Environmental pharmacology-Dosing the environment: IUPHAR review 36.

Pesticide action is predominantly measured as a toxicological outcome, with pharmacological impact of sublethal doses on bystander species left largely undocumented. Likewise, chronic exposure, which often results in responses different from acute administration, has also been understudied. In this article, we propose the application of standard pharmacological principles, already used to establish safe clinical dosing regimens in humans, to the 'dosing of the environment'.

Neuronal networks provide rapid neuroprotection against spreading toxicity.

Acute secondary neuronal cell death, as seen in neurodegenerative disease, cerebral ischemia (stroke) and traumatic brain injury (TBI), drives spreading neurotoxicity into surrounding, undamaged, brain areas. This spreading toxicity occurs via two mechanisms, synaptic toxicity through hyperactivity, and excitotoxicity following the accumulation of extracellular glutamate. To date, there are no fast-acting therapeutic tools capable of terminating secondary spreading toxicity within a time frame relevant to the emergency treatment of stroke or TBI patients.

Neonicotinoids target distinct nicotinic acetylcholine receptors and neurons, leading to differential risks to bumblebees.

There is growing concern over the risk to bee populations from neonicotinoid insecticides and the long-term consequences of reduced numbers of insect pollinators to essential ecosystem services and food security. Our knowledge of the risk of neonicotinoids to bees is based on studies of imidacloprid and thiamethoxam and these findings are extrapolated to clothianidin based on its higher potency at nicotinic acetylcholine receptors. This study addresses the specificity and consequences of all three neonicotinoids to determine their relative risk to bumblebees at field-relevant levels (2.

Chronic exposure to neonicotinoids increases neuronal vulnerability to mitochondrial dysfunction in the bumblebee (Bombus terrestris).

The global decline in the abundance and diversity of insect pollinators could result from habitat loss, disease, and pesticide exposure. The contribution of the neonicotinoid insecticides (e.g.

5-Hydroxytryptamine (5-HT) cellular sequestration during chronic exposure delays 5-HT3 receptor resensitization due to its subsequent release.

The serotonergic synapse is dynamically regulated by serotonin (5-hydroxytryptamine (5-HT)) with elevated levels leading to the down-regulation of the serotonin transporter and a variety of 5-HT receptors, including the 5-HT type-3 (5-HT3) receptors. We report that recombinantly expressed 5-HT3 receptor binding sites are reduced by chronic exposure to 5-HT (IC50 of 154.0 ± 45.

The risk of insecticides to pollinating insects.

A key new risk to our pollinators has been identified as exposure to neonicotinoid insecticides. These discoveries have refuelled the debate over whether or not the neonicotinoid insecticides should be banned and conflicting evidence is used in this battle. However, the issue is not black or white, but gray.

Prolonged inhibition of 5-HT₃ receptors by palonosetron results from surface receptor inhibition rather than inducing receptor internalization.

Background And Purpose: The 5-HT₃ receptor antagonist palonosetron is an important treatment for emesis and nausea during cancer therapy. Its clinical efficacy may result from its unique binding and clearance characteristics and receptor down-regulation mechanisms. We investigated the mechanisms by which palonosetron exerts its long-term inhibition of 5-HT₃ receptors for a better understanding of its clinical efficacy.

Cholinergic pesticides cause mushroom body neuronal inactivation in honeybees.

Pesticides that target cholinergic neurotransmission are highly effective, but their use has been implicated in insect pollinator population decline. Honeybees are exposed to two widely used classes of cholinergic pesticide: neonicotinoids (nicotinic receptor agonists) and organophosphate miticides (acetylcholinesterase inhibitors). Although sublethal levels of neonicotinoids are known to disrupt honeybee learning and behaviour, the neurophysiological basis of these effects has not been shown.

Exposure to acetylcholinesterase inhibitors alters the physiology and motor function of honeybees.

Cholinergic signaling is fundamental to neuromuscular function in most organisms. Sub-lethal doses of neurotoxic pesticides that target cholinergic signaling can alter the behavior of insects in subtle ways; their influence on non-target organisms may not be readily apparent in simple mortality studies. Beneficial arthropods such as honeybees perform sophisticated behavioral sequences during foraging that, if influenced by pesticides, could impair foraging success and reduce colony health.

The microsporidian parasites Nosema ceranae and Nosema apis are widespread in honeybee (Apis mellifera) colonies across Scotland.

Nosema ceranae is spreading into areas where Nosema apis already exists. N. ceranae has been reported to cause an asymptomatic infection that may lead, ultimately, to colony collapse.

High-affinity fluorescent ligands for the 5-HT(3) receptor.

The synthesis, photophysical and biological characterization of a small library of fluorescent 5-HT(3) receptor ligands is described. Several of these novel granisetron conjugates have high quantum yields and show high affinity for the human 5-HT(3)AR.

RIC-3 exclusively enhances the surface expression of human homomeric 5-hydroxytryptamine type 3A (5-HT3A) receptors despite direct interactions with 5-HT3A, -C, -D, and -E subunits.

Although five 5-hydroxytryptamine type 3 (5-HT3) subunits (A-E) have been cloned, knowledge on the regulation of their assembly is limited. RIC-3 has been identified as a chaperone specific for the pentameric ligand-gated nicotinic acetylcholine and 5-HT(3) receptors. Therefore, we examined the impact of RIC-3 on differently composed 5-HT(3) receptors with the focus on 5-HT3C, -D, and -E subunits.

Leptin regulates AMPA receptor trafficking via PTEN inhibition.

The hormone leptin can cross the blood-brain barrier and influences numerous brain functions (Harvey, 2007). Indeed, recent studies have demonstrated that leptin regulates activity-dependent synaptic plasticity in the CA1 region of the hippocampus (Shanley et al., 2001; Li et al.

Rapid dendritic and axonal responses to neuronal insults.

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system playing critical roles in basal synaptic transmission and mechanisms of learning and memory. Under normal conditions, glutamate is sequestered within synaptic vesicles (approximately 100 mM) with extracellular glutamate concentrations being limited (<1 microM), via retrieval by plasma-membrane transporters on neuronal and glial cells. In the case of central nervous system trauma, stroke, epilepsy, and in certain neurodegenerative diseases, increased concentrations of extracellular glutamate (by vesicular release, cell lysis and/or decreased glutamate transporter uptake/reversal) stimulate the overactivation of local ionotropic glutamate receptors that trigger neuronal cell death (excitotoxicity).

The promiscuous role of the epsilon subunit in GABAA receptor biogenesis.

The formation of alpha1beta2gamma2epsilon receptors suggests that the epsilon subunit does not displace the single gamma2 subunit in alpha1beta2gamma2 receptors. Thus, epsilon must replace alpha and/or beta subunit(s) if the pentameric receptor structure is to be preserved. To assess the potential for which subunit is replaced in alphabetaepsilon and alphabetagammaepsilon receptors we analyzed the assembly and functional expression of the epsilon subunit with respect to alpha1, beta2 and gamma2 subunits.

Dendritic and mitochondrial changes during glutamate excitotoxicity.

Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system (CNS) and is normally stored intracellularly. However, in instances of CNS injury or disease, increased concentrations of extracellular glutamate can result in the over-activation of ionotropic glutamate receptors and trigger neuronal cell death (termed excitotoxicity). Two early hallmarks of such neuronal toxicity are mitochondrial dysfunction (depolarisation, decreased ATP synthesis, structural collapse and potential opening of the permeability transition pore) and the formation of focal swellings (also termed varicosities/beads) along the length of the dendrites.

Leptin promotes rapid dynamic changes in hippocampal dendritic morphology.

Recent studies have implicated the hormone leptin in synaptic plasticity associated with neuronal development and learning and memory. Indeed, leptin facilitates hippocampal long-term potentiation and leptin-insensitive rodents display impaired hippocampal synaptic plasticity suggesting a role for endogenous leptin. Structural changes are also thought to underlie activity-dependent synaptic plasticity and this may be regulated by specific growth factors.

Mitochondrial dysfunction and dendritic beading during neuronal toxicity.

Mitochondrial dysfunction (depolarization and structural collapse), cytosolic ATP depletion, and neuritic beading are early hallmarks of neuronal toxicity induced in a variety of pathological conditions. We show that, following global exposure to glutamate, mitochondrial changes are spatially and temporally coincident with dendritic bead formation. During oxygen-glucose deprivation, mitochondrial depolarization precedes mitochondrial collapse, which in turn is followed by dendritic beading.

Differential subcellular localization of RIC-3 isoforms and their role in determining 5-HT3 receptor composition.

RIC-3 has been identified as a chaperone molecule involved in promoting the functional expression of nicotinic acetylcholine and 5-HT(3) receptors in mammalian cells. In this study, we examined the effects of RIC-3a (isoform a) and a truncated isoform (isoform d) on RIC-3 localization, mobility, and aggregation and its effect on 5-HT3 receptor composition in mammalian cells. Human RIC-3a possesses an amino-terminal signal sequence that targets it to the endoplasmic reticulum where it is distributed within the reticular network, often forming large diffuse "slicks" and bright "halo" structures.

Naturally occurring variations in the human 5-HT3A gene profoundly impact 5-HT3 receptor function and expression.

Background: The serotonin [5-hydroxytryptamine (5-HT)]-gated ion channel 5-HT3 is involved in the mediation of postoperative and radiotherapy/chemotherapy-induced nausea/emesis and in irritable bowel syndrome. It has also been suggested to play a role in various psychiatric diseases. Five naturally occurring single nucleotide polymorphisms leading to amino acid changes have been identified in the human 5-HT3A gene.

Generation and functional characterization of fluorescent, N-terminally tagged CB1 receptor chimeras for live-cell imaging.

N-terminally tagged CB1 receptor fusion proteins, incorporating enhanced green fluorescent protein (GFP) or super-ecliptic pHluorin (SEP), were generated to study CB1 receptor trafficking and cell surface receptor expression in live COS7 and HEK293 cells and hippocampal neurons. An artificial signal sequence (SS) was required for efficient surface expression of CB1 receptor chimeras, which behaved like wild-type CB1 receptors in functional assays. Treatment with cannabinoid ligands led to a rapid down-regulation of SS-GFP-CB1 from the plasma membrane in COS7 and HEK293 cells, associated with trafficking into cytosolic vesicles.

An essential role for constitutive endocytosis, but not activity, in the axonal targeting of the CB1 cannabinoid receptor.

In central neurons, the cell-surface distribution of cannabinoid receptor subtype-1 (CB(1)) is highly polarized toward axons and is associated with synaptic terminals, in which it is well-positioned to modulate neurotransmitter release. It has been suggested that high levels of constitutive activity mediate CB(1) receptor axonal targeting, leading to domain-specific endocytosis. We have investigated further the mechanisms that underlie CB(1) receptor axonal polarization in hippocampal neurons and found that constitutive activity is not an essential requirement for this process.