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Rationale: Lead-exposure during developmental periods may alter reinforcing patterns of drugs of abuse in adulthood. Anxiety related mechanisms may also influence drug intake. Interactions between the two altering factors may exist. Objectives: The present study examined the effects of perinatal lead-exposure on cocaine self-administration after a GABAA antagonist pre-treatment. Methods: Female rats were exposed to a regimen of 16 mg lead daily for 30 days prior to breeding with un-exposed males. This continued throughout gestation and lactation until postnatal day (PND) 21. On PND 63, animals were implanted with indwelling jugular catheters. After a 7 day recovery period, animals were trained to self-administer 0.50 mg/kg cocaine intravenously [IV]. After stable responding had been established, testing procedures began using combinations of 0.03 and 0.06 mg/kg cocaine [IV] and 0.00, 0.50, 1.00 and 2.00 mg/kg bicuculline (a GABAA antagonist) intraperitoneal [IP]. Results: Bicuculline pre-treatment caused directionally opposite effects in both treatment groups (Group 0-Lead and Group 16-Lead) at the 0.06 mg/kg cocaine dose. Group 0-Lead animals showed an increase in self-administration, while Group 16-Lead animals showed a decrease in responding on the active (cocaine) lever. Results at the 0.03 mg/kg cocaine dose showed no discernable pattern. Group 0-Lead animals decreased in active lever responding at the 2.00 mg/kg bicuculline dose. Group 16-Lead animals showed no differences in responding at any dose of bicuculline. Conclusions: These data further suggest the influential role of GABA in mediating cocaine reward and the ability of developmental lead-exposure to alter mechanisms mediating drug responsiveness even after exposure has terminated.

Rationale: Lead-exposure during developmental periods may alter reinforcing patterns of drugs of abuse in adulthood. Anxiety related mechanisms may also influence drug intake. Interactions between the two altering factors may exist. Objectives: The present study examined the effects of perinatal lead-exposure on cocaine self-administration after a GABAA antagonist pre-treatment. Methods: Female rats were exposed to a regimen of 16 mg lead daily for 30 days prior to breeding with un-exposed males. This continued throughout gestation and lactation until postnatal day (PND) 21. On PND 63, animals were implanted with indwelling jugular catheters. After a 7 day recovery period, animals were trained to self-administer 0.50 mg/kg cocaine intravenously [IV]. After stable responding had been established, testing procedures began using combinations of 0.03 and 0.06 mg/kg cocaine [IV] and 0.00, 0.50, 1.00 and 2.00 mg/kg bicuculline (a GABAA antagonist) intraperitoneal [IP]. Results: Bicuculline pre-treatment caused directionally opposite effects in both treatment groups (Group 0-Lead and Group 16-Lead) at the 0.06 mg/kg cocaine dose. Group 0-Lead animals showed an increase in self-administration, while Group 16-Lead animals showed a decrease in responding on the active (cocaine) lever. Results at the 0.03 mg/kg cocaine dose showed no discernable pattern. Group 0-Lead animals decreased in active lever responding at the 2.00 mg/kg bicuculline dose. Group 16-Lead animals showed no differences in responding at any dose of bicuculline. Conclusions: These data further suggest the influential role of GABA in mediating cocaine reward and the ability of developmental lead-exposure to alter mechanisms mediating drug responsiveness even after exposure has terminated.

Aufgabe der elektrophysiologischen Studie zur Charakterisierung der neuronalen hypothalamischen Plastizität beim Haushuhn war es, den Einfluss des Alters sowie GABAerger Substanzen auf die Feuerrate und die Temperatursensitivität (thermischer Koeffizient: TC) von Hypothalamusneuronen mittels extrazellulärer Ableitungen in Hirnschnitten zu untersuchen. Im Vergleich zu adulten Vögeln und Säugetieren wurde bei juvenilen Hühnern eine hohe neuronale Kältesensitivität nachgewiesen, die offensichtlich eine spezifische Eigenschaft juveniler Vögel ist. Die Ontogenese der neuronalen hypothalamischen Thermosensitivität ist deutlich artspezifisch. Einige Neurone wiesen eine inherente Kältesensitivität auf. Eine mögliche zentrale Rolle kältesensitiver Neurone im Rahmen der Thermoregulation juveniler Hühner wurde postuliert. Muscimol und Baclofen hemmen signifikant die Feuerrate der Hypothalamusneurone, unabhängig von der jeweiligen Thermosensitivität. Demgegenüber bewirken Bicucullin und CGP35348 einem Anstieg der Feuerrate. Nur bei kältesensitiven Neuronen wurde der TC signifikant durch GABAB-Rezeptor-Liganden verändert (signifikant erhöht durch Baclofen und durch CGP35348 gehemmt). Der Effekt von Muscimol und Baclofen auf Feuerrate und TC wurde durch Co-Perfusion mit einer 10-fach höheren Konzentration der entsprechenden Antagonisten Bicucullin und CGP35348 aufgehoben. Der wesentliche GABAerge Einfluss auf thermosensitive und –insensitive Hypothalamusneurone ist mit dem bei Säugetieren nachgewiesenen vergleichbar. Der einzige Unterschied betrifft die GABAB-Rezeptor vermittelte Änderung des TC. Beim Hühnerküken betraf dies die kältesensitiven und beim Säugetier die wärmesensitiven Neurone. Der grundlegende Mechanismus der GABAergen Beeinflussung thermosensitiver und –insensitiver Neurone scheint einen älteren evolutionären Ursprung zu haben. Eine funktionelle Rolle GABAerger Substanzen im Rahmen der zentralen Kontrolle der Körpertemperatur beim Vogel ist möglich. / In the present electrophysiological studies, characterization of neuronal hypothalamic plasticity in the chicken aims to investigate the influence of age during development by extracellular recordings. High neuronal cold sensitivity has been found in juvenile chicken in contrast to adult mammals and birds. High hypothalamic cold sensitivity seems to be a specific characteristic feature in juvenile birds. Between species a species specificity of the early development of neuronal hypothalamic thermosensitivity could be clearly demonstrated. Existence of inherent nature to a certain degree suggests a possible thermoregulatory role of cold-sensitive neurons in chicken. The effects of the GABAergic substances on neuronal tonic activity (firing rate) and temperature sensitivity (temperature coefficient) in hypothalamic neurons have been examined. Muscimol and baclofen in equimolar concentrations significantly inhibited tonic activity, regardless of their type of thermosensitivity. In contrast bicuculline and CGP 35348 increased firing rate. Temperature coefficient was significantly changed by ligands of GABAB receptors, restricted to cold-sensitive neurons. The TC was significantly increased by baclofen and significantly decreased by CGP 35348. Effects of muscimol and baclofen on firing rate and TC were prevented by co-perfusion of appropriate antagonists bicuculline and CGP 35348, respectively in tenfold higher concentration. Thus the main effects of GABA in chicken are similar with that described in mammals. The only difference is in respect of the GABAB receptors mediated change restricted to cold-sensitive neurons in chicken but in mammals only seen in warm-sensitive neurons. However, the results indicate that the fundamental mechanism of GABAergic influence in chicken are conserved during evolution. The response of hypothalamic neurons to temperature changes suggest a possible functional role of GABAergic substances in the control of body temperature in birds.