MATERIALS AND METHODS: Adult male rats were used to assess the effects of the selective mu opioid receptor antagonist D: -Phe-Cys-Tyr-D: -Trp-Arg-Thr-Pen-Thr (CTAP) on acute hyperactivity, locomotor sensitization, and conditioned place preference induced by cocaine. Intracerebroventricular administration of CTAP, 4 microg, was paired with peripheral injections of cocaine, 10-15 mg/kg. RESULTS: Mu receptor blockade significantly attenuated cocaine-induced hyperactivity, as well as the development of behavioral sensitization. Pretreatment with CTAP also prevented the development of conditioned place preference to cocaine. Administration of CTAP alone had neither effect on locomotor activity nor did it demonstrate aversive or rewarding properties. CONCLUSIONS: These results suggest that activation of mu opioid receptors by endogenous opioids is an important contributor to cocaine-induced hyperactivity and the development of behavioral sensitization and conditioned reward.

NOP receptor antagonist, JTC-801, blocks cannabinoid-evoked hypothermia in rats.

The present study used the endpoint of hypothermia to investigate cannabinoid and nociceptin/orphanin FQ (N/OFQ) interactions in conscious animals. Prior work has established that cannabinoids produce hypothermia by activating central cannabinoid CB(1) receptors. The administration of N/OFQ into the brain also causes significant hypothermia. Those data suggest a link between cannabinoid CB(1) receptors and N/OFQ peptide (NOP) receptors in the production of hypothermia. Therefore, we determined if NOP receptor activation is required for cannabinoid-evoked hypothermia and if cannabinoid CB(1) receptor activation is necessary for N/OFQ-induced hypothermia. In actual experiments, a cannabinoid agonist, WIN 55212-2 (2.5, 5, and 10 mg/kg, i.p.), caused significant hypothermia in male Sprague-Dawley rats (200-225 g). A NOP receptor antagonist, JTC-801 (1 mg/kg, i.p.), did not affect body temperature. For combined administration, JTC-801 (1 mg/kg, i.p.) blocked a significant proportion of the hypothermia caused by each dose of WIN 55212-2 (2.5, 5, and 10 mg/kg, i.p.). JTC-801 (1 mg/kg, i.p.) also blocked the hypothermia caused by another cannabinoid agonist, CP-55, 940 (1 mg/kg, i.p.). In separate experiments, the direct administration of N/OFQ (9 microg/rat, i.c.v.) into the brain produced significant hypothermia. The hypothermic effect of N/OFQ was blocked by JTC-801 (1 mg/kg, i.p.) but not by a selective cannabinoid CB(1) antagonist, SR 141716A (5 mg/kg, i.m.). The finding that a NOP receptor antagonist abolishes a significant percentage of cannabinoid-induced hypothermia suggests that NOP receptor activation is required for cannabinoids to produce hypothermia. This interaction, quantitated in the present study, is the first evidence that NOP receptors mediate a cannabinoid-induced effect in conscious animals.

Behavioral sensitization to binge-pattern cocaine administration is not associated with changes in protein levels of four major G-proteins.

Behavioral sensitization is a characteristic sequelae of repeated cocaine exposure. It likely occurs due to long-lasting neuroadaptations produced by cocaine, although the exact nature of these adaptations has yet to be defined. The goal of the present study was to determine if behavioral sensitization to cocaine is accompanied by alterations in G-protein levels. Adult male rats were administered cocaine or saline three times daily in a binge-pattern for 1, 3, or 14 days and activity monitored. Levels of four major G-protein alpha-subunits, Galphas, Galphaolf, Galphao and Galphai1, and their mRNAs were measured in the nucleus accumbens, caudate putamen, and cingulate/frontal cortex using Western blot analysis and in situ hybridization, respectively. Fourteen days of binge-pattern cocaine administration resulted in behavioral sensitization as evidenced by increased behavioral activity over the 14 days of drug exposure. Results demonstrated that Galphaolf mRNA expression was significantly reduced in the nucleus accumbens after 1, 3 or 14 days of cocaine, whereas Galphai1 mRNA was increased following 3, but not 1 or 14 days of cocaine in the caudate putamen, nucleus accumbens and cingulate cortex. Galphas and Galphao mRNA expression were not altered in any region investigated at any time point. In contrast to gene expression, protein levels of the four G-protein alpha-subunits were not significantly different from saline-injected rats in the caudate putamen, nucleus accumbens, or frontal cortex following 1, 3, or 14 days of cocaine administration. These results suggest that alterations in the level of G-proteins are not necessary for the development of cocaine-induced sensitization.

Use of the Herb Gymnema sylvestre to Illustrate the Principles of Gustatory Sensation: An Undergraduate Neuroscience Laboratory Exercise.

