Now showing 1 - 4 of 4
  • Publication
    The effect of nicotine induced behavioral sensitization on dopamine D1 receptor pharmacology: An in vivo and ex vivo study in the rat
    Behavioral sensitization is a phenomenon which can develop following repeated intermittent administration of a wide range of psychostimulants. The mechanism underlying this phenomenon is putatively involved in many neuropsychiatric disorders (incl. drug addiction) and therefore, understanding of its mechanism is of great importance. Although these different drugs have diverse molecular targets located across the brain, they share the ability to increase the release of dopamine. The aim of the present study is to investigate the effect of the dopamine D1 ligands on nicotine induced behavioral sensitization and their molecular consequences in the striatum. Wistar rats were chronically intermittent (5 days) treated with vehicle or nicotine (0.4 mg/kg; s.c.) and locomotor activity was measured. After the establishment of sensitization, rats were withdrawn for a period of 5 days followed by administration of a nicotine challenge, with or without a pre-challenge of SCH-23390 (0.03 mg/kg; i.p., a dopamine D1 antagonist) given 30 min prior to the nicotine. Either 45 min or 24 h post-challenge, the dorsal striatum was isolated and used to assess the effect of forskolin, dopamine, and dopamine D1 ligands on intracellular cAMP accumulation ex vivo. The cAMP levels were measured using LC-MS/MS. Acute nicotine administration significantly increased locomotor activity and subsequent chronic nicotine administration induced the development of locomotor sensitization. Moreover, following the 5 days withdrawal period, a nicotine challenge produced a robust sensitized response (i.e. expression of sensitization) and was antagonized by SCH-23390. Nicotine induced sensitization had no effect on forskolin stimulated cAMP accumulation however, it increased the efficacy of dopamine for the dopamine D1 receptor, and decreased the potency of D1 agonists. These effects were antagonized by in vivo pre-challenge with SCH-23390. Moreover, a time dependent effect was observed between tissue taken at 45 min and 24 h post-challenge. In conclusion, the present findings provide a connection between behavioral sensitization and intracellular cAMP accumulation through the dopamine D1 receptor. Therefore D1 signaling in the dorsal striatum may play an important role in the underlying mechanism of the expression of nicotine induced behavioral sensitization.
      554Scopus© Citations 12
  • Publication
    Effects of a combination of 3,4-methylenedioxymeth amphetamine and caffeine on real time stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry
    It is well documented that caffeine exacerbates the hyperthermia associated with acute exposure to 3,4-methylenedioxymethamphetamine (MDMA) in rats. Previous reports have also indicated that MDMA-related enhancement of dopamine release is exacerbated in the presence of caffeine. In the present study we have examined whether the effects of MDMA on real-time stimulated dopamine release, in the absence of uptake inhibition, are accentuated in the presence of caffeine. Isolated striatal slices from adult male Wistar rats were treated acutely with MDMA, caffeine, or a combination, and their effects on single and 5 pulse stimulated dopamine release monitored using the technique of fast cyclic voltammetry. Caffeine at 10 or 100 μM had no significant effect on single pulse stimulated dopamine release. However 100 μM caffeine caused a significant peak increase in 5 pulse stimulated dopamine release. Both 1 and 30 μM MDMA gave rise to a significant increase in both single and 5-pulse dopamine release and reuptake. A combination of 100 μM caffeine and 1 or 30 μM MDMA did not significantly enhance the effects of MDMA on single or 5 pulse dopamine release and reuptake when compared to that applied alone. Utilizing single action potential dependent dopamine release, these results do not demonstrate a caffeine-enhanced MDMA-induced dopamine release.
    Scopus© Citations 4  282
  • Publication
    A comparison of the effects of the dopamine partial agonists aripiprazole and (−)-3-PPP with quinpirole on stimulated dopamine release in the rat striatum: Studies using fast cyclic voltammetry in vitro
    (Elsevier, 2012-07) ;
    The effects of aripiprazole, (-)-(3-hydroxyphenyl)-N-n-propylpiperidine ((-)-3-PPP) and quinpirole on single and multiple pulse stimulated dopamine release were investigated using the technique of fast cyclic voltammetry (FCV) in isolated rat striatal slices. Aripiprazole and (-)-3-PPP had no significant effect on single pulse dopamine release at concentrations from 10nM to 10mM indicating low agonist activity. The compounds failed to potentiate 5 pulse stimulated release of dopamine although inhibitory effects were seen at 10 mM for aripiprazole. Both compounds were tested against the concentration-response curve for quinpirole¿s inhibition of stimulated single pulse dopamine release. Aripiprazole and (-)-3-PPP shifted the concentration-response curve for quinpirole to the right. In each case this was a greater than a 100-fold shift for the 10 mM test compound. Whilst these results indicate that both compounds show little agonist activity on dopamine release and significant antagonism of the inhibitory effect of quinpirole on dopamine release, whether they are functionally selective dopamine D2 ligands remains controversial.
      539Scopus© Citations 6
  • Publication
    Frequency-dependent modulation of dopamine release by nicotine and dopamine D1 ligands: an in vitro fast cyclic voltammetry study in rat striatum
    Nicotine is a highly addictive drug and exerts this effect partially through the modulation of dopamine release and increasing extracellular dopamine in regions such as the brain reward systems. Nicotine acts in these regions on nicotinic acetylcholine receptors. The effect of nicotine on the frequency dependent modulation of dopamine release is well established and the purpose of this study was to investigate whether dopamine D1 receptor (D1R) ligands have an influence on this. Using fast cyclic voltammetry and rat corticostriatal slices, we show that D1R ligands are able to modulate the effect of nicotine on dopamine release. Nicotine (500nM) induced a decrease in dopamine efflux at low frequency (single pulse or 5 pulses at 10Hz) and an increase at high frequency (100Hz) electrical field stimulation. The D1R agonist SKF-38393, whilst having no effect on dopamine release on its own or on the effect of nicotine upon multiple pulse evoked dopamine release, did significantly prevent and reverse the effect of nicotine on single pulse dopamine release. Interestingly similar results were obtained with the D1R antagonist SCH-23390. In this study we have demonstrated that the modulation of dopamine release by nicotine can be altered by D1R ligands, but only when evoked by single pulse stimulation, and are likely working via cholinergic interneuron driven dopamine release.
      259Scopus© Citations 8