Browsing by Author "McGregor, IS"

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    5-HT1A Receptor
    (Springer-Verlag Berlin Heidelberg, 2010) Callaghan, PD; McGregor, IS; Thompson, MR
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    Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure
    (Springer Nature, 2007-06-20) Quinn, HR; Matsumoto, I; Callaghan, PD; Long, LE; Arnold, JC; Gunasekaran, N; Thompson, MR; Dawson, B; Mallet, PE; Kashem, MA; Matsda-Matsumoto, H; Iwazki, T; McGregor, IS
    The current study examined whether adolescent rats are more vulnerable than adult rats to the lasting adverse effects of cannabinoid exposure on brain and behavior. Male Wistar rats were repeatedly exposed to Δ9-tetrahydrocannabinol (Δ(9)-THC, 5 mg/kg i.p.) in a place-conditioning paradigm during either the adolescent (post-natal day 28+) or adult (post-natal day 60+) developmental stages. Adult rats avoided a Δ(9)-THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final Δ(9)-THC injection. In contrast, adolescent rats showed no significant place aversion. Adult Δ(9)-THC-treated rats produced more vocalizations than adolescent rats when handled during the intoxicated state, also suggesting greater drug-induced aversion. After a 10-15 day washout, both adult and adolescent Δ(9)-THC pretreated rats showed decreased social interaction, while onlyΔ (9)-THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last Δ(9)-THC injection, rats were euthanised and hippocampal tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual Δ(9)-THC being present in blood at this time. Proteomic analysis uncovered 27 proteins, many involved in regulating oxidative stress/mitochondrial functioning and cytoarchitecture, which were differentially expressed in adolescent Δ(9)-THC pretreated rats relative to adolescent controls. In adults, only 10 hippocampal proteins were differentially expressed in Δ(9)-THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated Δ(9)-THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippocampal alterations in adolescent than adult rats. © 2018 Springer Nature
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    Aggregation in quads but not pairs of rats exposed to cat odor or bright light
    (Elsevier Science BV, 2012-07-01) Bowen, MT; Keats, K; Kendig, MD; Cakic, V; Callaghan, PD; McGregor, IS
    In many prey species aggregation of individuals is a defensive strategy commonly employed in response to predators and predator-related cues. However, very little work has explored this adaptive response in laboratory rats. It is known that individual rats show characteristic defensive responses to predator odors, such as hiding, avoidance, inhibition of foraging, feeding and reproduction, and risk assessment directed toward the odor source. However, whether these species-typical responses in individuals are altered in the presence of other conspecifics is yet to be characterized. The present study therefore examined the defensive response of groups of two rats (dyads) or four rats (quads) to two unconditioned stressors: bright ambient light and cat odor (a 2 g ball of cat fur). The dyads and quads were formed from familiar cage mates and test sessions (20 min) occurred in a large open arena (1200 mm(2)) to which the rats had been extensively habituated under dark conditions. The results showed that when quads of rats were exposed to either cat odor or bright light in this arena, they showed characteristic increases in close social proximity, termed "huddling". A tight grouping of 3 (triplet) or 4 (quad) rats was commonly seen in response to cat fur, while triplets were more commonly seen in response to bright light. Interestingly there was no evidence for increased social proximity in dyads exposed to either stressor, only in quads. However, cat odor caused other signs of fear (such as decreased locomotor activity and increased defecation) in both quads and dyads. It is concluded that huddling is a rodent defensive strategy in rats when anxiogenic stimuli are encountered by larger groups of rats.© 2012, Elsevier Ltd.
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    Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents?
