Bicuculline microinjections into the ventral tegmental area of the rat: alteration of self-stimulation thresholds and of cytochrome oxidase activity in the brain.
Abuse of drugs that potentiate GABAergic neurotransmission, namely benzodiazepines, is difficult to understand because this potentiation should elicit, among other effects, a decrease in activity within the mesolimbic system. Abuse of benzodiazepines is difficult to understand since the opposite, namely an increase in mesolimbic activity, has been implicated in drug abuse as well as in the rewarding effect of direct mesolimbic stimulation. In order to evaluate how the activity of the mesolimbic system depends on mesolimbic GABAergic influence, a GABAA receptor antagonist, bicuculline methiodide, was unilaterally injected into the ventral tegmental area and its effect on self-stimulation thresholds derived from stimulations applied to the same area was evaluated. Microinjection of 15, 20 and 30 ng increased the stimulation threshold. This decrease in stimulation efficiency lasted no more than 15 min after which baseline levels were obtained. Such a decrease is paradoxical considering that the manipulation should have released the ventral tegmentum from a tonic inhibitory influence. The metabolic consequences of repeated injections of 30 ng bicuculline were furthermore evaluated by cytochrome oxidase histochemistry. The staining was found to be weak around the injection site and dense in the ipsilateral nucleus accumbens. Release of a tonic GABAergic inhibition added to some cytotoxic damage probably resulted in an increased metabolic activity of this system. The presently reported paradoxical response of the ventral tegmentum and mesolimbic system to a GABAergic challenge may account for the paradoxical relationship between some behavioral properties of the mesolimbic system and GABAergic drugs.
Sandner
G
G
U405 INSERM, Département de Psychiatrie, Hôpitaux Universitaires de Strasbourg, France. sandner@neurochem.u-strasbg.fr
Bielajew
C
C
Fouriezos
G
G
D000818:Animals; D001640:Bicuculline / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D003216:Conditioning, Operant / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D003576:Electron Transport Complex IV / Q000378:metabolism*; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D058787:GABA-A Receptor Antagonists; D006651:Histocytochemistry; D008297:Male; D008845:Microinjections; D051381:Rats; D012653:Self Stimulation / Q000187:drug effects* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000502:physiology*
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D003576:Electron Transport Complex IV; D001640:Bicuculline