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The article in the Journal of Physiology discusses an alternative hypothesis for slow pacemaking in mammalian neurons, challenging the prevailing view that a persistent Na+ current is solely responsible. The authors suggest that low conductance pores, possibly related to gating pore currents, may play a crucial role in generating a stable inward current for pacemaking. Experimental evidence using a blocker called XG supports this hypothesis, indicating a need for further research to identify the molecular targets involved. The study also acknowledges the complexity of neuronal firing mechanisms and ongoing experiments to explore the regulation of pacemaking in different cell types. [Extracted from the article]

Background: Myotonia congenita (MC) is a common channelopathy affecting skeletal muscle and which is due to pathogenic variants within the CLCN1 gene. Various alterations in the function of the channel have been reported and we here illustrate a novel one. Methods: A patient presenting the symptoms of myotonia congenita was shown to bear a new heterozygous missense variant in exon 9 of the CLCN1 gene (c.1010 T > G, p.(Phe337Cys)). Confocal imaging and patch clamp recordings of transiently transfected HEK293 cells were used to functionally analyze the effect of this variant on channel properties. Results: Confocal imaging showed that the F337C mutant incorporated as well as the WT channel into the plasma membrane. However, in patch clamp, we observed a smaller conductance for F337C at −80 mV. We also found a marked reduction of the fast gating component in the mutant channels, as well as an overall reduced voltage dependence. Conclusion: To our knowledge, this is the first report of a mixed alteration in the biophysical properties of hClC‐1 consisting of a reduced conductance at resting potential and an almost abolished voltage dependence. [ABSTRACT FROM AUTHOR]

The activation of N‐methyl‐D‐aspartate receptors (NMDARs) in substantia nigra pars compacta (SNc) dopamine (DA) cells is central to generate the bursting activity, a phasic signal linked to DA‐related behaviours via the change in postsynaptic DA release. NMDARs are recruited during excitatory synaptic transmission by glutamate release, but the glycine site level of occupancy of these receptors during basal action potential‐dependent activity is not known for SNc DA neurons. We explored NMDAR‐dependent signals during exogenous applications of co‐agonists in midbrain slices from juvenile rats. We found that both glycine and D‐serine strengthened the NMDAR‐dependent component of excitatory postsynaptic currents (EPSCs) in a concentration‐dependent manner. EPSCs were also increased by endogenous glycine via the blockade of the glycine transport. The glycine site of NMDARs contributing to synaptic transmission is therefore subsaturated. The behaviourally relevant burst firing was more sensitive to exogenous D‐serine and endogenous glycine than to exogenous glycine. The mechanisms regulating the availability of the co‐agonists exert consequently a critical influence on the excitability of DA neurons via NMDARs. The modulation of the phasic firing in DA neurons by ambient NMDAR co‐agonists may be important for nigral information processing and downstream motor‐related behaviour. [ABSTRACT FROM AUTHOR]

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal- or ethanol-evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol-sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol-sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol-sensitized mice. Finally, ethanol superfusion (10-100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol-sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol. [ABSTRACT FROM AUTHOR]

