Abstract
Opiates, like other addictive drugs, elevate forebrain dopamine levels and are thought to do so mainly by inhibiting GABA neurons near the ventral tegmental area (VTA), in turn leading to a disinhibition of dopamine neurons. However, cholinergic inputs from the laterodorsal (LDT) and pedunculopontine (PPT) tegmental nucleus to the VTA and substantia nigra (SN) importantly contribute, as either LDT or PPT lesions strongly attenuate morphine-induced forebrain dopamine elevations. Pharmacological blockade of muscarinic acetylcholine receptors in the VTA or SN has similar effects. M5 muscarinic receptors are the only muscarinic receptor subtype associated with VTA and SN dopamine neurons. Here we tested the contribution of M5 muscarinic receptors to morphine-induced dopamine elevations by measuring nucleus accumbens dopamine efflux in response to intra-VTA morphine infusion using in vivo chronoamperometry. Intra-VTA morphine increased nucleus accumbens dopamine efflux in urethane-anesthetized wildtype mice starting at 10 min after infusion. These increases were absent in M5 knockout mice and were similarly blocked by pre-treatment with VTA scopolamine in wildtype mice. Furthermore, in wildtype mice electrical stimulation of the PPT evoked an initial, short-lasting increase in striatal dopamine efflux, followed 5 min later by a second prolonged increase in dopamine efflux. In M5 knockout mice, or following systemic pre-treatment with scopolamine in wildtype mice, the prolonged increase in striatal dopamine efflux was absent. The time course of increased accumbal dopamine efflux in wildtype mice following VTA morphine was consistent with both the prolonged M5-mediated excitation of striatal dopamine efflux following PPT electrical stimulation and accumbal dopamine efflux following LDT electrical stimulation. Therefore, M5 receptors appear critical for prolonged PPT excitation of dopamine efflux and for dopamine efflux induced by intra-VTA morphine.
Highlights
Dopamine neurotransmission in the forebrain plays an important role in the reinforcing effects of drugs of abuse [1]
Our results suggest that ventral tegmental area (VTA) opiates may indirectly activate dopamine neurons through a mechanism involving a PPT/LDT cholinergic relay
In M5 knockout mice the same dose of intra-VTA morphine induced a slight decrease in accumbal dopamine efflux relative to saline, starting at 5.962.0 min, that returned to pre-injection baseline levels by 92.069.8 min and subsequently showed a slight increase to above baseline over the final 30 min (Fig. 2B)
Summary
Dopamine neurotransmission in the forebrain plays an important role in the reinforcing effects of drugs of abuse [1]. Opiate drugs like heroin and morphine are thought to affect dopaminergic neurotransmission through their actions near the ventral tegmental area (VTA), where opiates inhibit local gammaaminobutyric acid (GABA) neurons by acting on mu opioid receptors [2], leading to increased firing of dopamine neurons via disinhibition [3,4], and increased accumbal dopamine [5,6]. PPT or LDT lesions reduce most of the striatal or accumbal dopamine increases following systemic morphine [9,10]. VTA or SN infusions of the non-selective muscarinic receptor antagonist scopolamine reduce most striatal or accumbal dopamine increases following systemic morphine [11]. Intra-VTA infusion of the muscarinic antagonist atropine reduces morphine place preference in rats [14]
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