Table 1.

Neurotoxic effects derived from in vivo exposure to neonicotinoid pesticides in rodents.

Species	Dose and Time Exposition	Objectives	Results	Reference
Wistar rats	IMI: 0.5, 2 or 8 mg/kg/day orally for 3 months	Evaluate the effects of different doses of IMI on learning and memory in infant and adult rats	-Treatment with 2 and 8 mg/kg induced a decrease in learning in infant rats and with the 8 mg/kg dose in adult rats -Increased M1 receptor expression at doses of 2 and 8 mg/kg in adult rats.	[11]
Wistar rats	IMI: 0.06, 0.8 or 2.25 mg/kg/day orally for 28 days	Investigate the effects of IMI on cholinesterase activities, oxidative stress biomarkers and primary DNA damage in blood and brain tissue	-There were no alterations in total cholinesterase, AChE or butyrylcholinesterase activity in the brain -There was no change in CAT and SOD activity, but there was an increase in GSH-Px activity -Presence of IMI in brain tissue of animals treated with the two highest doses -Dose-dependent neuronal DNA damage	[15]
Wistar rats	IMI: 20 mg/kg orally Single dose	Evaluate pharmacokinetic and pharmacodynamic responses after single oral exposure	-The maximum concentration of IMI and its metabolites in the brain was observed at 12 h after exposure -Inhibition of brain AChE at 6–48 h after administration	[59]
Wistar rats	IMI: 10 or 20 mg/kg/day orally for 60 days	Assess the alterations induced by IMI in the biochemical, histopathological and protein profile in plasma and brain	-Decreased brain AChE activity	[117]
Wistar rats	IMI: 1 mg/kg/day orally for 30 days	Assess the effects of chronic exposure to IMI on the induction of oxidative stress and inflammation	-Increased NO production -Improved transcription of iNOS, eNOS and nNOS mRNA -Increase in LPO -Increased activity of xanthine oxidase -Increased CAT activity and decreased GSH levels -Increased expression of TNF-α, IL-1β, IL-6, and IFN-γ, but decreased IL-12	[128]
Sprague-Dawley rats	IMI: 1 mg/kg/day orally for 60 days	Evaluate the effects of IMI on neurobehavioral performance, oxidative stress and the induction of apoptosis in the brain of adult or adolescent rats	-Less exploratory activity, deficit of sensorimotor functions and depression -Reduction of serotonin, GABA and dopamine -Increase in the levels of protein carbonyl, 8-hidroxyguanosine and MDA, but reduction in the total antioxidant capacity -Neural degeneration -Increased expression of GFAP -Increase in Bax levels and decrease in Bcl-2 levels	[70]
Sprague-Dawley rats	IMI: 0.5 or 1 mg/kg/day orally for 60 days	Study the effects of IMI on stress by assessing cortisone and catecholamine levels, with a focus on behavioral alterations	-Behavioral deficits, particularly at the highest dose of IMI	[71]
CD-1 mice	IMI: 0.5 mg/kg/day infusion through an osmotic pump From GD4 until PND21	Assess the effects of IMI after an intrauterine and early postnatal exposure	-The offspring of mothers treated with IMI showed elevated motor activity, improved social dominance, reduced depressive behavior and a decrease in social aggression -Low levels of IMI were detected in the brains of treated mothers and traces of the pesticide in the brains of some pups after exposure to weaning	[57]
KM mice	IMI: 5 or 20 mg/kg/day orally for 28 days	Examine the histopathological, biochemical and metabolic alterations induced by IMI in the hippocampus and liver	-Hippocampal damage in animals treated with the highest dose -Alteration in the metabolic profile in the hippocampus at both doses	[112]
Wistar rats	ACE: 10, 20 or 40 mg/kg/day orally for 28 days	Investigate the effect of ACE on spatial memory and the vulnerability of the hippocampal glutamatergic system	-Alteration of learning, consolidation and memory retrieval processes, especially at the highest doses -Dose-dependent increase of pesticide concentration in the hippocampus -Neuronal degeneration and apoptosis in the dentate gyrus -Reduced glutamate levels -Reduced expression of NR1, NR2A and NR2B genes after exposure to the intermediate dose of ACE	[60]
Wistar rats	ACE: 3.14 mg/kg/day orally for 6 months	Assess the effects of ACE on membrane integrity and mitochondrial potential	-Decreased GSH levels and GSH-Px and CAT activities in mitochondria -Increased GST and SOD activity in the mitochondrial matrix -Increased levels of MDA -Increased membrane permeability and mitochondrial swelling and significant decrease in mitochondrial respiration (O2 consumption)	[156]
A/J mice	ACE: 71 or 710 μg/g/day orally for 3 and 7 days	Investigate the accumulation of ACE and expression of nAChRs in different areas of the brain	-Treatment with the pesticide produced no effects on the histology or on the expression of CD34 -Presence of higher concentrations of ACE in the midbrain -Decreased expression of nAChRs, especially those of the β2 subtype, in various brain regions of animals treated for 7 days with the highest dose of ACE	[61]
