Chronic corticotropin-releasing factor type 1 receptor antagonism with antalarmin regulates the dopaminergic system of Fawn-Hooded rats.
Corticotropin-releasing factor is a neuropeptide associated with the integration of physiological and behavioural responses to stress and also in the modulation of affective state and drug reward. The selective, centrally acting corticotropin-releasing factor type 1 receptor antagonist, antalarmin, is a potent anxiolytic and reduces volitional ethanol consumption in Fawn-Hooded rats. The efficacy of antalarmin to reduce ethanol consumption increased with time, suggestive of adaptation to reinforcement processes and goal-directed behaviour. The aim of the present study was to examine the effects of chronic antalarmin treatment on reward-related regions of Fawn-Hooded rat brain. Bi-daily antalarmin treatment (20 mg/kg, i.p.) for 10 days increased tyrosine hydroxylase messenger RNA expression throughout the ventral mesencephalon. Following chronic antalarmin the density of dopaminergic terminals within the basal ganglia and amygdaloid complex were reduced, as was dopamine transporter binding within the striatum. Receptor autoradiography indicated an up-regulation of dopamine D2, but no change in D1, binding in striatum, and Golgi-Cox analysis of striatal medium spiny neurones indicated that chronic antalarmin treatment increased spine density. Thus, chronic antalarmin treatment modulates dopaminergic pathways and implies that chronic treatment with drugs of this class may ultimately alter postsynaptic signaling mechanisms within the basal ganglia.
Department of Pharmacology, Monash University, Clayton, Victoria, Australia. Andrew.Lawrence@hfi.unimelb.edu.au
A J
AJ
Lawrence
C L
CL
Parish
F
F
Chen
D J
DJ
Lodge
E V
EV
Krstew
K
K
Card
D I
DI
Finkelstein
M K
MK
Horne
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D012054:Reinforcement, Psychology; D012201:Reward; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D000099052:CRF Receptor, Type 1
D011743:Pyrimidines; D011758:Pyrroles; D012333:RNA, Messenger; D018019:Receptors, Corticotropin-Releasing Hormone; D017447:Receptors, Dopamine D1; C103016:antalarmin; D000099052:CRF Receptor, Type 1; D003346:Corticotropin-Releasing Hormone; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine