Impact of acute and chronic nicotine administration on midbrain dopaminergic neuron activity and related behaviours in TRPV1 knock-out juvenile mice.

The addictive properties of nicotine, the main alkaloid in tobacco and tobacco-derived products, largely depend on its action on the activity of midbrain dopamine (DA) neurons. The transient receptor potential vanilloid 1 (TRPV1) channel has also been examined as an emerging contributor to addiction-related symptoms due to its ability to modulate midbrain neurons. Thus, the objective of our study was to explore the role of TRPV1 receptors (TRPV1Rs) on nicotine-induced behaviours and associated response of DA neuron activity. Both wild type juvenile mice and juvenile mice with invalidation of the TRPV1R gene were exposed to acute or chronic nicotine 0.3 mg/kg administration. We analysed locomotor activity in response to the drug. In addition, we performed cell-attached and whole-cell recordings from ventral tegmental area (VTA) neurons after nicotine exposure. Our results showed that the genetic deletion of TRPV1Rs reduced nicotine-induced locomotor sensitization. In addition, it provided evidence in support of TRPV1Rs being regulators of inhibitory synaptic transmission in the VTA. However, TRPV1Rs did not seem to modulate either nicotine-induced conditioning place preference or nicotine-evoked electrical activity of DA neurons. In conclusion, TRPV1Rs modulate nicotine-induced psychomotor sensitization in mice independently of a control on VTA DA neuron activity. Thus, TRPV1R control may depend on another key player of the mesolimbic circuit.

Arc reactivity in accumbens nucleus, amygdala and hippocampus differentiates cue over context responses during reactivation of opiate withdrawal memory.

Opiate withdrawal induces an early aversive state which can be associated to contexts and/or cues, and re-exposure to either these contexts or cues may participate in craving and relapse. Nucleus accumbens (NAC), hippocampus (HPC) and basolateral amygdala (BLA) are crucial substrates for acute opiate withdrawal, and for withdrawal memory retrieval. Also HPC and BLA interacting with the NAC are suggested to respectively mediate the processing of context and cue representations of drug-related memories. Here we used a paradigm of conditioned suppression of operant food seeking, allowing to differentiate context and cue related responses, to study the influence of withdrawal memories on operant behavior and the underlying neural substrates. catFISH for Arc mRNA expression was used to discriminate cellular responses during context and cue (flashing light) periods in this paradigm. We show that reactivation of the memory of the negative affective state of withdrawal suppresses active lever pressing for food, and this conditioned suppression is generalized to the context. Interestingly the behavioral responses during the context and cue light periods are associated with differential Arc mRNA activations within the NAC, BLA, and HPC. Indeed both periods led to NAC shell activation whereas the NAC core was responsive only following the cue light period. Moreover, BLA and HPC were more responsive during cue-light and context period respectively. These data further support the already reported differential role of these brain structures on cue vs context-induced reinstatement of operant behaviors, and highlight the existence of common mechanisms for the processing of positive and aversive emotional memories.

Nicotine self-administration induces CB1-dependent LTP in the bed nucleus of the stria terminalis.

Nicotine addiction is characterized by repetitive drug taking and drug seeking, both tightly controlled by cannabinoid CB1 receptors. The responsiveness of neurons of the bed nucleus of the stria terminalis (BNST) to infralimbic cortex (ILCx) excitatory inputs is increased in rats with active, but not passive, nicotine taking. Therefore, we hypothesize that acquisition of the learned association between nicotine infusion and a paired cue light permits the strengthening of the ILCx-BNST synapses after ILCx tetanic stimulation. We exposed rats to intravenous nicotine self-administration for 2 months. Using a combination of in vivo protocols (electrical stimulations, extracellular recordings, and pharmacological manipulations), we characterized the effects of 10 Hz stimulation of the ILCx on BNST excitatory responses, under different conditions of exposure to nicotine. In addition, we tested whether the effects of the stimulation were CB1 receptor-dependent. The results show that nicotine self-administration supports the induction of evoked spike potentiation in the BNST in response to 10 Hz stimulation of ILCx afferents. Although not altered by nicotine abstinence, this cellular adaptation was blocked by CB1 receptor antagonism. Moreover, blockade of BNST CB1 receptors prevented increases in time-out responding subsequent to ILCx stimulation and decreased cue-induced reinstatement. Thus, the synaptic potentiation within the BNST in response to ILCx stimulation seems to contribute to the cue-elicited responding associated with nicotine self-administration and is tightly controlled by CB1 receptors.