ICR mice	ACE: 5 mg/kg/day orally. From GD6 until GD18	Evaluate the effects of repeated maternal exposure to ACE on the neurodevelopment of the offspring	-Cortical hypoplasia, decreased neurogenesis and abnormal neuronal distribution in the neocortex -Increased number of microglial cells immunoreactive for Iba1 and amoeboid-like microglial cells -Increased activation of the M1 microglial phenotype	[65]
ICR mice	ACE, IMI: 5 mg/kg/day orally From PND12 until PND26	Evaluate the effects of ACE and IMI exposure on neurogenesis and microglial profiles in the dentate gyrus of the developing hippocampus	-Exposure to the two pesticides reduced neurogenesis in the hippocampal dentate gyrus -Both ACE and IMI increased the number of activated amoeboid and M1-type microglial cells.	[66]
Sprague-Dawley rats	CLO: 3.5 mM by local administration through a microdialysis probe	Determine the neurochemical effects and mechanisms of action of CLO on striatal dopamine release	-Increase in the in vivo release of striatal dopamine in a concentration-dependent manner -The increases were dependent on the presence of Ca+2 in the extracellular medium, the depolarization of the membrane, the vesicular storage of dopamine and independent of the dopamine transporter	[134]
Sprague-Dawley rats	CLO: 150 or 300 μmol by local administration through a microdialysis probe	Evaluate the role of some subtypes of nAChRs and mAChRs in CLO-induced striatal dopamine release	-Administration of selective α4β2 or α7-receptor antagonists decreased CLO-induced dopamine release in vivo -Pretreatment with a β2-subunit antagonist did not affect dopamine release -Pretreatment with an antagonist of mAChR blocked CLO-induced increases in extracellular dopamine levels	[135]
CD-1 mice	CLO: 0.003%, 0.006% or 0.012% orally. From 5 weeks of age of the F0 generation to 11 weeks of age of the F1 generation	Assess the effects of CLO exposure on reproduction and behavior over different generations	-Appearance of various adverse effects on neurobehavioral parameters -Adverse effects on exploratory behavior in mice of generations F0 and F1 -Although the pesticide produced adverse effects in males and females, these effects differed according to sex	[68]
CD-1 mice	CLO: 0.002%, 0.006% or 0.018% orally. Gestation and lactation periods	Assess the neurobehavioral effects of maternal exposure to CLO	-Occurrence of several adverse effects on offspring behavior -Adverse effects on exploratory and spontaneous behavior of the offspring with the intermediate dose of CLO -Although the pesticide produced adverse effects in males and females, these effects differed according to sex	[69]
C57BL/6J mice	CLO: 5 mg/kg orally Single dose	Investigate the role of aging in CLO-induced behavioral effects	-Decreased locomotor activity in aged mice, but not in adult mice -Higher concentrations of CLO and its metabolites in the brains of aged mice than in adult mice	[58]
C57BL/6N mice	CLO: 5 or 50 mg/kg orally Single dose	Evaluate the neurobehavioral effects of CLO and explore the brain regions targeted by neonicotinoids in mammals	-Induction of audible vocalizations (4–16 kHz) for highest dose -Anxiety-like behavior	[78]
C57BL/6N mice	DIN: 100, 500 or 2500 mg/kg/day orally for 6 weeks	Analyze the biochemical and behavioral effects of DIN exposure during the peripubertal period on the nigrostriatal pathway	-Increased locomotor activity in a dose-dependent manner, but no change in anxiety-like behavior -Increased TH expression in the substantia nigra.	[74]
C57BL/6NCrSlc mice	DIN: 100, 500 or 2500 mg/kg/day orally for 5 weeks	Investigate the relationship between subchronic DIN exposure and a depression-related phenotype	-Antidepressant activity was observed in the tail suspension test -No decrease in the number of serotonergic cells was observed	[87]

Abbreviations. IMI: imidacloprid; MDA: malondialdehyde; GFAP: glial fibrillary acidic protein; GD: gestational day; PND: postnatal day; NO: nitric oxide; iNOS: inducible nitric oxide synthase; eNOS: endothelial nitric oxide synthase; nNOS: neuronal nitric oxide synthase; LPO: lipid peroxidation; CAT: catalase; GSH: glutathione; TNF-α: tumor necrosis factor alpha; IL-1β: interleukin 1beta; IL-6: interleukin-6; IFN-γ: interferon gamma; IL-12: interleukin-12; CLO: clothianidin; nAChR: nicotinic acetylcholine receptor; mAChR: muscarinic acetylcholine receptor; ACE: acetamiprid; GSH-Px: glutathione peroxidase; GST: glutathione S-transferase; SOD: superoxide dismutase; Iba1: ionized calcium-binding adapter molecule 1; AChE: acetylcholinesterase; DIN: dinotefuran; CD34: cluster of differentiation 34; TH: tyrosine hydroxylase.