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Accumbal Noradrenaline That Contributes to the Alpha View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector J Neural Transm (2009) 116:389–394 DOI 10.1007/s00702-009-0190-4 BASIC NEUROSCIENCES, GENETICS AND IMMUNOLOGY - ORIGINAL ARTICLE Accumbal noradrenaline that contributes to the alpha- adrenoceptor-mediated release of dopamine from reserpine- sensitive storage vesicles in the nucleus accumbens is derived from alpha-methyl-para-tyrosine-sensitive pools M. M. M. Verheij Æ A. R. Cools Received: 8 May 2008 / Accepted: 24 January 2009 / Published online: 17 February 2009 Ó The Author(s) 2009. This article is published with open access at Springerlink.com Abstract Alpha-adrenoceptors in the nucleus accumbens Introduction are known to inhibit accumbal dopamine release from reserpine-sensitive pools. The aim of this study was to test It has been found that the sensitivity of alpha-adrenocep- our previously reported hypothesis that accumbal noradren- tors to noradrenergic agents depends on the amount of aline that controls the dopamine release from these storage noradrenaline that is available in the synapse. In case the vesicles is derived from alpha-methyl-para-tyrosine-sensitive synaptic noradrenaline levels increase, the conformation of pools. The sensitivity of accumbal alpha-adrenoceptors to alpha-adrenoceptors change into a state that makes them noradrenergic agents depends on the amount of noradrena- less sensitive to agonists and more sensitive to antagonists line that is available in the synapse. In case the synaptic (Cools et al. 1987, 1991; Tuinstra and Cools 2000a; Cools noradrenaline levels decrease, the conformation of alpha- and Tuinstra 2003; Aono et al. 2007). The opposite holds adrenoceptors changes into a state that makes these receptors also true: in case the synaptic noradrenaline levels more sensitive to its agonists. The effects of alpha-methyl- decrease the conformation of alpha-adrenoceptors change para-tyrosine, respectively reserpine, on the alpha-adreno- into a state that makes them more sensitive to agonists and ceptor-agonist-induced changes of accumbal dopamine less sensitive to antagonists (Cools et al. 1987, 1991; release were investigated. Alpha-methyl-para-tyrosine, Tuinstra and Cools 2000a; Cools and Tuinstra 2003). It is but not reserpine, made accumbal postsynaptic alpha- evident that these processes provide a homeostatic mech- adrenoceptors more sensitive to phenylephrine. These results anism, controlling the adrenergic activity at postsynaptic indicate that noradrenaline that inhibits the release of receptors. dopamine from reserpine-sensitive storage vesicles, via Alpha-adrenoceptors are known to control the release stimulation of accumbal postsynaptic alpha-adrenoceptors, is of dopamine. Both in vitro and in vivo experiments have derived from alpha-methyl-para-tyrosine-sensitive pools. revealed that stimulation of postsynaptic alpha-adreno- The clinical impact of these data is discussed. ceptors that are located on dopaminergic neurons inhibits the release of dopamine in the nucleus accumbens, Keywords Alpha-adrenoceptors Á Alpha-methyl-para- whereas inhibition of these receptors stimulates the tyrosine Á Noradrenaline–dopamine interactions Á release of dopamine in this brain structure (Nurse et al. Norepinephrine–dopamine interactions Á 1984, 1985; Russell et al. 1988, 1993; Tuinstra and Cools Nucleus accumbens Á Reserpine 2000a; Cools and Tuinstra 2003; see also Verheij and Cools 2008). It is generally accepted that presynaptic alpha-adrenoceptors regulate the amount of noradrenaline in the synapse and, accordingly, regulate the amount M. M. M. Verheij (&) Á A. R. Cools of noradrenaline at the level of postsynaptic alpha- Department of Cognitive Neuroscience, adrenoceptors. Interestingly, the noradrenaline agonist Division of Psychoneuropharmacology (PNF), phenylephrine (PE) has been found to act at accumbal Radboud University (RU) Nijmegen, Medical Centre, 6525 EZ Nijmegen, The Netherlands presynaptic, but not postsynaptic, alpha-adrenoceptors e-mail: [email protected] of otherwise untreated rats (Tuinstra and Cools 2000a, 123 390 M. M. M. Verheij, A. R. Cools 2000b; Cools and Tuinstra 2003; Aono et al. 2007; see Materials and methods also below). This action of PE has been found to reduce the synaptic noradrenaline levels (Aono et al. 2007), Rats were unilaterally implanted with a guide cannula which, in turn, results in an increased release of accumbal directed at the right nucleus accumbens (for procedures see dopamine in these rats (Tuinstra and Cools 2000a, 2000b; Verheij and Cools 2007). The rats were allowed to recover Cools and Tuinstra 2003). It has recently been demon- from surgery for the next 7–10 days in dialysis cages. At strated that the