Dopaminergic-GABAergic interplay and alcohol binge drinking

© 2019 Elsevier Ltd The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R −/− ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R −/− ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R −/− ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R −/− compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R −/− , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc

Numerical simulation of a turbulent oscillatory pipe flow

The importance of AMPA-type glutamate receptors has been demonstrated in neuronal plasticity and in adaptation to drugs of abuse. We studied the involvement of AMPA receptors in social interaction and anxiety and found that in several paradigms of agonistic behavior naïve male mice deficient for the GluR-A subunit- containing AMPA receptors are less aggressive than wild-type littermates. GluR-A deficient mice and wild-type littermates exhibited similar basic behavior and reflexes as monitored by observational Irwin's test, but they tended to be less anxious in elevated plus-maze and light-dark tests. Maternal aggression or male-female encounters were not affected which suggests that male hormones are involved in the expression of suppressed aggressiveness. However, testosterone levels and brain monoamines can be excluded and found to be similar between GluR-A deficient and wild-type littermates. The reduced AMPA receptor levels caused by the lack of the GluR-A subunit, and measured by a 30% reduction in hippocampal [3H]-S-AMPA binding, seem to be the reason for suppressed male aggressiveness. When we analyzed mice with reduced number of functional AMPA receptors mediated by the genomic introduced GluR-A(Q582R) channel mutation, we observed again male-specific suppressed aggression, providing additional evidence for GluR-A subunit-containing AMPA receptor involvement in aggression

Reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient mice

The importance of AMPA-type glutamate receptors has been demonstrated in neuronal plasticity and in adaptation to drugs of abuse. We studied the involvement of AMPA receptors in social interaction and anxiety and found that in several paradigms of agonistic behavior naive male mice deficient for the GluR-A subunit- containing AMPA receptors are less aggressive than wild-type littermates. GluR-A deficient mice and wild-type littermates exhibited similar basic behavior and reflexes as monitored by observational Irwin‘s test, but they tended to be less anxious in elevated plus-maze and light-dark tests. Maternal aggression or male-female encounters were not affected which suggests that male hormones are involved in the expression of suppressed aggressiveness. However, testosterone levels and brain monoamines can be excluded and found to be similar between GluR-A deficient and wild-type littermates. The reduced AMPA receptor levels caused by the lack of the GluR-A subunit, and measured by a 3 0 reduction in hippocampal [3H]-S-AMPA binding, seem to be the reason for suppressed male aggressiveness. When we analyzed mice with reduced number of functional AMPA receptors mediated by the genomic introduced GluR-A(Q582R) channel mutation, we observed again male-specific suppressed aggression, providing additional evidence for GluR-A subunit-containing AMPA receptor involvement in aggression

Basal Forebrain and Brainstem Cholinergic Neurons Differentially Impact Amygdala Circuits and Learning-Related Behavior

The central cholinergic system and the amygdala are well-known to be important for motivation and mnemonic processes. Different cholinergic populations innervate the amygdala but it is unclear how these projections impact amygdala activity and behavior. Using optogenetic circuit-mapping strategies in ChAT-cre mice we demonstrate that amygdala-projecting basal forebrain and brainstem ChAT-containing neurons can differentially affect amygdala circuits and behavior. Photoactivating ChAT terminals in vitro revealed the underlying synaptic impact of brainstem inputs to the central lateral division to be excitatory, mediated via the synergistic glutamatergic activation of AMPA and NMDA receptors. In contrast, stimulating NBm-ChAT inputs to the basal nucleus resulted in endogenous ACh release resulting in muscarinic receptor dependent biphasic inhibition-excitation responses onto principal neurons. Such a biphasic inhibitory-excitatory response profile is a physiological hallmark of neural oscillations and could thus form the basis of acetylcholine-mediated rhythmicity in amygdala networks. Consistent with this, in vivo NBm activation strengthened amygdala basal nucleus theta and gamma frequency rhythmicity, both of which continued for seconds after stimulation. Stimulation-evoked and ongoing increases in gamma and theta power were dependent on local nicotinic or muscarinic receptor activation, respectively. Activation of brainstem ChAT-containing neurons however resulted in a transient increase in central lateral amygdala network synchrony that was independent of cholinergic receptors. In addition, driving these respective inputs in behaving animals induced opposing appetitive and defensive learning-related behavioral changes. Since learning and memory is supported by both cellular and network-level processes in central cholinergic and amygdala networks, these results provide a route by which distinct cholinergic inputs can convey salient information to the amygdala and promote associative biophysical changes that underlie amygdala-dependent memories.This work was supported by the Royal Society, The Wellcome Trust (JAS), the Sigrid Juselius Foundation (TA), and by a Herchel Smith Fellowship (YAH)

Excessive novelty-induced c-Fos expression and altered neurogenesis in the hippocampus of GluA1 knockout mice

a−Amino−3−hydroxy−5−methyl−4−isoxazolepropionic acid (AMPA) receptor GluA1 subunit−deficient (GluA1) / )) mice display noveltyinduced hyperactivity, cognitive and social defects and may model psychiatric disorders, such as schizophrenia and depression / mania. We used c−Fos expression in GluA1) / ) mice to identify brain regions responsible for novelty−induced hyperlocomotion. Exposure to a novel cage for 2 h significantly increased c−Fos expression in many brain regions in both wild−type and knockout mice. Interestingly, the clearest genotype effect was observed in the hippocampus and its main input region, the entorhinal cortex, where the novelty−induced c−Fos expression was more strongly enhanced in GluA1) / ) mice. Their novelty−induced hyperlocomotion partly depended on the activity of AMPA receptors, as it was diminished by the AMPA receptor antagonist 2,3−dioxo−6−nitro−1,2,3,4− tetrahydrobenzo[f]quinoxaline−7−sulphonamide (NBQX) and unaffected by the AMPA receptor potentiator 2,3−dihydro−1,4−benzodioxin− 6−yl−1−piperidinylmethanone (CX546). The hyperlocomotion of GluA1) / ) mice was normalised to the level of wild−type mice within 5−6 h, after which their locomotion followed normal circadian rhythm and was not affected by acute or chronic treatments with the selective serotonin reuptake inhibitor escitalopram. We propose that hippocampal dysfunction, as evidenced by the excessive c− Fos response to novelty, is the major contributor to novelty−induced hyperlocomotion in GluA1) / ) mice. Hippocampal dysfunction was also indicated by changes in proliferation and survival of adult−born dentate gyrus cells in the knockout mice. These results suggest focusing on the functions of hippocampal formation, such as novelty detection, when using the GluA1) / ) mouse line as a model for neuropsychiatric and cognitive disorder

Dopaminergic-GABAergic interplay and alcohol binge drinking

The dopamine D-3 receptor (D3R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D3R increases GABA(A) alpha 6 subunit in the ventral striatum. Here we tested the hypothesis that D3R-dependent changes in GABA(A) alpha 6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs.We performed in vivo and ex vivo experiments in D3R knockout (D3R-/-) mice and wild type littermates (D3R+/+). Ro 15-4513, a high affinity alpha 6-GABA(A) ligand was used to study alpha 6 activity.At baseline, NAc alpha 6 expression was negligible in D3R+/+, whereas it was robust in D3R-/-; other relevant GABA(A) subunits were not changed. In situ hybridization and qPCR confirmed alpha 6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D3R+/+, but increased it in D3R-/-; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective alpha 6-GABA(A) antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D3R-/- compared to D3R+/+; Ro 15-4513 reduced the peak amplitude in the NAc of D3R-/-, but not in D3R+/+.We conclude that D3R-dependent enhanced expression of alpha 6 GABA(A) subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc