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 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.

Morphine withdrawal increases expression of GABA(A) receptor epsilon subunit mRNA in locus coeruleus neurons.

An increase in the activity of brain stem locus coeruleus noradrenergic neurons has been hypothesised to be a major factor accounting for opiate withdrawal symptoms. These neurons are under GABAergic inhibition. Their GABA(A) receptors have unique pharmacological properties, most likely due to the enriched expression of GABA(A) receptor subtypes containing novel epsilon and straight theta subunits. Using in situ hybridisation of cryostat sections, we now report a significant increase in the epsilon subunit mRNA expression after precipitation of opioid withdrawal by naloxone. Similar changes were detected in tyrosine hydroxylase mRNA expression. The results suggest increased formation of unique GABA(A) receptor subtype(s) in the locus coeruleus neurons during increased neuronal activity.

Morphine-induced dependence and sensitization are altered in mice deficient in AMPA-type glutamate receptor-A subunits.

AMPA-type glutamate receptors have been suggested to be involved in the neurobiological mechanisms of drug addiction. We have made use of two mouse lines, which both have modulated AMPA receptor responses. The first line is entirely deficient in glutamate receptor-A (GluR-A) subunits (A-/- knock-out line) and, in the second one, the Q582 residue of GluR-A subunits is replaced by an arginine residue (R/R mutants), which reduces the calcium permeability and channel conductance of the receptors containing this mutated subunit. Mice of both lines are healthy, but they show slightly increased locomotor activity. Acute morphine administration enhanced locomotor activity of the GluR-A-/- and GluR-A(R/R) mice, at least as much as that of their wild-type littermates. Only in the GluR-A-/- mice did we observe reduced tolerance development in tail-flick antinociception and less severe naloxone-precipitated withdrawal symptoms after treatment with increasing morphine doses, without differences in plasma and brain morphine levels when compared with wild type. Repeated daily morphine administration sensitized the locomotor activity responses in the GluR-A-/- and GluR-A(R/R) mice only when given in the measuring cages, whereas the wild-type mice showed slightly increased responses also when the repeated treatment was given in their home cages. Normal or even enhanced context-dependent sensitization was observed also with repeated amphetamine administration in the GluR-A subunit-deficient mice. The results indicate that AMPA receptors are involved in the acute and chronic effects of morphine, including context-independent sensitization, and that the GluR-A subunit itself is important for morphine tolerance and dependence.