Karine Guillem

Monoamine Oxidase Inhibition Dramatically Increases the Motivation to Self-Administer Nicotine in Rats

Nicotine is the major neuroactive compound of tobacco, which has, by itself, weak reinforcing properties. It is known that levels of the enzymes monoamine oxidase A (MAO-A) and MAO-B are reduced in the platelets and brains of smokers and that substances, other than nicotine, present in tobacco smoke have MAO-inhibitory activities. Here, we report that inhibition of MAO dramatically and specifically increases the motivation to self-administer nicotine in rats. These effects were more prominent in rats selected for high responsiveness to novelty than in rats with low responsiveness to novelty. The results suggest that the inhibition of MAO activity by compounds present in tobacco smoke may combine with nicotine to produce the intense reinforcing properties of cigarette smoking that lead to addiction.

Sugar addiction: pushing the drug-sugar analogy to the limit

Purpose of reviewTo review research that tests the validity of the analogy between addictive drugs, like cocaine, and hyperpalatable foods, notably those high in added sugar (i.e., sucrose). Recent findingsAvailable evidence in humans shows that sugar and sweetness can induce reward and craving that are comparable in magnitude to those induced by addictive drugs. Although this evidence is limited by the inherent difficulty of comparing different types of rewards and psychological experiences in humans, it is nevertheless supported by recent experimental research on sugar and sweet reward in laboratory rats. Overall, this research has revealed that sugar and sweet reward can not only substitute to addictive drugs, like cocaine, but can even be more rewarding and attractive. At the neurobiological level, the neural substrates of sugar and sweet reward appear to be more robust than those of cocaine (i.e., more resistant to functional failures), possibly reflecting past selective evolutionary pressures for seeking and taking foods high in sugar and calories. SummaryThe biological robustness in the neural substrates of sugar and sweet reward may be sufficient to explain why many people can have difficultly to control the consumption of foods high in sugar when continuously exposed to them.

Monoamine oxidase A rather than monoamine oxidase B inhibition increases nicotine reinforcement in rats

Although nicotine is considered to be responsible for the addictive properties of tobacco, growing evidence underlines the importance of non‐nicotine components in smoking reinforcement. It has been shown that tobacco smoke contains monoamine oxidase (MAO) A and B inhibitors and decreases MAO‐A and MAO‐B activity in smokers. Here, we investigated the effects of clorgyline hydrochloride (irreversible MAO‐A inhibitor; 2 mg/kg/day), selegiline (irreversible MAO‐B inhibitor; 4 mg/kg) and the beta‐carboline norharmane hydrochloride (reversible MAO‐B inhibitor; 5 mg/kg/day) treatments on nicotine self‐administration (30 µg/kg/infusion, free base) in rats. Independent of the responsiveness to novelty and locomotor activity stimulation, only clorgyline hydrochloride treatment increased the intake of nicotine in a fixed‐ratio schedule (FR5) of reinforcement. When a progressive‐ratio schedule was implemented, both clorgyline hydrochloride and norharmane hydrochloride treatments potentiated the reinforcing effects of nicotine, whereas selegiline had no effect. Taken together, these results indicate that MAO‐A inhibition interacts with nicotine to enhance its rewarding effects in rats and suggest that other compounds present in tobacco, such as beta‐carboline, may also play an important role in sustaining smoking behavior in humans.

Escalation of cocaine intake and incubation of cocaine seeking are correlated with dissociable neuronal processes in different accumbens subregions.

BACKGROUND Cocaine addiction is characterized by a progressive increase in drug intake and a persistent craving for the drug during prolonged abstinence. Whether these two prominent features of cocaine addiction are related to each other and are mediated by similar or different neuronal processes is currently unknown. METHODS Rats were first allowed to self-administer cocaine under long-access (6-hour) conditions to induce escalation of cocaine intake. Self-administration sessions were designed to measure both drug seeking and drug taking. After escalation, rats underwent a 1-month period of forced abstinence after which they were re-exposed to cocaine to induce re-escalation of cocaine intake. In vivo electrophysiologic recordings were conducted in the core and shell subregions of the nucleus accumbens (NAc) during cocaine intake escalation, after abstinence and during re-escalation. RESULTS After abstinence, escalated levels of cocaine taking decreased toward pre-escalation levels, whereas cocaine seeking increased persistently. These opposite postabstinence changes were uncorrelated. At the neuronal level, the postabstinence decrease in cocaine taking was correlated with a normalization of depressed neuronal activity in the NAc shell that had developed during escalation of cocaine intake. In contrast, the incubation-like increase in cocaine seeking was selectively correlated with a persistent increase in the proportion of neurons in the NAc core that phasically fire during cocaine seeking. CONCLUSIONS These findings show that cocaine taking and cocaine seeking evolve differently during abstinence from extended drug use and depend on dissociable neuronal processes in different subregions of the nucleus accumbens.