Key points The hyperpolarization-activated cation current Ih is expressed in dopamine neurons of the substantia nigra, but the subcellular distribution of the current and its role in synaptic integration remain unknown., We used cell-attached patch recordings to determine the localization profile of Ih along the somatodendritic axis of nigral dopamine neurons in slices from young rats., Ih density is higher in axon-bearing dendrites, in a membrane area close to the axon origin, than in the soma and axon-lacking dendrites., Dual current-clamp recordings revealed a similar contribution of Ih to the waveform of single excitatory postsynaptic potentials throughout the somatodendritic domain., The Ih blocker ZD 7288 increased the temporal summation in all dendrites with a comparable effect in axon- and non-axon dendrites., The strategic position of Ih in the proximity of the axon may influence importantly transitions between pacemaker and bursting activities and consequently the downstream release of dopamine., Abstract Dendrites of most neurons express voltage-gated ion channels in their membrane. In combination with passive properties, active currents confer to dendrites a high computational potential. The hyperpolarization-activated cation current Ih present in the dendrites of some pyramidal neurons affects their membrane and integration properties, synaptic plasticity and higher functions such as memory. A gradient of increasing h-channel density towards distal dendrites has been found to be responsible for the location independence of excitatory postsynaptic potential (EPSP) waveform and temporal summation in cortical and hippocampal pyramidal cells. However, reports on other cell types revealed that smoother gradients or even linear distributions of Ih can achieve homogeneous temporal summation. Although the existence of a robust, slowly activating Ih current has been repeatedly demonstrated in nigral dopamine neurons, its subcellular distribution and precise role in synaptic integration are unknown. Using cell-attached patch-clamp recordings, we find a higher Ih current density in the axon-bearing dendrite than in the soma or in dendrites without axon in nigral dopamine neurons. Ih is mainly concentrated in the dendritic membrane area surrounding the axon origin and decreases with increasing distances from this site. Single EPSPs and temporal summation are similarly affected by blockade of Ih in axon- and non-axon-bearing dendrites. The presence of Ih close to the axon is pivotal to control the integrative functions and the output signal of dopamine neurons and may consequently influence the downstream coding of movement. [ABSTRACT FROM AUTHOR]

Most serotonergic neurons display a prominent medium-duration afterhyperpolarization ( mAHP), which is mediated by small-conductance Ca2+-activated K+ ( SK) channels. Recent ex vivo and in vivo experiments have suggested that SK channel blockade increases the firing rate and/or bursting in these neurons. The purpose of this study was therefore to characterize the source of Ca2+ which activates the mAHP channels in serotonergic neurons. In voltage-clamp experiments, an outward current was recorded at −60 mV after a depolarizing pulse to +100 mV. A supramaximal concentration of the SK channel blockers apamin or (-)-bicuculline methiodide blocked this outward current. This current was also sensitive to the broad Ca2+ channel blocker Co2+ and was partially blocked by both ω-conotoxin and mibefradil, which are blockers of N-type and T-type Ca2+ channels, respectively. Neither blockers of other voltage-gated Ca2+ channels nor DBHQ, an inhibitor of Ca2+-induced Ca2+ release, had any effect on the SK current. In current-clamp experiments, m AHPs following action potentials were only blocked by ω-conotoxin and were unaffected by mibefradil. This was observed in slices from both juvenile and adult rats. Finally, when these neurons were induced to fire in an in vivo-like pacemaker rate, only ω-conotoxin was able to increase their firing rate (by ~30%), an effect identical to the one previously reported for apamin. Our results demonstrate that N-type Ca2+ channels are the only source of Ca2+ which activates the SK channels underlying the m AHP. T-type Ca2+ channels may also activate SK channels under different circumstances. [ABSTRACT FROM AUTHOR]

Midbrain dopaminergic neurons in the substantia nigra, pars compacta and ventral tegmental area are critically important in many physiological functions. These neurons exhibit firing patterns that include tonic slow pacemaking, irregular firing and bursting, and the amount of dopamine that is present in the synaptic cleft is much increased during bursting. The mechanisms responsible for the switch between these spiking patterns remain unclear. Using both in-vivo recordings combined with microiontophoretic or intraperitoneal drug applications and in-vitro experiments, we have found that M-type channels, which are present in midbrain dopaminergic cells, modulate the firing during bursting without affecting the background low-frequency pacemaker firing. Thus, a selective blocker of these channels, 10,10-bis(4-pyridinylmethyl)-9(10 H)-anthracenone dihydrochloride, specifically potentiated burst firing. Computer modeling of the dopamine neuron confirmed the possibility of a differential influence of M-type channels on excitability during various firing patterns. Therefore, these channels may provide a novel target for the treatment of dopamine-related diseases, including Parkinson’s disease and drug addiction. Moreover, our results demonstrate that the influence of M-type channels on the excitability of these slow pacemaker neurons is conditional upon their firing pattern. [ABSTRACT FROM AUTHOR]

