Laterodorsal tegmental stimulation elicits dopamine efflux in the rat nucleus accumbens by activation of acetylcholine and glutamate receptors in the ventral tegmental area

Abstract

Cholinergic and glutamatergic neurons in the laterodorsal tegmentum (LDT) and neighbouring mesopontine nuclei are thought to influence mesolimbic dopaminergic neuronal activity involved in goal-directed behaviours. We measured the changes in dopamine oxidation current (corresponding with dopamine efflux) in the nucleus accumbens (NAc) in response to electrical stimulation of the LDT using in vivo chronoamperometry in urethane-anaesthetized rats. LDT stimulation (35 Hz pulse trains for 60 s, 1 s intertrain interval) evoked a three-component change in dopamine efflux in the NAc: (i) an initial stimulation time-locked increase in the dopamine signal above baseline, followed by (ii) an immediate decrease below baseline, and thereafter by (iii) a prolonged increase in the dopamine signal above baseline. Intra-VTA infusion of the nicotinic receptor antagonist mecamylamine (5 microg/0.5 microL) or the ionotropic glutamate receptor antagonist kynurenate (10 microg/microL) attenuated the first LDT-elicited component. The second suppressive component was abolished by intra-LDT infusions of either the nonselective or the M2-selective muscarinic receptor antagonists scopolamine (100 microg/microL) and methoctramine (50 microg/microL), respectively. In contrast, intra-VTA infusions of scopolamine (200 microg/microL) resulted in a selective attenuation of the third facilitatory component, whereas both second and third components were abolished by systemic injections of scopolamine (5 mg/kg). These results suggest that the initial increase, subsequent decrease, and final prolonged increase in extracellular dopamine levels in the NAc are selectively mediated by LDT-elicited activation of (i) nicotinic and glutamatergic receptors in the VTA, (ii) muscarinic M2 autoreceptors on LDT cell bodies, and (iii) muscarinic receptors in the VTA, respectively.

Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

“…In support of this notion, it has been shown that acetylcholine levels in the VTA increase in response to feeding and drinking (Rada et al, 2000). Moreover, electrical or chemical stimulation of the pedunculopontine and laterodorsal tegmental nuclei (PPTg and LdTg), the brainstem nuclei containing acetylcholinergic neurons that send afferents to the VTA, induces burst firing of midbrain dopaminergic cells (Lokwan et al, 1999;Floresco et al, 2003) and increases dopamine release in the nucleus accumbens, in part by activating nAChRs and NMDA receptors in the VTA (Forster and Blaha, 2000). Our data suggest that under conditions of high cholinergic activity, acetylcholine may activate a7 nAChRs located on glutamatergic terminals to enhance glutamate release.…”

“…Another possibility could be that inhibition involving mAChRs occurs at the level of the LdTg. Increased levels of acetylcholine due to AChE inhibition in the LdTg might thus activate autoinhibitory mAChRs and, thereby, inhibit the activity of these cells (Luebke et al, 1993;Forster and Blaha, 2000) with a resulting decrease in the release of acetylcholine in the VTA. The fact that following the highest dose of galantamine there was no significant effect on firing rate or prefrontal dopamine output may be related to a similar mechanism.…”

Identification of Wake-Active Dopaminergic Neurons in the Ventral Periaqueductal Gray Matter

“…All of these neurotransmitters excite VTA dopaminergic neurons (Gronier and Rasmussen, 1998;Forster and Blaha, 2000;Lejeune and Millan, 2000;Uramura et al, 2001) and, hence, are probably also excitatory in the vPAG.…”

Previous Exposure to VTA Amphetamine Enhances Cocaine Self-Administration under a Progressive Ratio Schedule in an NMDA, AMPA/Kainate, and Metabotropic Glutamate Receptor-Dependent Manner

“…Of these, the descending excitatory amino acid projection from the PFC to the VTA has been particularly implicated in the induction of psychostimulant sensitization, because lesions of the PFC prevent the induction of locomotor sensitization by systemic and intra-VTA (Cador et al, 1999) AMPH. Interestingly, recent anatomical (Carr and Sesack, 2000), neurochemical (Takahata and Moghaddam, 2000), and electrophysiological (Lokwan et al, 1999) reports suggest that the PFC-VTA glutamatergic projection does not regulate VTA-NAcc DA neurons directly but rather via polysynaptic midbrain circuits using GABA, glutamate, acetylcholine, and perhaps other transmitters originating in the VTA and sites (eg pedunculopontine and laterodorsal nuclei; Lokwan et al, 1999;Forster and Blaha, 2000) projecting to it. The contribution of these local circuits as well as non-PFC originating glutamatergic afferents to the VTA to the enhancement of psychostimulant self-administration produced by previous exposure to AMPH remains to be elucidated.…”