D1 dopamine receptor-mediated LTP at GABA synapses encodes motivation to self-administer cocaine in rats.

Enhanced motivation to take drugs is a central characteristic of addiction, yet the neural underpinning of this maladaptive behavior is still largely unknown. Here, we report a D1-like dopamine receptor (DRD1)-mediated long-term potentiation of GABAA-IPSCs (D1-LTPGABA) in the oval bed nucleus of the stria terminalis that was positively correlated with motivation to self-administer cocaine in rats. Likewise, in vivo intra-oval bed nucleus of the stria terminalis DRD1 pharmacological blockade reduced lever pressing for cocaine more effectively in rats showing enhanced motivation toward cocaine. D1-LTPGABA resulted from enhanced function and expression of G-protein-independent DRD1 coupled to c-Src tyrosine kinases and required local release of neurotensin. There was no D1-LTPGABA in rats that self-administered sucrose, in those with limited cocaine self-administration experience, or in those that received cocaine passively (yoked). Therefore, our study reveals a novel neurophysiological mechanism contributing to individual motivation to self-administer cocaine, a critical psychobiological element of compulsive drug use and addiction.

Nicotine reinforcement is reduced by cannabinoid CB1 receptor blockade in the ventral tegmental area.

Cannabinoid type 1 (CB1) receptors control the motivational properties and reinforcing effects of nicotine. Indeed, peripheral administration of a CB1 receptor antagonist dramatically decreases both nicotine taking and seeking. However, the neural substrates through which the cannabinoid CB1 receptors regulate the voluntary intake of nicotine remain to be elucidated. In the present study, we sought to determine whether central injections of a CB1 receptor antagonist delivered either into the ventral tegmental area (VTA) or the nucleus accumbens (NAC) may alter nicotine intravenous self-administration (IVSA). Rats were first trained to self-administer nicotine (30 µg/kg/0.1 ml). The effect of central infusions of the CB1 antagonist AM 251 (0, 1 and 10 µg/0.5 µl/side) on nicotine-taking behavior was then tested. Intra-VTA infusions of AM 251 dose dependently reduced IVSA with a significant decrease for the dose 10 µg/0.5 µl/side. Moreover, operant responding for water was unaltered by intra-VTA AM 251 at the same dose. Surprisingly, intra-NAC delivery of AM 251 did not alter nicotine behavior at all. These data suggest that in rats chronically exposed to nicotine IVSA, the cannabinoid CB1 receptors located in the VTA rather than in the NAC specifically control nicotine reinforcement and, subsequently, nicotine-taking behavior.

Poor inhibitory control predicts sex-specific vulnerability to nicotine rewarding properties in mice.

