GABA(A) alpha 1 subunit knock-out mice do not show a hyperlocomotor response following amphetamine or cocaine treatment.
The GABA(A) receptor system provides the major inhibitory control in the CNS, with the alpha 1 beta 2 gamma 2 subunit combination being the most abundant and widely distributed form of the receptor. The alpha1 subunit knock-out (alpha1 KO) mice had a surprisingly mild overt phenotype, despite having lost approximately 60% of all GABA(A) receptors. The alpha1 KO mice had normal spontaneous locomotor activity, but were more sensitive to the sedating/ataxic effects of diazepam than wildtype (WT) mice. Pharmacological modulation of dopamine and N-methyl-D-aspartate (NMDA) receptors also produced altered responses in alpha1 KO mice compared with WT mice. As expected, the NMDA receptor antagonist MK801, amphetamine and cocaine increased locomotor activity in WT mice. Although MK801 increased locomotor activity in alpha1 KO mice, amphetamine and cocaine induced stereotypy not hyperlocomotion. Binding studies showed no gross changes in the total number of D1, D2 or NMDA receptors. Furthermore, pre-pulse inhibition of acoustic startle and the effects of cocaine in conditioned place preference were similar in both alpha1 KO and WT mice, indicating selective rather that global changes in response to dopaminergic agents. These data demonstrate subtle changes in behaviours mediated by neurotransmitters other than GABA in alpha1 KO mice and suggest that compensation may have occurred beyond the GABAergic system.
Reynolds
D S
DS
Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK. david_reynolds@merck.com
O'Meara
G F
GF
Newman
R J
RJ
Bromidge
F A
FA
Atack
J R
JR
Whiting
P J
PJ
Rosahl
T W
TW
Dawson
G R
GR
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001552:Benzazepines / Q000493:pharmacokinetics; D001667:Binding, Competitive / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000493:pharmacokinetics; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D018691:Excitatory Amino Acid Antagonists / Q000493:pharmacokinetics; D018757:GABA Modulators / Q000494:pharmacology; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects*; D021122:Protein Subunits / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects / Q000502:physiology; D013134:Spiperone / Q000493:pharmacokinetics
D001552:Benzazepines; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D018691:Excitatory Amino Acid Antagonists; D018757:GABA Modulators; D021122:Protein Subunits; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D013134:Spiperone; D016291:Dizocilpine Maleate; D000661:Amphetamine; D003042:Cocaine; D003975:Diazepam