Previous in vivo studies have shown that blockade of small-conductance Ca2+-activated potassium (SK) channels enhances burst firing in dopaminergic neurons. As bursting has been found to be physiologically relevant for the synaptic release of serotonin (5-HT), we investigated the possible role of SK channels in the control of this firing pattern in 5-HT neurons of the dorsal raphe nucleus. In these cells, bursts are usually composed of doublets consisting of action potentials separated by a small interval (< 20 ms). Both in vivo and in vitro extracellular recordings were performed, using anesthetized rats and rat brain slices, respectively. In vivo, the specific SK blocker UCL 1684 (200 μm) iontophoresed onto presumed 5-HT neurons significantly increased the production of bursts in 13 out of 25 cells. Furthermore, the effect of UCL 1684 persisted in the presence of both the GABAA antagonist SR 95531 (10 mm) and the GABAB antagonist CGP 35348 (10 mm), whereas these agents by themselves did not significantly influence the neuronal firing pattern. In vitro, bath superfusion of the SK channel blocker apamin (300 nm) induced bursting in only three out of 18 neurons, although it increased the coefficient of variation of the interspike intervals in all the other cells. Our results suggest that SK channel blockade promotes bursting activity in 5-HT neurons via a direct action. An input which is present only in vivo seems to be important for the induction of this firing pattern in these cells. [ABSTRACT FROM AUTHOR]

Neuronal Kv7 channels (also termed KCNQ channels) are the molecular correlate of the M-current. The Kv7 channels activate at rather negative membrane potentials (≤ 60 mV), thereby ‘fine-tuning’ the resting membrane potential. The Kv7 channels are widely expressed in the brain with the Kv7.2, Kv7.3 and Kv7.5 channels being the most abundant. The Kv7.4 subunit has the most restricted brain regional expression being present in discrete nuclei of brainstem only. Kv7 channels are expressed at different subcellular locations, being on both somatodendritic, axonal and terminal sites. This complex subcellular distribution of Kv7 channels enables them to participate in both pre- and postsynaptic modulation of basal and stimulated excitatory neurotransmission. Activation of neuronal Kv7 channels limits repetitive firing thereby potentially limiting the generation of long bursts, with subsequent inhibition of monoaminergic neurotransmitter release. In this review, we focus on the influence of Kv7 channels on dopaminergic and serotonergic neurotransmission. The data suggest a novel action of Kv7 channel openers which could translate into having therapeutic value in the treatment of disease states characterized by overactivity of dopaminergic (e.g. schizophrenia and drug abuse) and serotonergic neurotransmission (e.g. anxiety). [ABSTRACT FROM AUTHOR]

Background and purpose:The identification of potent and selective radioligands for the mapping of 5-HT receptors is interesting both for clinical and experimental research. The aim of this study was to compare the potency of a new putative 5-HT1A receptor antagonist, p-DMPPF, (4-(2-hydroxyphenyl)-1-[2′-[N-(2′′-pyridinyl)-p-fluorobenzamido]ethyl]piperazine) with that of the well-known 5-HT1A antagonists, WAY-100635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide) and its fluorobenzoyl analogue, p-MPPF (4-(2-methoxyphenyl)-1-[2′-[N-(2″-pyridinyl)-p-fluorobenzamido]ethyl]piperazine).Experimental approach:Single cell extracellular recordings of dorsal raphe (DR) neurones were performed in rat brain slices. The potency of each compound at antagonizing the effect of the 5-HT1A agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)-tetraline], was quantified using the Schild equation. The pharmacological profile of p-DMPPF was defined using competition binding assays.Key results:Consistently with a 5-HT1A receptor antagonist profile, incubation of slices with an equimolar (10 nM) concentration of each compound markedly reduced the inhibitory effect of 8-OH-DPAT on the firing rate of DR neurones, causing a significant rightward shift in its concentration-response curve. The rank order of potency of the antagonists was WAY-100635>p-DMPPFp-MPPF. The sensitivity of DR neurones to the inhibitory effect of 8-OH-DPAT was found to be heterogeneous. The binding experiments demonstrated that p-DMPPF is highly selective for 5-HT1A receptors, with a K i value of 7 nM on these receptors.Conclusions and implications:The potency of the new compound, p-DMPPF, as a 5-HT1A antagonist is similar to that of p-MPPF in our electrophysiological assay. Its selectivity towards 5-HT1A receptors makes it a good candidate for clinical development.British Journal of Pharmacology (2007) 152, 952–958; doi:10.1038/sj.bjp.0707431; published online 20 August 2007 [ABSTRACT FROM AUTHOR]

Peregrine falcon populations underwent devastating declines in the mid-20th century due to the bioaccumulation of organochlorine contaminants, becoming essentially extirpated east of the Great Plains and significantly reduced elsewhere in North America. Extensive re-introduction programs and restrictions on pesticide use in Canada and the United States have returned many populations to predecline sizes. A proper population genetic appraisal of the consequences of this decline requires an appropriate context defined by (i) meaningful demographic entities; and (ii) suitable reference populations. Here we explore the validity of currently recognized subspecies designations using data from the mitochondrial control region and 11 polymorphic microsatellite loci taken from 184 contemporary individuals from across the breeding range, and compare patterns of population genetic structure with historical patterns inferred from 95 museum specimens. Of the three North American subspecies, the west coast marine subspecies Falco peregrinus pealei is well differentiated genetically in both time periods using nuclear loci. In contrast, the partitioning of continental Falco peregrinus anatum and arctic Falco peregrinus tundrius subspecies is not substantiated, as individuals from these subspecies are historically indistinguishable genetically. Bayesian clustering analyses demonstrate that contemporary genetic differentiation between these two subspecies is mainly due to changes within F. p. anatum (specifically the southern F. p. anatum populations). Despite expectations and a variety of tests, no genetic bottleneck signature is found in the identified populations; in fact, many contemporary indices of diversity are higher than historical values. These results are rationalized by the promptness of the recovery and the possible introduction of new genetic material. [ABSTRACT FROM AUTHOR]

A vast body of experimental in vitro work and modelling studies suggests that the firing pattern and/or rate of a majority of midbrain dopaminergic neurons may be controlled in part by Ca2+-activated K+ channels of the SK type. However, due to the lack of suitable tools, in vivo evidence is lacking. We have taken advantage of the development of the water-soluble, medium potency SK blocker N-methyl-laudanosine (CH3-L) to test this hypothesis in anaesthetized rats. In the lateral ventral tegmental area, CH3-L iontophoresis onto dopaminergic neurons significantly increased the coefficient of variation of their interspike intervals and the percentage of spikes generated in bursts as compared to the control condition. The effect of CH3-L persisted in the presence of a specific GABAA antagonist, suggesting a direct effect. It was robust and reversible, and was also observed in the substantia nigra. Control experiments demonstrated that the effect of CH3-L could be entirely ascribed to its blockade of SK channels. On the other hand, the firing pattern of noradrenergic neurons was much less affected by CH3-L. We provide here the first demonstration of a major role of SK channels in the control of the switch between tonic and burst firing of dopaminergic neurons in physiological conditions. This study also suggests a new strategy to develop modulators of the dopaminergic (DA) system, which could be of interest in the treatment of Parkinson's disease, and perhaps other diseases in which DA pathways are dysfunctional. [ABSTRACT FROM AUTHOR]

In order to investigate the physiological properties of the melanin-concentrating hormone (MCH) we have generated and used mice from which the MCH receptor 1 gene was deleted (MCHR1 Neo/Neo mice). Complementary experimental approaches were used to investigate alterations in the learning and memory processes of our transgenic model. The ability of the knockout strain to carry out the inhibitory passive avoidance test was found to be considerably impaired although no significant differences were observed in anxiety levels. This impaired cognitive property prompted us to explore modifications inN-methyld-aspartate (NMDA) responses in the hippocampus. Intracellular recordings of CA1 pyramidal neurons in hippocampal slices from theMCHR1 Neo/Neo mice revealed significantly decreased NMDA responses. Finally, usingin situhybridization we found a 15% reduction in NMDAR1 subunit in the CA1 region. These results show for the first time a possible role for MCH in the control of the function of the NMDA receptor. [ABSTRACT FROM AUTHOR]

