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.

The perception of reward is crucial in many psychological processes. Wise (1982) has suggested that the neurotransmitter dopamine is involved in producing 'hedonic' responses to rewards. Dopamine is also involved in the control of movement and hunger. Testing dopamine's role in reward perception is therefore complicated by these other actions; the effects of manipulations can often be interpreted as actions on hunger or motor control, rather than on reward. Two methods are described in this thesis which isolate reward effects. The effects of dopaminergic drugs on the rewarding impact of exploration were investigated. The use of exploration eliminates the influence of hunger, while the impact of motor deficits was reduced by using choice measures. Control experiments assessed effects on activity and emotionality. Results indicated that dopamine was involved in exploratory reinforcement independently of its roles in hunger or simple motor control. Tests of whether dopamine is involved in hedonia, or merely in engaging responses to reinforcers, used the 'behavioural contrast' paradigm. Contrast occurs when animals over-react to unexpected changes in reinforcement and allow response elicitation effects to be dissociated from effects on hedonia. Although the dopamine anatagonist a-flupenthixol did not affect contrast induced by changes in reinforcement value, the introduction or withdrawal of the drug could, itself, induce contrast effects. It is concluded that dopamine is involved in hedonia independently of any involvement in response elicitation. A speculative model of the nature of dopamine’s involvement in hedonia is proposed and its implications for our understanding of Parkinson’s disease and schizophrenia, in which dopamine dysfunctions are implicated, are discussed.