Voluntary Nicotine Consumption Triggers In Vivo Potentiation of Cortical Excitatory Drives to Midbrain Dopaminergic Neurons

Active response to either natural or pharmacological reward causes synaptic modifications to excitatory synapses on dopamine (DA) neurons of the ventral tegmental area (VTA). Here, we examine these modifications using nicotine, the main addictive component of tobacco, which is a potent regulator of VTA DA neurons. Using an in vivo electrophysiological technique, we investigated the role of key components of the limbic circuit, the infralimbic cortex (ILCx) and the bed nucleus of the stria terminalis (BNST), in operant behaviors related to nicotine reward. Our results indicated that nicotine self-administration in rats, but not passive delivery, triggers hyperactivity of VTA DA neurons. The data suggest that potentiation of the ILCx-BNST excitatory pathway is involved in these modifications in VTA DA neurons. Thus, recruitment of these specific excitatory inputs to VTA DA neurons may be a neural correlate for the learned association between active responding and the reward experience.

Monoamine Oxidase Inhibition Dramatically Prolongs the Duration of Nicotine Withdrawal-Induced Place Aversion

BACKGROUND Long-lasting effects of withdrawal from nicotine are hypothesized to contribute to relapse and persistence of tobacco habits, and significant evidence supports a role of monoamine oxidase inhibitors (MAOI) contained in cigarette smoke as potent modulators of the rewarding effects of tobacco. METHODS With quantification of somatic signs of withdrawal and the place aversion conditioning paradigm, we assessed the effects of MAOI pretreatment on both somatic and aversive motivational components of mecamylamine-induced nicotine withdrawal in rats rendered dependent on nicotine by the subcutaneous implantation of osmotic minipumps (vehicle or nicotine tartrate 9 mg/kg/day). RESULTS In nicotine-infused rats, mecamylamine induced a place aversion that lasted 6 weeks. When nicotine-infused rats were also treated with a MAOI, mecamylamine-induced conditioned place aversion persisted for at least 8 months of abstinence. The MAOI treatment slightly decreased ratings of somatic signs induced by mecamylamine administration but had no effect on the threshold or the magnitude of mecamylamine-induced conditioned place aversion. CONCLUSIONS These results show that MAOI pretreatment induces a long-lasting conditioned placed aversion associated with nicotine withdrawal, possibly through a potentiation of learning and memory process, and provides some indications on protracted abstinence that might be useful for delineating the neurobiological substrate of relapse.

Abstinence from Cocaine and Sucrose Self-Administration Reveals Altered Mesocorticolimbic Circuit Connectivity by Resting State MRI

Previous preclinical studies have emphasized that drugs of abuse, through actions within and between mesocorticolimbic (MCL) regions, usurp learning and memory processes normally involved in the pursuit of natural rewards. To distinguish MCL circuit pathobiological neuroadaptations that accompany addiction from general learning processes associated with natural reward, we trained two groups of rats to self-administer either cocaine (IV) or sucrose (orally) followed by an identically enforced 30 day abstinence period. These procedures are known to induce behavioral changes and neuroadaptations. A third group of sedentary animals served as a negative control group for general handling effects. We examined low-frequency spontaneous fluctuations in the functional magnetic resonance imaging (fMRI) signal, known as resting-state functional connectivity (rsFC), as a measure of intrinsic neurobiological interactions between brain regions. Decreased rsFC was seen in the cocaine-SA compared with both sucrose-SA and housing control groups between prelimbic (PrL) cortex and entopeduncular nucleus and between nucleus accumbens core (AcbC) and dorsomedial prefrontal cortex (dmPFC). Moreover, individual differences in cocaine SA escalation predicted connectivity strength only in the Acb-dmPFC circuit. These data provide evidence of fronto-striatal plasticity across the addiction trajectory, which are consistent with Acb-PFC hypoactivity seen in abstinent human drug addicts, indicating potential circuit level biomarkers that may inform therapeutic interventions. They further suggest that available data from cross-sectional human studies may reflect the consequence of rather a predispositional predecessor to their dependence.