1 We have recently shown that the alkaloid methyl-laudanosine blocks SK channel-mediated afterhyperpolarizations (AHPs) in midbrain dopaminergic neurones. However, the relative potency of the compound on the SK channel subtypes and its ability to block AHPs of other neurones were unknown. 2 Using whole-cell patch-clamp experiments in transfected cell lines, we found that the compound blocks SK1, SK2 and SK3 currents with equal potency: its mean IC50S were 1.2, 0.8 and 1.8μM, respectively. IK currents were unaffected. In rat brain slices, methyl-laudanosine blocked apaminsensitive AHPs in serotonergic neurones of the dorsal raphe and noradrenergic neurones of the locus coeruleus with IC50s of 21 and 19μM, as compared to 15 μM in dopaminergic neurones. However, at 100 μM, methyl-laudanosine elicited a constant hyperpolarization of serotonergic neurones of about 9 mV, which was inconsistently (i.e. not in a reproducible manner) antagonized by atropinc and hence partly due to the activation of muscarinic receptors. 3 While exploring the pharmacology of related compounds, we found that methyl-noscapine also blocked SK channels. In cell lines, methyl-noscapine blocked SK1, SK2 and SK3 currents with mean IC50S of 5.9, 5.6 and 3.9 μM, respectively. It also did not block IK currents. Methyl-noscapine was slightly less potent than methyl-laudanosine in blocking AHPs in brain slices, its IC50S being 42, 37 and 29 μM in dopaminergic, scrotonergic and noradrenergic neurones, respectively. Interestingly, no significant non-SK effects were observed with methyl-noscapine in slices. At a concentration of 300 μM, methyl-noscapine elicited the same changes in excitability in the three neuronal types than did a supramaximal concentration of apamin (300nM). 4 Methyl-laudanosine and methyl-noscapine produced a rapidly reversible blockade of SK channels as compared with apamin. The difference between the IC50S of apamin (0.45 nM) and methyllaudanosine (1.8 μM) in SK3 cells was essentially due to a major difference in their k-1 (0.028s-1 for apamin and &ges;20s-1 for methyl-laudanosine). 5 These experiments demonstrate that both methyl-laudanosine and methyl-noscapine are medium potency, quickly dissociating, SK channel blockers with a similar potency on the three SK subtypes. Methyl-noscapine may be superior in terms of specificity for the SK channels. [ABSTRACT FROM AUTHOR]

1 It has been shown that the MAO (monoamine oxidase)-B inhibitor deprenyl (DPR, selegiline) protects some cell types against oxidative stress. By decreasing H[sub 2]O[sub 2] production, MAO-A inhibitors could also reduce oxidative stress. 2 This study reports the effect of the MAO-A inhibitors, pirlindole (PIR), dehydropirlindole (DHP), brofaromine (BRO) and moclobemide (MCL) on primary-cultured brain cells exposed to iron-mediated toxicity. A comparison with trolox (TRO), a hydrosoluble vitamin-E analogue that protects against such an induced stress, was performed. 3 Rat hippocampal or cortical cultured cells were exposed either to 2 μM FeSO[sub 4] alone or in the presence of PIR, DHP, BRO, DPR, MCL or TRO. Cell survival (lactate-dehydrogenase measurements, 16h incubation), intracellular peroxide production (DCF-fluorescence, 1 h incubation), lipoperoxidation (TBARS-fluorescence, 6 h incubation) and mitochondrial function (MTT-test, 16 h incubation) were assessed. 4 PIR, DHP and TRO significantly protected cultures (P<0.05) against Fe[sup 2+]-induced toxicity in a concentration-dependent manner. The EC[sub 50s] of these compounds were 6, 12 and 19 μM, respectively, in hippocampal cells. For cortical cell cultures incubated in the presence of iron and PIR or DHP, EC[sub 50s] were 5 and 6 μM respectively. All Hill coefficients were close to unity. BRO, MCL and DPR were not protective in any type of culture. The IC[sub 50s] for the inhibition of MAO-A were 2, 2 and 0.2 μM for PIR, DHP and BRO, respectively. PIR, DHP and TRO, but not DPR, induced a significant decrease in both intracellular peroxide production and lipoperoxidation. They also improved mitochondrial function. 5 These experiments show that PIR and DHP can protect hippocampal and cortical neurons against oxidative stress at pharmacologically relevant concentrations. This protective effect seems unrelated to inhibition of MAO-A, but possibly involves free radical scavenging. [ABSTRACT FROM AUTHOR]