    (International Journal of Neuropsychopharmacology., 2011-05-01) Karanges, E; Li, KM; Motbey, CP; Callaghan, PD; Katsifis, A; McGregor, IS
    Selective serotonin reuptake inhibitor use is associated with increased risk of suicidal ideation in adolescent humans, yet the neuropharmacological basis of this phenomenon is unknown. Consequently, we examined the behavioural and neurochemical effects of chronic paroxetine (PRX) treatment in adult and adolescent rats. Rats received PRX in their drinking water (target dose 10 mg/kg) for 22 d, during which time they were assessed for depression- and anxiety-like behaviours. Subsequent ex-vivo analyses examined serum PRX concentrations, striatal neurotransmitter content, and regional serotonin and dopamine transporter (SERT, DAT) binding density. After 11–12 d treatment, PRX-treated adolescent rats showed a significant inhibition of social interaction while adults were unaffected. After 19–20 d treatment, adolescents failed to show an antidepressant-like effect of PRX treatment on the forced swim test (FST), while PRX-treated adults showed a typical decrease in immobility and increase in swimming. Two PRX-treated adolescents died unexpectedly after the FST suggesting a compromised response to physical stress. Despite their greater apparent adverse reaction to the drug, adolescents had significantly lower plasma PRX than adults at day 22 of treatment. Chronic PRX treatment had similar effects in adults and adolescents on striatal 5-HT (unchanged relative to controls) and 5-HIAA levels (decreased), while markers of dopaminergic function (DOPAC, HVA, DA turnover) were increased in adults only. SERT density was up-regulated in the amygdala in PRX-treated adolescents only while DAT density in the nucleus accumbens was down-regulated only in PRX-treated adults. These data suggest that the immature rat brain responds differently to PRX and that this might be of use in modelling the atypical response of human adolescents to antidepressants. The age-specific PRX-induced changes in dopaminergic markers and SERT and DAT binding provide clues as to the neural mechanisms underlying adverse PRX effects in adolescent humans. © 2011, Cambridge University Press
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    Entactogen
    (Springer-Verlag Berlin Heidelberg, 2010) Callaghan, PD; McGregor, IS; Thompson, MR
    Entactogens are drugs, including MDMA (Ecstasy) and other MDxx structure compounds, that cause distinctive prosocial, emotional, and sensory effects in users. Most of them are substituted amphetamine compounds of the phenethylamine class. © 2010 Springer-Verlag Berlin Heidelberg
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    From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long‐term adverse consequences of drug use?
    (The British Pharmacological Society, 2009-01-29) McGregor, IS; Callaghan, PD; Hunt, GE
    Addictive drugs can profoundly affect social behaviour both acutely and in the long-term. Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology. In this review we focus on the ‘social neuropeptide’ oxytocin and its possible role in acute and long-term effects of commonly used drugs. Oxytocin regulates social affiliation and social recognition in many species and modulates anxiety, mood and aggression. Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects. Oxytocin interacts with the mesolimbic dopamine system to facilitate sexual and social behaviour, and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behaviour. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behaviour. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems. Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders. © 2019 The British Pharmacological Society
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    Herbal ecstasy
    (Springer-Verlag Berlin Heidelberg, 2010) Callaghan, PD; McGregor, IS; Thompson, MR
    Herbal ecstasy tablets, legally sold in many countries, usually contain the sympathomimetic herb Ephedra (Ma Huang) rather than the drug Ecstasy (MDMA). © 2010 Springer-Verlag Berlin Heidelberg
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    High levels of intravenous mephedrone (4-methylmethcathinone) self-administration in rats: neural consequences and comparison with methamphetamine
    (British Association for Psychopharmacology, 2013-06-05) Motbey, CP; Clemens, KJ; Apetz, N; Winstock, AR; Ramsey, J; Li, KM; Wyatt, NA; Callaghan, PD; Bowen, MT; Cornish, JL; McGregor, IS
