Behavioural Brain Research 130 (2002) 149 – 169 Intrinsic membrane properties and synaptic inputs regulating the firing activity of the dopamine neurons Pernilla Grillner a, *, Nicola B. Mercuri b a Department of Physiology and Pharmacology, Karolinska Institutet, S171 77, Stockholm, Sweden b IRCCS Fondazione Santa Lucia, Uniersity of Rome ‘Tor Vergata’, Rome, Italy Received 15 August 2000; accepted 13 August 2001 Abstract Dopamine (DA) neurones of the ventral mesencephalon are involved in the control of reward related behaviour, cognitive functions and motor performances, and provide a critical site of action for major categories of neuropsychiatric drugs, such as antipsychotic agents, dependence producing drugs and anti-Parkinson medication. The midbrain DA neurones are mainly located in the substantia nigra pars compacta (SNPC) and the ventral tegmental area (VTA). Intrinsic membrane properties regulate the activity of these neurones. In fact, they possess several conductances that allow them to fire in a slow pacemaker-like mode. The internal set of membrane currents interact with afferent synaptic inputs which, especially in in vivo conditions, contribute to accelerate or decelerate the firing activity of the cells in accordance with the necessity to optimise the release of dopamine in the terminal fields. In particular, discrete excitatory and inhibitory inputs transform the firing from a low regular into a bursting pattern. The bursting activity promotes dopamine release being very important in cognition and motor performances. In the present paper we review electrophysiological data regarding the role of glutamatergic and cholinergic and GABAergic afferent inputs in regulating the midbrain DAergic neuronal activity. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Dopamine neurones; Synaptic transmission; NMDA receptors; L-type Ca 2 + channels; GABA A and GABA B IPSP; Presynaptic inhibition; Metabotropic glutamate receptors; Muscarinic receptors; Nicotinic receptors www.elsevier.com/locate/bbr 1. Introduction 1.1. Dopaminergic systems of the midbrain 1.1.1. Anatomy Dopamine was discovered as an independent neuro- transmitter in the 1950s [27]. The description of the neuronal populations containing dopamine and their anatomical distribution was subsequently made possible by the introduction of the histochemical formaldehyde fluorescence technique by Falck and Hillarp [56] by which the monoaminergic neurones in the brain could be visualised. Dahlstro ¨ m and Fuxe [45] subsequently provided a more detailed description of the dopaminer- gic systems in the rat brain. The dopamine neurones of the midbrain are mainly located in three distinct areas, the retrorubral field (A8), the substantia nigra pars compacta (SNPC; A9) and the ventral tegmental area (VTA; A10), which contain 70–75% of the dopamine neurones in the brain. They are organised in two princi- pal dopaminergic systems that are named according to their respective projection areas (see for review [11,188]. The nigrostriatal system thus originates in the SNPC and projects to the dorsal striatum, i.e. caudate and putamen [3], and the mesolimbocortical system projects from the VTA to the limbic areas of the ventral stria- tum (i.e. nucleus accumbens), amygdala and olfactory tubercle, as well as limbic cortices such as the medial prefrontal, cingulate and entorhinal [4,11,188]. The do- pamine neurones of the retrorubral field (A8) also project to the dorsal striatum and can be viewed as a caudal extension of SNPC [128,188]. 1.1.2. Physiological characteristics of the midbrain dopamine neurones The dopaminergic neurones of the SNPC and VTA have been well characterised by the use of electrophysi- * Corresponding author. E-mail addresses: pernilla.grillner@fyfa.ki.se (P. Grillner), Mercurin@uniroma2.it (N.B. Mercuri). 0166-4328/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII:S0166-4328(01)00418-1