Understanding the neurobiology of relapse to cocaine addiction and in related psychopathologies
Final Report Abstract
Antipsychotic medications are commonly used to treat psychosis and other mental conditions and are particularly effective as short-term intervention in most patients. Instead, chronic antipsychotic treatment is very often characterized by decreased therapeutic efficacy and a parallel surge of motor and metabolic side effects. This clinical outcome motivates patients to reduce or to stop antipsychotic intake. The discontinuation of antipsychotic treatment by itself exacerbates the symptoms of mental illness such as psychosis and increases the probability of future relapse. Most of these side effects are defined as antipsychotic-induced behavioral supersensitivity a condition interpreted as increased sensitivity of the dopamine D2-type receptor to endogenous dopamine. Specifically, it is thought that chronic antipsychotics increase membrane expression and/or function of the D2 receptor. Although these interpretations are very popular and there are some studies supporting this line of thinking, multiple preclinical and clinical studies show that increasing D2 receptor expression or function is not precisely related to behavioral supersensitivity. For example, antipsychotic-induced supersensitivity can be observed: 1) in absence of D2 receptor changes in animal models, 2) either during ongoing treatment with significant D2 receptor blockade or after antipsychotic discontinuation. Furthermore it has been shown that 3) increased membrane expression or function of the D2 receptor is more likely associated with high doses whereas antipsychotic-induced supersensitivity can be detected with lower doses (which are less likely to alter receptor expression) and long-term treatment of antipsychotics, 4) Human imaging studies and meta-analyses of studies on human patients with psychosis that have been treated or have discontinued treatment reveal only modest changes in D2 receptor expression in some patients or not at all. Given this inconsistent body of literature, we set out to describe the definitive neurobiological mechanisms and symptoms of antipsychotic-induced behavioral supersensitivity. By combining cutting edge viral vectors for cell-type specific labeling as well as electrophysiology, behavior, imaging and genetic approaches we found a clear neurobiological pathway to antipsychotic-induced behavioral supersensitivity that specifically involves enhanced excitability of D2 receptor expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). D2-MSNs are the most common neuron type in the striatum and the NAcore is part of the ventral striatum that encodes reward, cognition and motor outputs. Within this brain region D2-MSNs play a major role in normal and pathological behaviors, including psychosis and substance use disorder. Our approach indicates that antipsychotic-induced behavioral supersensitivity is not mediated by the suggested increased expression of the D2 receptor or by enhanced sensitivity of dopaminergic signaling via the D2 receptor. By using a sensor detecting dopamine signaling on D2-MSNs, we found that dopamine was unable to generate inhibitory currents canonically generated by D2 receptor stimulation. On the contrary, a proportion of D2-MSNs were excited at baseline and paradoxically in response to cocaine, suggesting that the constitutive dopamine signaling at the D2 receptor is lost and D2-MSNs can no longer be inhibited by dopamine during antipsychotic-induced supersensitivity. If the D2 receptor was more sensitive during antipsychotic-induced supersensitivity due to increased expression or function, it would have enhanced inhibitory currents instead. A fundamental consequence deriving from the loss of inhibitory inputs at the D2 receptor is enhanced excitatory modulation of D2-MSNs, which results in hyperexcitation of D2- MSNs and in synaptic plasticity during antipsychotic-induced behavioral supersensitivity. This excitatory plasticity was long-lasting and resulted in an increased ratio of the AMPA and NMDA receptors. While NMDA currents decreased, we