    Mephedrone (MMC) is a relatively new recreational drug that has rapidly increased in popularity in recent years. This study explored the characteristics of intravenous MMC self-administration in the rat, with methamphetamine (METH) used as a comparator drug. Male Sprague-Dawley rats were trained to nose poke for intravenous MMC or METH in daily 2 h sessions over a 10 d acquisition period. Dose-response functions were then established under fixed- and progressive-ratio (FR and PR) schedules over three subsequent weeks of testing. Brains were analyzed ex vivo for striatal serotonin (5-HT) and dopamine (DA) levels and metabolites, while autoradiography assessed changes in the regional density of 5-HT and serotonin transporter (SERT) and DA transporter (DAT) and induction of the inflammation marker translocator protein (TSPO). Results showed that MMC was readily and vigorously self-administered via the intravenous route. Under a FR1 schedule, peak responding for MMC was obtained at 0.1 mg/kg/infusion, versus 0.01 mg/kg/infusion for METH. Break points under a PR schedule peaked at 1 mg/kg/infusion MMC versus 0.3 mg/kg/infusion for METH. Final intakes of MMC were 31.3 mg/kg/d compared to 4 mg/kg/d for METH. Rats self-administering MMC, but not METH, gained weight at a slower rate than control rats. METH, but not MMC, self-administration elevated TSPO receptor density in the nucleus accumbens and hippocampus, while MMC, but not METH, self-administration decreased striatal 5-hydroxyindolacetic acid (5-HIAA) concentrations. In summary, MMC supported high levels of self-administration, matching or exceeding those previously reported with other drugs of abuse. Copyright © 2020 by British Association for Psychopharmacology
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    MDMA-induced c-Fos expression in oxytocin-containing neurons is blocked by pretreatment with the 5-HT-1A receptor antagonist WAY 100635
    (Elsevier, 2011-08-10) Hunt, GE; McGregor, IS; Cornish, JL; Callaghan, PD
    The popular party drug MDMA (3,4-methylenedioxymethamphetamine, “Ecstasy”) increases sociability in both humans and laboratory animals. Recent research suggests that these prosocial effects may involve serotonin (5-HT)-stimulated hypothalamic release of the neuropeptide oxytocin. WAY 100635, a 5-HT1A receptor antagonist, prevents MDMA-induced increases in plasma oxytocin and also reduces MDMA-mediated increases in social interaction in rats. The present study used c-Fos immunohistochemistry to determine the possible role of 5-HT1A receptors in MDMA-mediated activation of oxytocin synthesizing neurons. Male Wistar rats (n = 8/group) were administered MDMA (10 mg/kg, i.p.) with or without WAY 100635 (1 mg/kg, i.p.) pre-treatment and c-Fos expression was then assessed throughout the brain. MDMA significantly increased locomotor activity and this effect was partly prevented by WAY 100635, in agreement with previous studies. WAY 100635 significantly reduced MDMA-induced c-Fos expression in a subset of brain regions examined. A particularly prominent reduction was seen in the oxytocin-positive neurons of the supraoptic nucleus and paraventricular hypothalamus, with more modest reductions in the Islands of Calleja, median preoptic nucleus, somatosensory cortex and nucleus of the solitary tract. WAY 100635 did not alter MDMA-induced c-Fos expression in the striatum, thalamus, or central amygdala. These results indicate that MDMA's action on oxytocin producing cells in the hypothalamus is mediated through 5-HT1A receptors and that certain specific cortical, limbic and brainstem sites are also activated by MDMA via these receptors. © 2011, Elsevier Ltd.
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    Mephedrone in adolescent rats: residual memory impairment and acute but not lasting 5-HT depletion
    (PLOS, 2012-09-18) Motbey, CP; Karanges, E; Li, KM; Wilkinson, S; Winstock, AR; Ramsey, J; Hicks, C; Kendig, MD; Wyatt, NA; Callaghan, PD; McGregor, IS
    Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([125I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted. © 2012 Motbey et al.
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    Methylenedioxymethamphetamine (MDMA)
    (Springer-Verlag Berlin Heidelberg, 2010) McGregor, IS; Thompson, MR; Callaghan, PD
    MDMA is a popular recreational drug that is renowned for its ability to produce euphoria and unique prosocial effects. It is the best known and most commonly used member of the family of phenethylamines (substitutes for amphetamines) that are sometimes known as entactogens, empathogens, or the MDxx class of drugs. MDMA has multiple neurochemical effects, the most prominent of which is to promote the release of serotonin via an action on the serotonin transporter (SERT). The prosocial effects of MDMA have recently been linked to the release of the neuropeptide oxytocin. High doses of MDMA can cause long-term depletion of serotonin in the brains of laboratory animals, but whether this also occurs in humans and whether this leads to associated psychopathology such as depression and cognitive impairment remains unclear. © 2010 Springer-Verlag Berlin Heidelberg
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    Oxytocin
    (Springer-Verlag Berlin Heidelberg, 2010) Callaghan, PD; McGregor, IS; Thompson, MR
    Oxytocin is a nine amino acid neuropeptide (nonapeptide), synthesized in the magnocellular neurosecretory cells of the hypothalamus and released both within the brain and from the posterior pituitary gland into the bloodstream. Oxytocin exerts peripheral actions that promote uterine contractions and the milk let-down reflex and is also increasingly recognized for its central effects that can lead to lasting changes in social behavior, mood and emotion in many mammalian species. Recent studies show that intranasal administration of oxytocin can modify social cognition, social memory, interpersonal behavior, and associated brain activation in human subjects. © 2010 Springer-Verlag Berlin Heidelberg
