Cocaine Selectively Reorganizes Excitatory Inputs to Substantia Nigra Pars Compacta Dopamine Neurons

Abstract

Substantia nigra pars compacta (SNc) dopamine neurons and their targets are involved in addiction and cue-induced relapse. However, afferents onto SNc dopamine neurons themselves appear insensitive to drugs of abuse, such as cocaine, when afferents are collectively stimulated electrically. This contrasts with ventral tegmental area (VTA) dopamine neurons, whose glutamate afferents react robustly to cocaine. We used an optogenetic strategy to isolate identified SNc inputs and determine whether cocaine sensitivity in the mouse SNc circuit is conferred at the level of three glutamate afferents: dorsal raphé nucleus (DR), pedunculopontine nucleus (PPN), and subthalamic nucleus (STN). We found that excitatory afferents to SNc dopamine neurons are sensitive to cocaine in an afferent-specific manner. A single exposure to cocaine led to PPN-innervated synapses reducing the AMPA-to-NMDA receptor-mediated current ratio. In contrast to work in the VTA, this was due to increased NMDA receptor function with no change in AMPA receptor function. STN synapses showed a decrease in calcium-permeable AMPA receptors after cocaine, but no change in the AMPA-to-NMDA ratio. Cocaine also increased the release probability at DR-innervated and STN-innervated synapses, quantified by decreases in paired-pulse ratios. However, release probability at PPN-innervated synapses remained unaffected. By examining identified inputs, our results demonstrate a functional distribution among excitatory SNc afferent nuclei in response to cocaine, and suggest a compelling architecture for differentiation and separate parsing of inputs within the nigrostriatal system. Prior studies have established that substantia nigra pars compacta (SNc) dopamine neurons are a key node in the circuitry that drives addiction and relapse, yet cocaine apparently has no effect on electrically stimulated excitatory inputs. Our study is the first to demonstrate the functional impact of a drug of abuse on synaptic mechanisms of identified afferents to the SNc. Optogenetic dissection of inputs originating from dorsal raphé, pedunculopontine, and subthalamic nuclei were tested for synaptic modifications following cocaine exposure. Our results demonstrate that cocaine differentially induces modifications to SNc synapses depending on input origin. This presents implications for understanding dopamine processing of motivated behavior; most critically, it indicates that dopamine neurons selectively modulate signal reception processed by afferent nuclei.

Dopamine and addiction: what have we learned from 40 years of research

“…DA neurons from the SNc can selectively modulate the information processed by different input nuclei. For example, the AMPA/NMDA ratio is decreased at the PPTg-inputs to SNc, whereas it is unchanged in the STN-inputs to SNc (Beaudoin et al 2018).…”

“…A single exposure to drugs and in particular psychostimulants, also alter the activity of SNc DA neurons and play a role in the increased expression of behavior mediated by DA release in the DSt (Zahniser et al 1998;Wolf 1998). A recent study, using optogenetics, has highlighted changes in specific glutamatergic afferents onto SNc neurons following a single cocaine exposure (Beaudoin et al 2018). Whereas previous studies showed that a single exposure to cocaine increases EPSCs in the VTA but failed to find an effect in the SNc (Ungless et al 2001;Lammel et al 2011), this could be due to the use of non-specific electrical stimulation of SNc DA neurons excitatory inputs.…”

“…Whereas previous studies showed that a single exposure to cocaine increases EPSCs in the VTA but failed to find an effect in the SNc (Ungless et al 2001;Lammel et al 2011), this could be due to the use of non-specific electrical stimulation of SNc DA neurons excitatory inputs. Thus, cocaine-induced plasticity appears to be dependent on the types of afferents involved, specifically the STN-SNc and PPTg-SNc (Beaudoin et al 2018). DA neurons from the SNc can selectively modulate the information processed by different input nuclei.…”

Genome-wide association meta-analysis of cocaine dependence: Shared genetics with comorbid conditions

“…Furthermore, the analysis of the promoter-associated mark H3K4me3 in individual cells/tissues Woo et al 2017) highlighted a nominal enrichment of SNP heritability in brain tissues and neuronal cell lines. The highest enrichment was observed in substantia nigra, which plays an important role in reward and thus it may be related to the development of the dependence (Beaudoin et al 2017).…”

Neurophysiological and neuropsychological damages produced by cocaine in adult populations

“…Men have higher rates of risk of death from cocaine use in relation to women. 17 This is because adult males have a higher risk of heart attacks and consume higher doses of cocaine in search of adrenaline and altered states of consciousness. The adverse effects of cocaine use are clearly seen in the cardiovascular system, since they produce significant increases in heart rate, generate alterations in blood pressure and adversely affect the contractility of the left ventricle of the heart.…”