RATIONALE: The risk of becoming addicted to tobacco varies greatly from individual to individual, raising the possibility of behavioural biomarkers capable of predicting sensitivity to nicotine reward, a crucial step in the development of nicotine addiction. Amongst all of nicotine's pharmacological properties, one of central importance is the enhancement of cognitive performances, which depend on the balance between attentional processes and inhibitory control. However, whether the cognitive enhancement effects of nicotine are predictive of sensitivity to its rewarding properties is still unknown. OBJECTIVE: Using male and female mice, we investigated whether the effects of nicotine on cognitive performances are predictive of sensitivity to the rewarding properties of nicotine and, if so, whether this relationship is sex dependent. METHODS: Naïve male and female mice were first assessed for their performances in both baseline conditions and following nicotine injection (0.15 and 0.30 mg/kg) in a cued-Fixed Consecutive Number task (FCNcue) measuring both optimal (attention) and premature (inhibitory control) responding. Next, all mice underwent nicotine-induced conditioned place preference (CPP) in order to evaluate inter-individual differences in response to nicotine reward (0.30 mg/kg). RESULTS: Results showed that males and females benefited from the effect of nicotine as a cognitive enhancer in the FCNcue task. However, only those males displaying poor inhibitory control, namely high-impulsive animals, subsequently displayed sensitivity to nicotine reward. In females, sensitivity to nicotine reward was independent of FCNcue performances, in both basal and nicotine conditions. CONCLUSION: Thus, our study suggests that poor inhibitory control and its modulation by nicotine may be a behavioural biomarker for sensitivity to nicotine reward and consequent vulnerability to nicotine addiction in males but not females.

A single mild juvenile TBI in male mice leads to regional brain tissue abnormalities at 12 months of age that correlate with cognitive impairment at the middle age.

Traumatic brain injury (TBI) has the highest incidence amongst the pediatric population and its mild severity represents the most frequent cases. Moderate and severe injuries as well as repetitive mild TBI result in lasting morbidity. However, whether a single mild TBI sustained during childhood can produce long-lasting modifications within the brain is still debated. We aimed to assess the consequences of a single juvenile mild TBI (jmTBI) at 12 months post-injury in a mouse model. Non-invasive diffusion tensor imaging (DTI) revealed significant microstructural alterations in the hippocampus and the in the substantia innominata/nucleus basalis (SI/NB), structures known to be involved in spatial learning and memory. DTI changes paralled neuronal loss, increased astrocytic AQP4 and microglial activation in the hippocampus. In contrast, decreased astrocytic AQP4 expression and microglia activation were observed in SI/NB. Spatial learning and memory were impaired and correlated with alterations in DTI-derived derived fractional ansiotropy (FA) and axial diffusivity (AD). This study found that a single juvenile mild TBI leads to significant region-specific DTI microstructural alterations, distant from the site of impact, that correlated with cognitive discriminative novel object testing and spatial memory impairments at 12 months after a single concussive injury. Our findings suggest that exposure to jmTBI leads to a chronic abnormality, which confirms the need for continued monitoring of symptoms and the development of long-term treatment strategies to intervene in children with concussions.

Locus coeruleus activation during environmental novelty gates cocaine-induced long-term hyperactivity of dopamine neurons.

A key feature of the brain is the ability to handle novelty. Anything that is new will stimulate curiosity and trigger exploration. Novelty preference has been proposed to predict increased sensitivity to cocaine. Different brain circuits are activated by novelty, but three specific brain regions are critical for exploring a novel environment: the noradrenergic neurons originating from the locus coeruleus (LC), the dopaminergic neurons from the ventral tegmental area (VTA), and the hippocampus. However, how exploring a novel environment can interfere with the reward system and control cocaine impact on VTA dopamine neuron plasticity is unclear. Here, we first investigated the effects of exposure to a novel environment on the tonic electrophysiological properties of VTA dopamine neurons. Then, we explored how exposure to a novel environment controls cocaine-evoked plasticity in dopamine neurons. Our findings indicate that LC controls VTA dopamine neurons under physiological conditions but also after cocaine.

Flavor additives facilitate oral self-administration of nicotine solution in mice.