alpha-adrenoceptor-mediated release of 3 days prior to the start of the experiment, each rat was accumbal dopamine is not derived from alpha-methyl- gently picked up (three times per day) in order to habituate para-tyrosine (AMPT)-sensitive dopamine pools (Tuinstra to the procedure assessed on the day when accumbal and Cools 2000b; see also Verheij and Cools 2008). In dopamine was measured. At the start of the experiment, a fact, the alpha-adrenoceptor-mediated dopamine release is dialysis probe was connected to a swivel and accumbal derived from reserpine (RES)-sensitive pools of dopamine dialysates were analyzed for dopamine according to pre- (Cools and Verheij 2002; Verheij and Cools submitted; viously described procedures (see Verheij and Cools 2007). see also Verheij and Cools 2008). It is currently unknown The probes had an in vitro recovery of 10–12% for dopa- which type of noradrenergic pool releases noradrenaline mine (Verheij and Cools 2007). The dopamine sensitivity that inhibits accumbal dopamine release from these was 500 fg per sample (Verheij and Cools 2007). This storage pools. On the basis of previously reported neu- sensitivity has repeatedly been shown to be sufficient for rochemical data, however, it has been hypothesized that detecting the currently observed changes in the amount of accumbal noradrenaline derived from AMPT-sensitive dopamine (De Leonibus et al. 2006; Verheij and Cools pools controls the alpha-adrenoceptor-mediated release of 2007; Verheij et al. 2008). accumbal dopamine from RES-sensitive vesicles (Saigusa As soon as the dopamine samples differed less than et al. 1999). 10%, three baseline samples were taken and one group of Given the fact that stimulation of postsynaptic alpha- rats was treated with 0.1 mM (2 ll/min for 40 min, intra- adrenoceptors in the nucleus accumbens inhibits the accumbens) of AMPT or its solvent (Ringer), whereas release of accumbal dopamine (see above), the inability another group of rats was treated with 1 mg/kg (1 ml/kg, of the alpha-adrenoceptor agonist PE to decrease the i.p.) of RES or its solvent (pH = 2.4). At 40 and 100 min amount of accumbal dopamine in otherwise untreated rats after AMPT or its solvent and at 24 h after RES or its (Tuinstra and Cools 2000a, 2000b; see also above) has solvent, rats were subjected to a 40 min lasting intra-ac- been ascribed to the presence of a relatively high amount cumbens infusion of 0.01 mM (2 ll/min) of the alpha-1 of noradrenaline in the synapses of these rats (Tuinstra adrenoceptor agonist PE. and Cools 2000a). Under these conditions it can be The AMPT- and RES-induced changes of accumbal predicted that an experimentally induced decrease of the dopamine over time have already been published elsewhere amount of synaptic noradrenaline makes the accumbal (time effects of AMPT: Tuinstra and Cools 2000b; time postsynaptic alpha-adrenoceptors sensitive to PE. AMPT effects of RES: Verheij and Cools 2007). The dopamine is known to reduce the alpha-adrenoceptor-mediated decreasing effects of these agents were found to be maxi- release of noradrenaline (Brannan et al. 1991; McTavish mal and stable throughout the period that PE was given et al. 1999). (see Tuinstra and Cools 2000b and Verheij and Cools In order to test whether the noradrenaline release at the 2007). Modified Ringer solution served as control for PE. level of postsynaptic alpha-adrenoceptors in the nucleus At the end of the microdialysis experiments, rats were accumbens is derived from AMPT-sensitive pools, the given an overdose of pentobarbital and were intracardially effects of AMPT on the PE-induced accumbal dopamine perfused with paraformaldehyde. Vibratome sections were release were established. Combining the above-mentioned cut to verify the location of the microdialysis probe. considerations results in the hypothesis that AMPT makes It is important to realize that one can only measure a PE- the accumbal postsynaptic alpha-adrenoceptors sensitive induced increase of accumbal dopamine under the condition to PE. It is hypothesized that PE decreases the amount of that the presynaptic pools of dopamine are not empty. For accumbal dopamine in AMPT-treated rats (postsynaptic this reason, experiments were performed in high responders action) in contrast to PE that will increase the amount of to novelty (HR) that were selected from the Nijmegen out- accumbal dopamine in control rats (presynaptic action). In bred strain of Wistar rats (Cools et al. 1990). It has order to establish whether RES-sensitive pools contribute previously been reported that an environmental or phar- to the release of accumbal noradrenaline at postsyn- macological challenge could still increase accumbal aptic alpha-adrenoceptors as well, the effects of RES dopamine levels in these
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