The Indian herb Gymnema sylvestre has been used in traditional Ayurvedic medicine for 2000 years, most recently for the treatment of diabetes. Loose leaf Gymnema sylvestre can be prepared as a tea and will impair the ability to taste sugar by blocking sweet receptors on the tongue. This report describes a laboratory exercise easily applied to an undergraduate neuroscience course that can be used to illustrate the principles of gustatory sensation. Combined with a preceding lecture on the primary taste sensations, students experience and appreciate how the primary tastes are combined to produce overall taste. In addition, the exercises outlined here expand upon previously published demonstrations employing Gymnema sylvestre to include illustrations of the different sensory transduction mechanisms associated with each of the four or five primary taste modalities. Students compare their qualitative primary taste experiences to salt, sugar, aspartame, chocolate, and sweet-sour candy prior to and following exposure to Gymnema sylvestre. The herb's impairment of sweet sensation is profound and dramatically alters the perception of sweetness in sugar, chocolate, and candy without altering the perception of the other primary tastes. The exercise has an indelible effect on students because the herb's intense effect compels students to rely on their unique personal experiences to highlight the principles of gustatory sensation.

Repeated intracerebroventricular forskolin administration enhances behavioral sensitization to cocaine.

Repeated cocaine exposure produces behavioral sensitization expressed as an increased locomotor response to subsequent drug administration. Chronic cocaine administration also results in increased activity of adenylyl cyclase and cyclic-AMP (cAMP) dependent protein kinase (PKA) in the nucleus accumbens. To investigate the relationship between cocaine-induced behavioral sensitization and cAMP signaling, the present study examined the effect of forskolin, a direct adenylyl cyclase activator, on cocaine-induced hyperlocomotion and behavioral sensitization to cocaine. Rats were given intracerebroventricular (i.c.v.) injections of a water soluble form of forskolin (7DMB-forskolin) or vehicle 10 min prior to intraperitoneal (i.p.) cocaine or saline administration on 7 consecutive days. Acute or chronic forskolin alone had no effect on locomotor activity at the doses tested. On days 1 and 2, the activity of rats that received i.c.v. forskolin paired with cocaine was not significantly different from rats that received i.c.v. injections of vehicle co-administered with cocaine. By the third day of forskolin/cocaine co-administration, rats displayed enhanced cocaine-induced hyperlocomotor activity compared to rats that received cocaine alone, an effect that persisted through day 7. When challenged with cocaine on day 14, animals that had previously received forskolin paired with cocaine on days 1-7 displayed similar locomotor activity to animals that received cocaine only. These results suggest that alterations in adenylyl cyclase activity and/or cAMP levels may underlie the hyperlocomotor response to cocaine and may play a role in behavioral sensitization.

GABA(A) and mu-opioid receptor binding in the globus pallidus and endopeduncular nucleus of animals symptomatic for and recovered from experimental Parkinsonism.

The expression of parkinsonian motor symptoms may be partly attributed to an increase in GABAergic neurotransmission from hyperactive GABA/enkephalinergic striatopallidal efferents. The present study measured pallidal GABA(A) and mu-opioid receptor binding in normal cats and cats symptomatic for and recovered from MPTP-induced parkinsonism. GABA(A) receptor binding was significantly decreased in the globus pallidus (GP) in symptomatic cats and returned to normal levels in spontaneously recovered cats. Mu-opioid receptor binding in the GP was significantly decreased in symptomatic cats and remained significantly decreased in recovered cats. These results suggest that GABA(A) but not mu-opioid receptor binding may correlate with the expression of parkinsonian motor deficits and may reflect increased pallidal GABA and ENK release in parkinsonian animals. Upon recovery from experimental parkinsonism, however, pallidal GABA(A) receptor binding returns to normal levels while mu-opioid receptor binding reflecting enkephalin release remains elevated.

Disruption of G(i/o) protein signaling in the nucleus accumbens results in a D1 dopamine receptor-mediated hyperactivity.

Intra-accumbens infusion of pertussis toxin (PTX) results in a progressive and persistent locomotor hyperactivity and sensitizes rats to the locomotor-activating effects of cocaine. The present study further defined the hyperactivity resulting from inactivation of accumbens Gi/Go proteins and tested the hypothesis that PTX-induced hyperactivity is mediated by dopamine D1 receptors. PTX (0.15 microg/side) infused bilaterally into the nucleus accumbens of rats resulted in a progressive increase in locomotor activity that peaked at 218% of preinjection activity levels 15 days after injection and persisted for greater than 5 weeks postinjection. Administration of the D1 receptor antagonist SCH23390 16 and 23 days after PTX injections dose dependently attenuated PTX-induced hyperactivity. D1 receptor blockade did not significantly alter activity in sham-injected animals. These findings support the hypothesis that the hyperactivity resulting from PTX-mediated inactivation of G(i/o) proteins reflects increased nucleus accumbens D1 receptor activation and suggest that striatal D1 receptors are important mediators of activity-related behavior, such as cocaine-induced hyperactivity.

Clavulanic acid reduces rewarding, hyperthermic and locomotor-sensitizing effects of morphine in rats: a new indication for an old drug?

BACKGROUND: Despite the efficacy of ceftriaxone (CTX) in animal models of CNS diseases, including drug addiction, its utility as a CNS-active therapeutic may be limited by poor brain penetrability and cumbersome parenteral administration. An alternative is the ß-lactamase inhibitor clavulanic acid (CA), a constituent of Augmentin that prevents antibiotic degradation. CA possesses the ß-lactam core necessary for CNS activity but, relative to CTX, possesses: (1) oral activity; (2) 2.5-fold greater brain penetrability; and (3) negligible antibiotic activity. METHODS: To compare the effectiveness of CA (10mg/kg) and CTX (200mg/kg) against centrally-mediated endpoints, we investigated their effects against morphine's rewarding, hyperthermic, and locomotor-sensitizing actions. Endpoints were based on prior evidence that CTX attenuates morphine-induced physical dependence, tolerance, and hyperthermia. RESULTS: As expected, rats treated with morphine (4 mg/kg) displayed hyperthermia and conditioned place preference (CPP). Co-treatment with CTX or CA inhibited development of morphine-induced CPP by approximately 70%. Morphine's hyperthermic effect was also suppressed, with CTX and CA producing 57% and 47% inhibition, respectively. Locomotor sensitization induced by repeated morphine exposures was inhibited by CA but not CTX. CONCLUSIONS: The present findings are the first to suggest that CA disrupts the in vivo actions of morphine and point toward further studying CA as a potential therapy for drug addiction. Further, its ability to disrupt morphine's rewarding effects at 20-fold lower doses than CTX identifies CA as an existing, orally-active alternative to direct CTX therapy for CNS diseases.

Glutamate transporter activation enhances nicotine antinociception and attenuates nicotine analgesic tolerance.

Analgesic tolerance is partially mediated by enhanced glutamatergic transmission in the CNS. ß-lactam antibiotics, through glutamate transporter subtype 1 (GLT-1) activation, reduce extracellular glutamate levels and attenuate tolerance to morphine analgesia in rats. Similar to opioids, nicotine has potent analgesic properties that are subject to tolerance. The purpose of this study was to evaluate the effects of ceftriaxone, a ß-lactam antibiotic and GLT-1 activator on nicotine antinociception and its tolerance. Rats were pretreated for 5 days with ceftriaxone (200 mg/kg, intraperitoneally) before evaluating their analgesic response to nicotine (1.0 or 2.5 mg/kg, subcutaneously) for seven consecutive days using the tail-flick assay. Ceftriaxone-treated rats displayed an enhanced antinociceptive response to nicotine and unlike saline-injected controls, did not develop tolerance to nicotine's analgesic effects. These results suggest that GLT-1 transporter activation enhances and preserves nicotine antinociception and identify ß-lactam antibiotics as potential complementary therapeutic agents for the treatment of chronic pain.

Cocaine alters mu but not delta or kappa opioid receptor-stimulated in situ [35S]GTPgammaS binding in rat brain.

Chronic cocaine administration produces alterations in mu and kappa opioid receptor density as well as striatal and accumbens opioid-regulated adenylyl cyclase activity, suggesting a psychostimulant responsive interaction between opioidergic and dopaminergic systems. Stimulation of G-protein-coupled opioid receptors inhibits adenylyl cyclase production of cyclic AMP. The present study employed in situ [(35)S]GTPgammaS binding to measure opioid receptor-stimulated activation of G-proteins in response to acute and chronic cocaine exposure. Male Fischer rats received acute (1 or 3 days) or chronic (14 days) binge pattern cocaine administration. Three and 14 days of cocaine injections resulted in greater increases in the ability of the mu receptor agonist DAMGO to stimulate [(35)S]GTPgammaS binding in both the core and the shell of the nucleus accumbens, all regions of the caudate putamen and the cingulate cortex compared with saline-matched controls. The greatest increases in DAMGO-stimulated [(35)S]GTPgammaS binding were observed in the dorsal areas of the caudate putamen in animals that received 14 days of cocaine. No significant changes in delta (DPDPE), or kappa (dynorphin A(1-17)) receptor-stimulated [(35)S]GTPgammaS binding were found in any brain region in response to cocaine administration. These results demonstrate that binge pattern cocaine administration induce changes in mu but not delta or kappa opioid receptor-mediated G-protein activity. This study provides support for the hypothesis that the addictive properties of both psychostimulants and opiates may share common neurochemical signaling substrates.