Reproductive success in the male rat depends on the ability to recognize appropriate sexual cues, motivation to respond to those cues, and coordination of the necessary motor sequences required to optimize sexual performance and an ejaculatory response. Early maternal environment is important in the normal development of copulatory behavior. Manipulation of this early social stimulation results in alterations in male sexual behavior and in the functioning of mediating endocrine and neurotransmitter systems. The present series of studies were designed to explore the effects of early life maternal deprivation and replacement maternal licking-like stimulation on the development of male rat sexual behavior and the neurophysiological mechanisms which mediate sexual performance with specific attention to the dopamine (DA) and androgen systems. Long-Evans male rats were reared with or without their mothers through the use of the artificial rearing (AR) paradigm. Half of the AR rats were provided with licking-like stimulation, consisting of periodic stroking with a paintbrush. In study 1, AR and maternally-reared (MR) rats were tested in adulthood for sexual behavior. Neuronal activation in response to copulation was assessed using an antibody against the protein product of the immediate early gene c-fos in brain regions that sub-serve sexual behavior. Study 2 explored whether sexual behavioral deficits observed in AR males can be reversed by later sexual experience. In this study, animals were sacrificed following a ninth copulatory trial and Fos immunoreactivity, androgen and estrogen-α receptors were assessed. In study 3, the effects of early maternal deprivation on partner preference in both males that are differentially reared, and, female preference towards these males were investigated. This explored if any behavioral deficits observed in AR males could be attributed to differences in their attractivity to females. Study 4 investigated the effects of early maternal deprivation on androgen sensitivity in adult males. Copulatory response to a receptive female was examined post-castration in AR and MR males and again following testosterone replacement. In study 5, levels of extracellular DA were investigated in the nucleus accumbens, an area critical in motivation, prior to and during copulation in sexually experienced AR and MR males using Microdialysis.

The short form of dopamine D2 receptor (D2S) functions as a presynaptic autoreceptor on dopamine neurons and has an inhibitory effect on dopaminergic tone. D2-MAPKs pathway is involved in many physiological events like production of prolactin and tyrosine hydroxylase (TH) expression. However, the effect of D2S receptor signalling on MAPKs is cell type specific, and is not fully understood.A recent study in our lab has identified a Gαi-interacting ras-MAPK inhibitor RASA3. Here, we showed that RASA3 is the key effector in D2-induced inhibition of MAPK by knockdown of endogenous RASA3 in the GH4 cell using RASA3 siRNA. We have also transfected a dominant negative RASA3 to compete with the endogenous RASA3 for the binding site on Ras. Both RASA3-siRNA and dominant negative RASA3 blocked D2S-induced inhibition of MAPK activation, clearly implicating that RASA3 is a key effector in Gαi3-dependent D2S mediated MAPKs inhibition To determine whether RASA3’s inhibitory effect could be reconstituted in fibroblast cells, the effect of RASA3 on D2-mediated ERK1/2 activation in COS7 cells was tested. Our results show that both active Gαi2 (or Gαi3) and active RASA3 are required for optimal inhibition of ERK1/2 activation in fibroblast COS7 cells.

Thèse d'exercice : Pharmacie : Université de Nantes : 2004. / Bibliogr. 4 f.

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The psychostimulant effects of cocaine can be associated with environmental stimuli and thus can be easily conditioned in a laboratory setting. In rats, both behavioural stimulant and reinforcing effects of cocaine have been induced by presentation of stimuli previously paired with cocaine treatment. The stimulant locomotor response evoked by contextual stimuli is termed conditioned activity. It is hypothesized that haloperidol and the specific D3 receptor antagonist ABT-127 will produce a doubly dissociable effect on acquisition vs. expression of cocaine conditioned activity. Male rats received three 1-hr sessions of habituation to activity monitoring chambers (outfitted with infrared emitters and detectors), one session each day, over 3 days during which no drug was administered. The conditioning phase began on the next day and consisted of three 1-hr sessions, one every 48 hrs. Rats were pre-treated intraperitoneally (IP) with haloperidol (50 µg/kg) or ABT-127 (1 mg/kg) (or vehicle) 1 hr and 0.5 hr before being placed into the activity chambers, respectively, and with the indirect-acting dopamine agonist cocaine (10 mg/kg) or saline immediately before placement into the chambers. The expression phase took place 48 hrs following the last conditioning session. Animals received a single injection of haloperidol, ABT-127 (or vehicle) 1 hr or 0.5 hr prior to placement in the activity chambers and saline was administered immediately before. Analyses revealed a significant interaction of drug by phase. In agreement with my hypothesis, haloperidol given during the conditioning phase blocked the acquisition of conditioned activity but failed to block the expression of conditioning when given on the test day. In contrast, ABT-127, when given before cocaine during conditioning failed to block the acquisition of conditioned activity but blocked the expression of conditioning when administered on the test day. Results suggest that D2 receptors are necessary for acquisition but not initial expression and D3 receptors are required for expression but not acquisition of cocaine conditioned activity. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2007-09-19 01:00:11.058

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The short form of dopamine D2 receptor (D2S) functions as a presynaptic autoreceptor on dopamine neurons and has an inhibitory effect on dopaminergic tone. D2-MAPKs pathway is involved in many physiological events like production of prolactin and tyrosine hydroxylase (TH) expression. However, the effect of D2S receptor signalling on MAPKs is cell type specific, and is not fully understood.A recent study in our lab has identified a Gαi-interacting ras-MAPK inhibitor RASA3. Here, we showed that RASA3 is the key effector in D2-induced inhibition of MAPK by knockdown of endogenous RASA3 in the GH4 cell using RASA3 siRNA. We have also transfected a dominant negative RASA3 to compete with the endogenous RASA3 for the binding site on Ras. Both RASA3-siRNA and dominant negative RASA3 blocked D2S-induced inhibition of MAPK activation, clearly implicating that RASA3 is a key effector in Gαi3-dependent D2S mediated MAPKs inhibition To determine whether RASA3’s inhibitory effect could be reconstituted in fibroblast cells, the effect of RASA3 on D2-mediated ERK1/2 activation in COS7 cells was tested. Our results show that both active Gαi2 (or Gαi3) and active RASA3 are required for optimal inhibition of ERK1/2 activation in fibroblast COS7 cells.