mGluR5 knockout mice exhibit normal conditioned place-preference to cocaine

Metabotropic glutamate receptor 5 (mGluR5) null mutant (-/-) mice have been reported to totally lack the reinforcing or locomotor stimulating effects of cocaine. We tested mGluR5 -/- and +/+ mice for their locomotor and conditioned place- preference response to cocaine. Unlike the previous finding, here we show that compared to mGluR5 +/+ mice, -/- mice exhibit no difference in the locomotor response to low to moderate doses of cocaine (10 or 20 mg/kg). A high dose of cocaine (40 mg/kg) resulted in a blunted rather than absent locomotor response. We tested mGluR5 -/- and +/+ mice for conditioned place-preference to cocaine and found no group differences at a conditioning dose of 10 mg/kg, suggesting normal conditioned rewarding properties of cocaine. These results differ substantially from Chiamulera et al. (2001) and replicates Olsen et al., (2010), who found normal cocaine place-preference in mGluR5 -/- mice at 5 mg/kg. Our results indicate mGluR5 receptors exert a modulatory rather than necessary role in cocaine-induced locomotor stimulation and exert no effect on the conditioned rewarding effects of cocaine

Gulf War Syndrome: A role for organophosphate induced plasticity of locus coeruleus neurons

Gulf War syndrome is a chronic multi-symptom illness that has affected about a quarter of the deployed veterans of the 1991 Gulf War. Exposure to prolonged low-level organophosphate insecticides and other toxic chemicals is now thought to be responsible. Chlorpyrifos was one commonly used insecticide. The metabolite of chlorpyrifos, chlorpyrifos oxon, is a potent irreversible inhibitor of acetylcholinesterase, much like the nerve agent Sarin. To date, the target brain region(s) most susceptible to the neuroactive effects of chlorpyrifos oxon have yet to be identified. To address this we tested ability of chlorpyrifos oxon to influence neuronal excitability and induce lasting changes in the locus coeruleus, a brain region implicated in anxiety, substance use, attention and emotional response to stress. Here we used an ex vivo rodent model to identify a dramatic effect of chlorpyrifos oxon on locus coeruleus noradrenergic neuronal activity. Prolonged exposure to chlorpyrifos oxon caused acute inhibition and a lasting rebound excitatory state expressed after days of exposure and subsequent withdrawal. Our findings indicate that the locus coeruleus is a brain region vulnerable to chlorpyrifos oxon-induced neuroplastic changes possibly leading to the neurological symptoms affecting veterans of the Gulf War

Control over stress induces plasticity of individual prefrontal cortical neurons: A conductance-based neural simulation

Behavioral control over stressful stimuli induces resilience to future conditions when control is lacking. The medial prefrontal cortex(mPFC) is a critically important brain region required for plasticity of stress resilience. We found that control over stress induces plasticity of the intrinsic voltage-gated conductances of pyramidal neurons in the PFC. To gain insight into the underlying biophysical mechanisms of this plasticity we used the conductance- based neural simulation software tool, NEURON, to model the increase in membrane excitability associated with resilience to stress. A ball and stick multicompartment conductance-based model was used to realistically fit passive and active data traces from prototypical pyramidal neurons in neurons in rats with control over tail shock stress and those lacking control. The results indicate that the plasticity of membrane excitability associated with control over stress can be attributed to an increase in Na+ and Ca2+ T-type conductances and an increase in the leak conductance. Using simulated dendritic synaptic inputs we observed an increase in excitatory postsynaptic summation and amplification resulting in elevated action potential output. This realistic simulation suggests that control over stress enhances the output of the PFC and offers specific testable hypotheses to guide future electrophysiological mechanistic studies in animal models of resilience and vulnerability to stress

Nicotinic α7 acetylcholine receptor-mediated currents are not modulated by the tryptophan metabolite kynurenic acid in adult hippocampal interneurons

The  tryptophan  metabolite,  kynurenic  acid (KYNA),  is  classically  known  to  be  an antagonist  of ionotropic glutamate receptors. Within the last decade several reports have been published suggesting that KYNA also blocks nicotinic acetylcholine receptors (nAChRs) containing the α7 subunit (α7*). Most of these reports involve either indirect measurements of KYNA effects on α7 nAChR function, or are reports of KYNA effects in complicated in vivo systems.  However, a recent report investigating KYNA interactions with α7 nAChRs failed to detect an interaction using direct measurements of α7 nAChRs function.  Further, it showed that a KYNA blockade of α7 nAChR stimulated GABA release (an indirect measure of α7 nAChR function) was not due to KYNA blockade of the α7 nAChRs. The current study measured the direct effects of KYNA on α7-containing nAChRs expressed on interneurons in the hilar and CA1 stratum radiatum regions of the mouse hippocampus and on interneurons in the CA1 region of the rat hippocampus.  Here we show that KYNA does not block α7* nACHRs using direct patch-­clamp recording of α7 currents in adult brain slices

Sociability is decreased following deletion of the _trpc4_ gene

Shyness and social anxiety are predominant features of some psychiatric disorders including autism, schizophrenia, anxiety and depression. Understanding the cellular and molecular determinants of sociability may reveal therapeutic approaches to treat individuals with these disorders and improve their quality of life. Previous experiments from our laboratory have identified selective mRNA and protein expression of a nonselective cation channel known as the canonical transient receptor potential channel 4 (TRPC4s) in brain regions implicated in emotional regulation and anxiety. TRPC4 is highly expressed in the corticolimbic regions of the mammalian brain. We hypothesized that robust corticolimbic expression of TRPC4 may regulate the brain’s response to emotion and anxiety resulting in changes in social interaction. Here we test trpc4 gene knockout rats in a model of social anxiety/interaction. We found that the Trpc4 knockout animals spent significantly less time exploring a juvenile intruder rat compared to their wild-type counterparts and Sprague-Dawley (SD) rats. Furthermore, Trpc4 wild-type (Fisher 344) rats explored the juvenile significantly less than the SD rats. These findings indicate that the _trpc4_ gene plays a role in modulating cellular excitability in specific regions of the brain associated sociality and/or anxiety