found increased expression of Ca2+-permeable AMPA receptors, a glutamatergic ion channel involved in several types of synaptic plasticity. This synaptic adaptation leads to increased Ca2+ events in D2-MSNs that we detected using in vivo imaging, during the expression of antipsychotic-induced behavioral supersensitivity. Independently we also found plasticity in astrocyte motility that enhances excitatory signaling in the NAcore. Overall, our study suggests that antipsychotic-induced behavioral supersensitivity is driven by enhanced excitatory transmission onto NAcore D2-MSNs. We obtained confirmation of the causality of NAcore D2-MSN hyperexcitability in behavioral supersensitivity since chemogenetic restoration of the D2 receptor-dependent inhibitory current (i.e. Gi signaling) in D2-MSNs was sufficient to prevent the supersensitive response to cocaine. Separately, we also characterized the most common behavioral symptoms associated with antipsychotic-induced supersensitivity. Animals that had undergone antipsychotic discontinuation displayed antipsychotic treatment resistance, however they did not show the expected oral dyskinesia, which instead was highly expressed during ongoing antipsychotic treatment. Importantly, animals that discontinued antipsychotic treatment maintained elevated cocaine-seeking during withdrawal and in response to cues compared to cocaine-addicted controls. These behavioral findings are highly clinically relevant and point to antipsychotic discontinuation as a potential underlying factor contributing to the epidemiological observation that substance use disorder is often comorbid with schizophrenia and other psychiatric disorders where patients are medicated with antipsychotic drugs. Altogether our study will help to guide future experimental approaches in medicine to prevent or treat behavioral supersensitivity by specifically targeting the increased excitability of D2-MSNs and their potentiated glutamatergic inputs rather than preventing putative receptor changes.
Publications
- A dopaminergic mechanism of antipsychotic drug efficacy, failure, and failure reversal: the role of the dopamine transporter. Mol Psychiatry. 2018 Sep; 25(9):2101-2118
Amato D, Canneva F, Cumming P, Maschauer S, Groos D, Wrosch JK et al.
(See online at https://doi.org/10.1038/s41380-018-0114-5) - Dopamine, the antipsychotic molecule: a perspective on mechanisms underlying antipsychotic response variability. Neurosci Biobehav Rev. 2018 Feb; 85:146-159
Amato D, Vernon AC, Papaleo F
(See online at https://doi.org/10.1016/j.neubiorev.2017.09.027) - Hypofunctional Dopamine Uptake and Antipsychotic Treatment Resistant Schizophrenia. Frontiers in Psychiatry. 2019 May; 10:314
Amato D, Kruyer A, Samaha AN, Heinz A
(See online at https://doi.org/10.3389/fpsyt.2019.00314) - Neuronal signature of an antipsychotic response. In revision – Molecular Psychiatry
Parrilla-Carrero J, Kruyer A, Chalhoub R, Angelis A, Powell C, Jhou T, Resendez S, Amato D
(See online at https://doi.org/10.21203/rs.3.rs-72975/v1) - Opportunities for innovation and translation in behavioral neuroscience. Pharmacol Biochem Behav. 2020 Aug; 195:172957
Hall FS, Amato D, Baracz SJ
(See online at https://doi.org/10.1016/j.pbb.2020.172957) - Accumbens D2-MSN hyperactivity drives behavioral supersensitivity. Mol Psychiatry 26, 6159–6169 (2021)
Kruyer A, Parrilla-Carrero J, Powell C, Brandt L, Gutwinski S, Angelis A, Chalhoub R, Jhou T, Kalivas PW, Amato D
(See online at https://dx.doi.org/10.1038/s41380-021-01235-6) - Presynaptic vesicular accumulation is required for the antipsychotic action of haloperidol. Journal of Psychopharmacology. 2021 Jan; 35(1):65-77
Uzuneser T, Weiss EM, Dahlmanns EM, Amato D, Kornhuber J, Alzheimer C, Jan Hellmann J, Kaindl J, Hübner H, Löber S, Gmeiner P; Grömer TW, Müller CP
(See online at https://doi.org/10.1177/0269881120965908) - The pharmacotherapy of schizophrenia: Mechanisms of antipsychotic accumulation, therapeutic action and failure. Behav Brain Res. 2021 Apr 9; 403:113144
Chestnykh DA, Amato D, Kornhuber J, Müller CP
(See online at https://doi.org/10.1016/j.bbr.2021.113144)