Preference for Cocaine is Represented in the Orbitofrontal Cortex by an Increased Proportion of Cocaine Use-Coding Neurons

Cocaine addiction is a harmful preference for drug use over and at the expense of other nondrug-related activities. Here we identify in the rat orbitofrontal cortex (OFC) a mechanism that explains individual preferences between cocaine use and an alternative, nondrug action. OFC neuronal activity was recorded while rats performed each of these 2 actions separately or while they chose between them. First, we found that these actions are encoded by 2 nonoverlapping neuronal populations and that the relative size of the cocaine population represented individual preferences. A larger relative size was only observed in cocaine-preferring individuals. Second, OFC neurons encoding a given individuals preferred action progressively fired more than other action-coding neurons few seconds before the preferred action was actually chosen, suggesting a prechoice neuronal competition for action selection. In cocaine-preferring rats, this manifested by a prechoice ramping-up activity in favor of the cocaine population. Finally, pharmacological manipulation of prechoice activity in favor of the cocaine population caused nondrug-preferring rats to shift their choice to cocaine. Overall, this study suggests that an individual preference for cocaine is represented in the OFC by a population size bias that systematically advantages cocaine use-coding neurons during prechoice competition for action selection.

Acute Effects of Nicotine Amplify Accumbal Neural Responses during Nicotine-Taking Behavior and Nicotine-Paired Environmental Cues

Nicotine self-administration (SA) is maintained by several variables, including the reinforcing properties of nicotine-paired cues and the nicotine-induced amplification of those cue properties. The nucleus accumbens (NAc) is implicated in mediating the influence of these variables, though the underlying neurophysiological mechanisms are not yet understood. In the present study, Long-Evans rats were trained to self-administer nicotine. During SA sessions each press of a lever was followed by an intravenous infusion of nicotine (30 µg/kg) paired with a combined light-tone cue. Extracellular recordings of single-neuron activity showed that 20% of neurons exhibited a phasic change in firing during the nicotine-directed operant, the light-tone cue, or both. The phasic change in firing for 98% of neurons was an increase. Sixty-two percent of NAc neurons additionally or alternatively showed a sustained decrease in average firing during the SA session relative to a presession baseline period. These session decreases in firing were significantly less prevalent in a group of neurons that were activated during either the operant or the cue than in a group of neurons that were nonresponsive during those events (referred to as task-activated and task-nonactivated neurons, respectively). Moreover, the session decrease in firing was dose-dependent for only the task-nonactivated neurons. The data of the present investigation provide supportive correlational evidence for two hypotheses: (1) excitatory neurophysiological mechanisms mediate the NAc role in cue-maintenance of nicotine SA, and (2) a differential nicotine-induced inhibition of task-activated and task-nonactivated neurons mediates the NAc role in nicotine-induced amplification of cue effects on nicotine SA.

Neuronal representation of individual heroin choices in the orbitofrontal cortex

Drug addiction is a harmful preference for drug use over and at the expense of other non‐drug‐related activities. We previously identified in the rat orbitofrontal cortex (OFC) a mechanism that influences individual preferences between cocaine use and an alternative action rewarded by a non‐drug reward (i.e. sweet water). Here, we sought to test the generality of this mechanism to a different addictive drug, heroin. OFC neuronal activity was recorded while rats responded for heroin or the alternative non‐drug reward separately or while they chose between the two. First, we found that heroin‐rewarded and sweet water‐rewarded actions were encoded by two non‐overlapping OFC neuronal populations and that the relative size of the heroin population represented individual drug choices. Second, OFC neurons encoding the preferred action—which was the non‐drug action in the large majority of individuals—progressively fired more than non‐preferred action‐coding neurons 1 second after the onset of choice trials and around 1 second before the preferred action was actually chosen, suggesting a pre‐choice neuronal competition for action selection. Together with a previous study on cocaine choice, the present study on heroin choice reveals important commonalities in how OFC neurons encode individual drug choices and preferences across different classes of drugs. It also reveals some drug‐specific differences in OFC encoding activity. Notably, the proportion of neurons that non‐selectively encode both the drug and the non‐drug reward was higher when the drug was heroin (present study) than when it was cocaine (previous study). We will discuss the potential functional significance of these commonalities and differences in OFC neuronal activity across different drugs for understanding drug choice.