Opioid-induced rewards, locomotion, and dopamine activation: A proposed model for control by mesopontine and rostromedial tegmental neurons

Abstract

Opioids, such as morphine or heroin, increase forebrain dopamine (DA) release and locomotion, and support the acquisition of conditioned place preference (CPP) or self-administration. The most sensitive sites for these opioid effects in rodents are in the ventral tegmental area (VTA) and rostromedial tegmental nucleus (RMTg). Opioid inhibition of GABA neurons in these sites is hypothesized to lead to arousing and rewarding effects through disinhibition of VTA DA neurons. We review findings that the laterodorsal tegmental (LDTg) and pedunculopontine tegmental (PPTg) nuclei, which each contain cholinergic, GABAergic, and glutamatergic cells, are important for these effects. LDTg and/or PPTg cholinergic inputs to VTA mediate opioid-induced locomotion and DA activation via VTA M5 muscarinic receptors. LDTg and/or PPTg cholinergic inputs to RMTg also modulate opioid-induced locomotion. Lesions or inhibition of LDTg or PPTg neurons reduce morphine-induced increases in forebrain DA release, acquisition of morphine CPP or self-administration. We propose a circuit model that links VTA and RMTg GABA with LDTg and PPTg neurons critical for DA-dependent opioid effects in drug-naïve rodents.

Keywords: Acetylcholine; Addiction; GABA; Glutamate; Laterodorsal tegmental nucleus; Morphine; Pedunculopontine tegmental nucleus; Reward.

Figure 1. Increases in accumbal DA induced by LDTg electrical stimulation depend mainly on VTA muscarinic AChRs

(A) Chronoamperometric recordings depicting the time course of increases on NAcc DA efflux following LDTg electrical stimulation (arrow) in rats. Accumbal DA increases immediately following LDTg electrical stimulation (Phase 1) depend on nicotinic AChRs and ionotropic GLU receptors in the VTA. This is followed by decreases in DA (Phase 2) that depend on LDTg M2 and M4 muscarinic autoreceptors. DA levels then increase again and remain elevated for approximately 60 min (Phase 3). This late and prolonged phase in increased accumbal DA efflux is completely blocked by VTA infusions of the mAChR antagonist scopolamine (Figure adapted from Yeomans et al., 2001). (B) Chronoamperometric recordings depicting the time course of increases on NAcc DA efflux following LDTg electrical stimulation (arrow) in wild-type (top panel) and M5 knockout (bottom panel) mice. LDTg electrical stimulation in mice induces the same tri-phasic increases in accumbal DA efflux as in rats and systemic pretreatment with the muscarinic AChR antagonist scopolamine selectively blocks the late prolonged phase in increased accumbal DA efflux (top panel, red squares and blue triangles, respectively). Knockout mice lacking M5 receptors – the only mAChR subtype expressed by VTA DA neurons (Vilaró et al., 1990) – selectively abolishes the late prolonged phase in increased accumbal DA efflux (Figure adapted from Forster et al., 2002b).

Figure 2. Increases in accumbal DA induced by intravenous morphine are attenuated by excitotoxic lesions of the LDTg (A) or by VTA pretreatment with the muscarinic AChR antagonist scopolamine (B)

(A) Chronoamperometric recordings depicting the time course of increases on NAcc DA efflux induced by intravenous morphine (2 mg/kg) administration (arrow) in LDT-lesioned (LDT-X; red triangles) and sham control (blue squares) rats. In sham control rats, systemic injection of morphine induces long-lasting increases in accumbal DA. In LDTg-lesioned rats these increases are markedly attenuated. Points represent the mean changes in the chronoamperometric responses and solid lines the SEM. Red and blue dashed lines correspond, respectively, to the effects of pedunculopontine tegmental nucleus and sham lesions on morphine-evoked increases in striatal DA efflux (Figure adapted from Forster et al., 2002a). (B) Chronoamperometric recordings depicting time course of increases in NAcc DA efflux induced by intravenous morphine (2 mg/kg) administration following VTA pretreatment with scopolamine (SCO; 200 µg) or vehicle (PBS). Systemic injection of morphine induces long-lasting increases in accumbal DA release (blue dashed line). VTA muscarinic AChR blockade strongly reduces these increases (red circles). Arrows indicate termination of intra-VTA infusion and commencement of i.v. injection, red circles represent mean changes in the chronoamperometric responses with respect to baseline (0%), and solid black lines the SEM. (Figure adapted from Miller et al., 2005).

Figure 3. Opposite effects of virally-mediated upregulation of M5 AChRs in VTA and RMTg

(A) VTA sites where virally-mediated upregulation of M5 receptors increases morphine-induced locomotion in wild-type mice are shown with green spots. RMTg sites where virally-mediated upregulation of M5 receptors decreased morphine-induced locomotion are shown with red spots. Sites at which control viral vectors were infused are shown by blue spots (VTA) and orange spots (RMTg) (Franklin and Paxinos, 2007). (B) Virally-mediated upregulation of M5 receptors in VTA (left; green bars) significantly increased total locomotion at two doses of morphine relative to VTA control viral vectors (blue bars). No differences were observed for saline locomotion. By contrast, virally-mediated upregulation of M5 receptors in RMTg (right; red bars) significantly reduced total locomotion at the 30 mg/kg morphine dose relative to RMTg control vectors (orange bars). No differences were observed for saline locomotion (Figures adapted from Wasserman et al., 2013).

Figure 4. Model of midbrain and pontine control of morphine-induced locomotion

RMTg GABA neurons tonically inhibit VTA DA neurons and LDTg/PPTg ACh neurons. VTA GABA neurons also tonically inhibit VTA DA neurons and LDTg/PPTg ACh neurons. Opioids inhibit RMTg and VTA GABA neurons through agonism of the μ-opioid receptor, leading to disinhibition of VTA DA and LDTg/PPTg ACh neurons. The now disinhibited LDTg and PPTg ACh neurons increase ACh efflux to the VTA and the RMTg. ACh efflux in the VTA leads to activation of M5 muscarinic receptors on DA neurons, resulting in increased NAcc DA efflux and DA-mediated locomotion. ACh efflux in the RMTg further modulates opioid locomotion via M3 and M4 muscarinic ACh receptors. Plus signs (+) indicate excitatory signals, minus signs (−) indicate inhibitory signals. μ, μ-opioid receptor; GLU, glutamate; NAcc, nucleus accumbens.