Abstract
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase recently implicated in biochemical, physiological, and behavioral responses to ethanol. Thus, manipulation of ALK signaling may represent a novel approach to treating alcohol use disorder (AUD). Ethanol induces adaptations in glutamatergic synapses onto nucleus accumbens shell (NAcSh) medium spiny neurons (MSNs), and putative targets for treating AUD may be validated for further development by assessing how their manipulation modulates accumbal glutamatergic synaptic transmission and plasticity. Here, we report that Alk knockout (AlkKO) mice consumed greater doses of ethanol, relative to wild-type (AlkWT) mice, in an operant self-administration model. Using ex vivo electrophysiology to examine excitatory synaptic transmission and plasticity at NAcSh MSNs that express dopamine D1 receptors (D1MSNs), we found that the amplitude of spontaneous excitatory post-synaptic currents (EPSCs) in NAcSh D1MSNs was elevated in AlkKO mice and in the presence of an ALK inhibitor, TAE684. Furthermore, when ALK was absent or inhibited, glutamatergic synaptic plasticity – long-term depression of evoked EPSCs – in D1MSNs was attenuated. Thus, loss of ALK activity in mice is associated with elevated ethanol consumption and enhanced excitatory transmission in NAcSh D1MSNs. These findings add to the mounting evidence of a relationship between excitatory synaptic transmission onto NAcSh D1MSNs and ethanol consumption, point toward ALK as one important molecular mediator of this interaction, and further validate ALK as a target for therapeutic intervention in the treatment of AUD.
Highlights
One major objective of neuropsychopharmacological research is the identification and validation of novel targets for medication developments for substance use disorders (SUDs) – especially prevalent SUDs such as alcohol use disorder (AUD)
We recently proposed that novel targets for the treatment of AUD might be validated for their potential therapeutic development by assessing how their manipulation modulates N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) of alphaamino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)-mediated excitatory post-synaptic currents (EPSCs) in nucleus accumbens (NAc) shell (NAcSh) medium spiny neurons (MSNs) (Renteria et al, 2016a)
We examined the effects of Alk deletion or acute pharmacological inhibition of Anaplastic lymphoma kinase (ALK) on the physiology of D1 dopamine receptor-expressing MSNs (D1MSNs) in the nucleus accumbens shell (NAcSh), and focused subsequent investigation on glutamatergic input to these neurons since our prior and current work implicates excitatory synaptic plasticity (i.e., NMDAR-dependent LTD) of NAcSh D1MSNs in ethanol-induced neuroadaptations
Summary
One major objective of neuropsychopharmacological research is the identification and validation of novel targets for medication developments for substance use disorders (SUDs) – especially prevalent SUDs such as alcohol use disorder (AUD). The receptor tyrosine kinase anaplastic lymphoma kinase (ALK) has been implicated as a modulator of biochemical, physiological, and behavioral responses to ethanol and psychostimulants AlkKO did not show the escalation in two-bottle choice ethanol drinking that normally results from repeated cycles of chronic, intermittent, ethanol (CIE) vapor exposure and withdrawal. This pattern of effects was paralleled in spontaneous gamma-aminobutyric acid (GABA) transmission in the central nucleus of the amygdala (CeA): ethanol naïve AlkKO exhibited greater frequency of GABAergic inhibitory post-synaptic current (IPSC) events relative to AlkWT, but CIE did not increase IPSC frequency in AlkKO as it did in AlkWT. Single nucleotide polymorphisms in human ALK were associated with behavioral sensitivity to ethanol in an experimental setting (Lasek et al, 2011b) and alcohol dependence in a meta-analysis of genome-wide association studies (Wang et al, 2011)
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