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    The psychopharmacology of MDMA
    (National Drug and Alcohol Research Centre, 2010) Thompson, MR; Callaghan, PD; McGregor, IS
    The psychoactive drug 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy, E, XTC) has an interesting history and a fascinating pharmacology. As discussed in Chapter 2, MDMA was first synthesised in 1912 and patented by the company E. Merck in 1914. Although commonly thought to have been designed as an appetite suppressant, the original patent bears no record of this and simply states that MDMA was deemed to contain primary constituents for therapeutically active compounds. The first reported pharmacological study involving MDMA occurred in 1927 although it was of limited scope and basic toxicology studies were not undertaken until the 1950s. Toxicology studies by Merck in 1952 provided little insight into the pharmacology of MDMA focusing on its effects on flies. Further studies at the University of Michigan, supported by the US Army, reported LD values for five different species, the lowest LD value being found in dogs, the highest in mice. As mentioned in Chapters 3 and 13, the first systematic use of MDMA was as an adjunct to insight-oriented psychotherapy4, with administration of MDMA producing an easily controllable altered state of consciousness with positive emotional and sensual overtones. The colloquial term for MDMA changed from “Empathy” as had been used by therapists in the 1970s, to “Ecstasy”, emphasising the drug’s euphoric effects. Heavy media attention in 1985 sensationalised Ecstasy’s euphoric effects. Despite this surge in popularity, the settings in which Ecstasy was used in the middle of the 1980’s typically involved two individuals or a small and intimate group5. This was soon to change with the emergence of the “rave” scene. In 1986, MDMA became a Schedule 1 drug in the USA, deemed to possess no recognised therapeutic value despite claims to the contrary. By the 1990s, ecstasy had became intrinsically linked to the club and rave culture, with use by groups of young people attending all-night dance parties where vigorous dancing occurred to highly repetitive and hypnotic “techno” music. This was thought to have originated in Europe in the late 1980s. Patterns of use in Australia largely mimicked those seen abroad, with dance parties, private parties and nightclubs listed as the most popular venues for use. Its popularity has continued to grow, and the contexts of use broadened. © 2010 NDARC
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    Social interaction test
    (Springer-Verlag Berlin Heidelberg, 2010) Callaghan, PD; McGregor, IS; Thompson, MR
    Two animals, typically rats or mice, are placed into an arena and their interactions, for example, investigation, following, and grooming, are recorded for a period of time, usually 5 to 10 min. Social behaviors such as following, adjacent lying, and anogenital sniffing are recorded by an observer or via automated image analysis. Many drugs modulate behavior on the social interaction test: benzodiazepines, MDMA, and oxytocin tend to increase social interaction while amphetamines, cannabinoids, NMDA antagonists, and withdrawal from various drugs of abuse tend to decrease social interaction. In the high-light version of the then test, the arena is brightly illuminated and this creates an aversive situation for the animals, which results in low levels of social interaction. In this configuration, it is possible to identify drugs or manipulations that reduce the inferred level of anxiety in the animals, that is, they result in an increased level of social interaction. In the low-light version, the arena is only illuminated with low, typically red light in order to minimize aversive cues. In this configuration, the level of interaction will be maximal and it is possible to test drugs or manipulations that reduce the normal level of social interactions. In addition to light level, which is the strongest experimental factor, the animals’ familiarity with the arena can be varied, for example, by having been introduced to the arena prior to the testing session, and whether the animals know each other prior to the testing session. Familiarity with the arena will reduce the level of aversive cues, but will also increase the level of territorial behavior, resulting in more fighting between the animals. Familiarity between the animals being tested can reduce the level of aversive cues during the testing situation and the level of fighting, because a hierarchy does not have to be established, but it may also increase variability in the data, because the animals will have a preestablished rank that not will be present if they are unfamiliar to each other. © 2010 Springer-Verlag Berlin Heidelberg