Initial rewarding effects of cocaine and amphetamine assessed in a day using the single‐exposure place preference protocol

Abstract

In rodents, only a single dose of cocaine or amphetamine is required to cause a marked increase in extracellular dopamine, induce hyperlocomotion and cause persistent plasticity changes within dopaminergic neurons of the ventral tegmental area (VTA). The initial drug experience is suggested to predict vulnerability of developing addiction, but only few studies have assessed the perception of reward accompanying this initial exposure. We recently presented an approach to assess the initial rewarding effects of cocaine in mice with a single-exposure place preference (sePP) protocol, avoiding repeated drug injections. Here, we demonstrate a condensed version of the sePP, allowing assessment of initial subjective reward-perception within a day. By using this protocol, we demonstrate that a single exposure to both cocaine and amphetamine is sufficient to induce place preference. Furthermore, we use chemogenetics ( Designer Receptors Exclusively Activated by Designer Drugs [DREADD]) to show that both inhibitory and stimulatory modulation of VTA DA signalling disrupts cocaine-induced place preference in the condensed sePP. Our findings support the presence of initial reward-perception of both cocaine and amphetamine, and the formation of drug-context association. In addition, our data support that VTA DA signalling prior to drug exposure affects either reward-perception or the time during which associations are formed, thereby preventing induction of cocaine-induced place preference in the sePP. The easy and timesaving sePP protocol should form a critical basis for further deciphering the complex mechanisms underlying the progression from the initial drug experience to escalating drug intake and addiction.

Effects of brief inhibition of the ventral tegmental area dopamine neurons on the cocaine seeking during abstinence

“…Moreover, dopamine is critically involved in a number of processes that all shape goal‐directed behavior: de novo learning, updating behavior in light of changing rewards or environments, action selection and initiation. While it is possible to dissect experimentally these phenomena, eg, by studying action initiation, 58 by differentiating valence from salience, ie, “liking” from “wanting,” or motivation to pursue a reward, 66,67 and by studying differential receptor mechanisms engaged in expression versus acquisition of learned behavior, 68 bottom‐up manipulation of these components by modulation of the VTA is an ongoing challenge. With the recent advent of advanced intersectional genetic tools, and resulting characterization of different populations of VTA DA neurons exhibiting different properties 69 and projecting to different output structures, 70 such manipulations will be much more practical.…”

mPD5, a peripherally restricted PICK1 inhibitor for treating chronic pain

“…Initial perception of the drugs was measured by single exposure place preference experiments performed in an elongated three compartment apparatus (67.5 cm x 24 cm) with a biased design of different floor textures and wall pattens and a neutral zone in the middle. We have previously shown that mice of both genders exhibit a strong bias towards the striped compartment, and that a single exposure of psychostimulants in the grey compartment sufficiently changes the preference towards that compartment (Jensen et al ., 2021; Runegaard et al ., 2017; Runegaard et al , 2019). For further details of the setup, we refer to (Runegaard et al ., 2017).…”

Addiction in focus: molecular mechanisms, model systems, circuit maps, risk prediction and the quest for effective interventions

“…Of significant interest from a preclinical perspective, mechanistic approaches further used a behavioural biomarker (demand for cocaine) to predict progression to addiction and response to treatment with orexin‐based therapies (James et al ., ). Efforts to avoid repeated drug injections and to allow assessment of initial subjective reward perception, in mice produced a condensed version of a place preference protocol, showing that a single exposure to both cocaine and amphetamine is sufficient to induce place preference (Runegaard et al ., ). These data also suggest that measuring VTA DA signalling prior to drug exposure can add to the tools available to further decipher the complex mechanisms underlying the progression from initial drug experience to escalating drug intake and addiction.…”