Neurochemical and Behavioral Consequences of Ethanol and/or Caffeine Exposure: Effects in Zebrafish and Rodents

: Zebrafish are increasingly being utilized to model the behavioral and neurochemical effects of pharmaceuticals and, more recently, pharmaceutical interactions. Zebrafish models of stress establish that both caffeine and ethanol influence anxiety, though few studies have implemented co-administration to assess the interaction of anxiety and reward-seeking. Caffeine exposure in zebrafish is teratogenic, causing developmental abnormalities in the cardiovascular, neuromuscular, and nervous systems of embryos and larvae. Ethanol is also a teratogen and, as an anxiolytic substance, may be able to offset the anxiogenic effects of caffeine. Co-exposure to caffeine and alcohol impacts neuroanatomy and behavior in adolescent animal models, suggesting stimulant substances may moderate the impact of alcohol on neural circuit development. Here, we review the literature describing neuropharmacological and behavioral consequences of caffeine and/or alcohol exposure in the zebrafish model, focusing on neurochemistry, locomotor effects, and behavioral assessments of stress/anxiety as reported in adolescent/juvenile and adult animals. The purpose of this review is twofold: (1) describe the work in zebrafish documenting the effects of ethanol and/or caffeine exposure and (2) compare these zebrafish studies with comparable experiments in rodents. We focus on specific neurochemical pathways (dopamine, serotonin, adenosine, GABA, adenosine), anxiety-type behaviors (assessed with novel tank, thigmotaxis, shoaling), and locomotor changes resulting from both individual and co-exposure. We compare findings in zebrafish with those in rodent models, revealing similarities across species and identifying conservation of mechanisms that potentially reinforce co-addiction.

Prenatal Caffeine Exposure: Association with Neurodevelopmental Outcomes

In this podcast, Dr. Peter Manza and Dr. Rui Zhang discuss their co-authored JCPP paper ‘Prenatal Caffeine Exposure: Association with Neurodevelopmental Outcomes in 9- to 11- year old children’.

Prenatal smoking, alcohol and caffeine exposure and offspring externalising disorders: A systematic review and meta-analysis

Background and aims: Several studies have indicated that there is an association between maternal prenatal substance use and offspring externalising disorders. However, it is uncertain whether this relationship is causal. Therefore, we updated a previously conducted systematic review to determine if the literature supports 1) a causal role of maternal prenatal substance use on offspring externalising disorders and 2) whether these associations differ across externalising disorders. Methods: We searched Web of Science, Embase, PsycINFO and Medline databases. We included studies that examined smoking, alcohol or caffeine use during pregnancy as an exposure, and diagnosis of attention-deficit hyperactivity disorder (ADHD), conduct disorder (CD) and oppositional-defiant disorder (ODD) in offspring as an outcome. Studies on non-English language, fetal alcohol syndrome and comorbid autism spectrum disorders were excluded. Risk of bias assessment was conducted using Newcastle Ottawa Scale (NOS) and where possible meta-analysis was conducted for studies classed as low risk of bias. Results: We included 63 studies. All studies were narratively synthesised, and 7 studies were meta-analysed on smoking and ADHD. The majority of studies (46 studies) investigated the association between smoking and ADHD. Studies which accounted for genetic effects indicate that the association between smoking and ADHD is unlikely to be causal. Studies on alcohol exposure in all the outcomes reported inconsistent findings and no strong conclusions on causality can be made. Studies on caffeine exposure were mostly limited to ADHD and these studies do not support a causal effect. Conclusions: There is no causal relationship between maternal smoking during pregnancy and attention-deficit hyperactivity (ADHD) in offspring. However, given that the majority of identified studies investigated the association between ADHD and smoking exposure, findings with alcohol and caffeine exposures and conduct disorder (CD) and oppositional-defiant disorder (ODD) need more research, especially using more genetically sensitive designs.

Experimental study of pre- and postnatal caffeine exposure and its observable effects on selected neurotranmitters and behavioural attributes at puberty

Caffeine is globally consumed as a stimulant in beverage drinks; it is also ingested in purified forms as power and tablets. Concerns have been raised about the potential consequences of intrauterine and early life caffeine exposure on brain health. This study modeled caffeine exposure during pregnancy and early postanal life until puberty, and the potential consequences. Caffeine powder was dissolved in distilled water. Thirty-two (n = 32) pregnant mice (Mus musculus) were divided into four groups- A, B, C and D. Group A animals served as a control, receiving placebo. Caffeine doses in mg/kg body weight were administered as follows: Group B, 10mg/kg; Group C, 50mg/kg; Group D, 120mg/kg. Prenatal caffeine exposure [phase I] lasted throughout pregnancy. Half the number of offspring were sacrificed at birth; the rest were recruited into phase II and the experiment continued till day 35, marking puberty. Brain samples were processed following sacrifice. γ-aminobutyric acid (GABA), acetylcholine (ACh), and serotonin (5Ht) neurotransmitters were assayed in homogenates to evaluate functional neurochemistry. Anxiety and memory as neurobehavioural attributes were observed using the elevated plus and Barnes’ mazes respectively. Continuous caffeine exposure produced positive effects on short and long-term memory parameters; the pattern interestingly was irregular and appeared more effective with the lowest experimental dose. Anxiety test results showed no attributable significant aberrations. Caffeine exposure persistently altered the neurochemistry of selected neurotransmitters including ACh and 5Ht, including when exposure lasted only during pregnancy. ACh significantly increased in group BC+ to 0.3475µgg-1 relative to control’s 0.2508µgg-1; pre-and continuous postnatal exposure in Group B increased 5Ht to 0.2203 µgg-1 and 0.2213 µgg-1 respectively relative to control’s 0.1863 µgg-1. From the current investigation, caffeine exposure in pregnancy had persistent effects on brain functional attributes including neurotransmitters activities, memory and anxiety. Caffeine in moderate doses affected memory positively but produced negative effects at the higher dosage including increased anxiety tendencies.