Noradrenergic neurons have been implicated in the development of ethanol dependence and tolerance. Moreover, the development of an hyposensltivity of alpha 2 adrenoceptors has been postulated during long-term exposition to ethanol. In order to test the putative role of alpha 2 receptors in ethanol intoxication, we have studied the interaction between ethanol and yohimbine, an alpha 2 antagonist, on the spontaneous firing rate of rat locus coeruleus (LC) in an in vitro slice model. The spikes from single neurons were recorded by glass microelectrodes. Ethanol at 100 mm, a concentration that parallels the behavioral effects in the human and in the animals, inhibits the firing activity of some LC cells. This inhibition was quickly reversed after stopping the ethanol perfusion and was observed for each further administration. However, if yohimbine (20 μm) was simultaneously perfused, the ethanol-induced inhibition was rapidly antagonized. This effect is reversible after long time washout of yohimbine. This suggests that alpha 2 adrenoceptors could beimplicated in the inhibitory effect of ethanol on LC noradrenergic neurons and perhaps inthe development of tolerance. However, other hypotheses are discussed, because yohimbine can also antag onize other types of receptors. [ABSTRACT FROM AUTHOR]

Monoaminergic neurons have been shown to play a role in both the intoxicating and chronic effects of ethanol. We present here the results of a study about the acute effects of ethanol on serotonergic raphe nucleus, noradrenergic locus coeruleus, and dopaminergic ventral tegmental area. These nuclei were investigated electrophysiologically by recording the spontaneous firing rate of single neurons using glass microelectrodes, both in vivo in chloral hydrate anesthetized rats and in vitro in brain slices. Ethanol was perfused intravenously at a rate ranging from 0.2 mg/kg/min to 0.2 g/kg/min in vivo, and at concentrations between 10-8 M and 1 M in vitro. We observed that each monoaminergic nucleus had its own pattern of responses to acute ethanol perfusion, and that high and low concentrations have different actions, suggesting a biphasic effect. For example, in slices, ethanol concentrations higher than 10 mM induce an excitation in most raphe and ventral tegmental area neurons, and an inhibition of firing in locus coeruleus neurons. The results were comparable in the in vivo model, but much more heterogenous. We conclude that the effect of ethanol on the monoaminergic neurons is specific of the type of neuron, and that a biphasic effect is commonly found. [ABSTRACT FROM AUTHOR]

Small-conductance Ca2+-activated K+ channels (SK channels) underlie the medium duration after hyperpolarization that follows single or trains of action potentials in many types of neurons. Three subtypes of SK subunits, SK1 (KCa2.1), SK2 (KCa2.2) and SK3 (KCa2.3), have been cloned and are expressed differentially within the central nervous system (CNS). A paper in this issue of BJP reports the discovery of the first example of a positive modulator displaying not only selectivity for SK channels over other channels, but also a subtype selectivity among SK and analogous channels (SK3>SK2⋙SK1=IK). Together with other recent progress in the field, this finding enriches the repertoire of tools available to test the hypothesis that SK channels may be targets for future CNS drugs.British Journal of Pharmacology (2007) 151, 568–570; doi:10.1038/sj.bjp.0707282; published online 8 May 2007 [ABSTRACT FROM AUTHOR]

Midbrain dopaminergic (DA) neurones sustain important physiological functions such as control of motricity, signalling of the error in prediction of rewards and modulation of emotions and cognition. Moreover, their degeneration leads to Parkinson's disease and they may be dysfunctional in other pathological states, such as schizophrenia and drug abuse. A subset of DA neurones has been known for many years to contain releasable peptides such as neurotensin and cholecystokinin. However, recent experimental evidence indicates that the phenotype of DA neurones may be much more diverse, since it is suggested that, under certain conditions, they may also release glutamate, cannabinoids and even serotonin.British Journal of Pharmacology (2005) 146, 167–169. doi:10.1038/sj.bjp.0706328; published online 11 July 2005 [ABSTRACT FROM AUTHOR]