LAUSR

Substance addiction inflicts an enormous burden on patients with formidable costs to society. Loss of control over substance use is a hallmark of addiction. It marks the stage where substance use has progressed from casual to compulsive and persists despite negative consequences. It is thought that this progression arises after lengthy and excessive substance use, as a result of neurobiological dysfunctions. One of the neural mechanisms that has been proposed to contribute to loss of control use is exaggerated involvement of the dorsolateral striatum (DLS), which mediates habitual behaviour [1,2]. This study examines how changes in DLS functioning contribute to loss of control over reward seeking. First, we assessed the effect of long-term exposure to alcohol on synaptic plasticity in a cortical projection onto neurons in the DLS. To map cortical inputs towards the DLS, rats were bilaterally injected with a retrograde rabies virus (Rabies-SadDG-GFP) in the DLS. Using immunohistochemistry, we found GFP expression in different cortical areas, including the primary and secondary motor cortex. Next, voluntary home-cage alcohol consumption was monitored in outbred Lister-Hooded rats. We used a two-month intermittent alcohol access paradigm and found substantial individual variation in alcohol intake, consistent with our previous findings. Based on a rank score of their voluntary alcohol intake, low and high consuming animals were then selected and bilaterally injected with an adeno-associated Channelrhodopsin virus (AAV5-CamKII-Chr2-eYFP) targeted at the identified motor cortices that project onto neurons in the DLS. Whole-cell patch clamp recordings were performed to measure optically induced excitatory post-synaptic currents in neurons in the DLS. Our preliminary results indicate increased facilitation of paired-pulse responses in the DLS in rats that show a high voluntary alcohol consumption. This increase is caused by reduced amplitude of the first post-synaptic response, indicative of a reduced presynaptic release probability. In parallel, we assessed whether activation of the DLS is sufficient to drive habitual behaviour and loss of control over sucrose seeking. To investigate habitual behavior, changes in sensitivity for outcome devaluation were measured after pre-feeding animals with either sucrose or chow before operant training. Loss of control over sucrose seeking was examined in a task in which we measure continued responding during a conditioned cue that predicts probabilistic footshock punishment. To enhance neuronal activity of the DLS, rats received bilateral injections of an adeno-associated DREADD virus (AAV5-hSyn-hMD3q-mCherry). Systemic clozapine N-oxide (CNO) injections did not change the sensitivity to outcome devaluation. Furthermore, we show that the presentation of the footshock-predictive cue profoundly suppresses responding for sucrose, but this is unaffected by CNO injections. In sum, our data indicate that long-term ingestion of large quantities of alcohol modulates short-term synaptic plasticity in glutamatergic cortical inputs into the DLS. However, chemogenetic activation of the DLS does not seem sufficient to evoke habitual or compulsive behaviour.