RATIONALE: Tobacco products are very addictive, partly because they contain nicotine which is reinforcing, but also because they include appealing aromas and tastes. Flavor additives are such sensory stimuli which enhance attractiveness, as well as use and abuse of tobacco and vaping products. Yet, the interaction between these flavor additives and nicotine remains poorly understood. OBJECTIVES: We want to understand how flavors may reduce nicotine' aversive taste and how it may enhance its voluntary oral self-administration in mice. METHODS: We first studied the effect of flavor additives on nicotine solution palatability in a free bottle choice paradigm. Second, we investigated the effect of vanilla flavoring on the different stages of nicotine (40 µg/ml) oral self-administration in mice. RESULTS: We show that adding flavors increase nicotine palatability and facilitate acquisition and maintenance of oral self-administration when compared to nicotine-alone group. Mice adapt their operant behavior depending on changes in nicotine concentration. All mice reinstate nicotine seeking upon presentation of associated cues. Nevertheless, vanilla-flavored nicotine was not more reinforcing than vanilla-flavored water which was reinforcing enough to drive similar operant response rates. CONCLUSIONS: Flavor additives increase nicotine oral consumption and help maintaining operant behavior in mice. Moreover, flavors can be very attractive and can have high reinforcing value by themselves. Thus, it is crucial that the investigation on how taste signals play an important role in modulating oral nicotine intake in rodent models remains explored.

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.

Circulating Triglycerides Gate Dopamine-Associated Behaviors through DRD2-Expressing Neurons.

Energy-dense food alters dopaminergic (DA) transmission in the mesocorticolimbic (MCL) system and can promote reward dysfunctions, compulsive feeding, and weight gain. Yet the mechanisms by which nutrients influence the MCL circuitry remain elusive. Here, we show that nutritional triglycerides (TGs), a conserved post-prandial metabolic signature among mammals, can be metabolized within the MCL system and modulate DA-associated behaviors by gating the activity of dopamine receptor subtype 2 (DRD2)-expressing neurons through a mechanism that involves the action of the lipoprotein lipase (LPL). Further, we show that in humans, post-prandial TG excursions modulate brain responses to food cues in individuals carrying a genetic risk for reduced DRD2 signaling. Collectively, these findings unveil a novel mechanism by which dietary TGs directly alter signaling in the reward circuit to regulate behavior, thereby providing a new mechanistic basis by which energy-rich diets may lead to (mal)adaptations in DA signaling that underlie reward deficit and compulsive behavior.

The addition of five minor tobacco alkaloids increases nicotine-induced hyperactivity, sensitization and intravenous self-administration in rats.

Several minor tobacco alkaloids have been found to exhibit properties pharmacologically relevant to the addictive profile of tobacco; however, little is known of their effects on a behavioural model of drug addiction. In this study we compared the locomotor and reinforcing effects of intravenous nicotine (30 microg/kg per infusion) vs. a cocktail of nicotine plus five minor alkaloids found in tobacco smoke (anabasine, nornicotine, anatabine, cotinine and myosmine). Rats were initially tested for their locomotor response to nicotine or nicotine plus the minor alkaloids with six intravenous injections over 1 h. We then assessed the spontaneous acquisition of intravenous self-administration with nicotine or nicotine plus the minor alkaloids, under a fixed-ratio 1 schedule followed by responding on a fixed-ratio 5 schedule, progressive-ratio schedule and a single within-session ascending dose-response test. The activity test was repeated following the progressive-ratio phase to assess locomotor sensitization. A second group of rats were then tested on the locomotor procedure to better clarify the role of each individual minor alkaloid in nicotine-induced locomotor activity. Compared to nicotine alone, addition of the minor tobacco alkaloids increased locomotor activity and increased locomotor sensitization following self-administration. During fixed-ratio 5, progressive ratio and the dose-response test, rats receiving nicotine plus the minor alkaloids responded significantly more than those receiving nicotine alone. Testing of each minor alkaloid in the second experiment indicated that anatabine, cotinine and myosmine individually increased nicotine-induced locomotor activity. These results suggest that the minor tobacco alkaloids, particularly anatabine, cotinine and myosmine, may increase the motivation for nicotine and thus facilitate smoking behaviour.

The motivation for exercise over palatable food is dictated by cannabinoid type-1 receptors.

The lack of intrinsic motivation to engage in, and adhere to, physical exercise has major health consequences. However, the neurobiological bases of exercise motivation are still unknown. This study aimed at examining whether the endocannabinoid system (ECS) is involved in this process. To do so, we developed an operant conditioning paradigm wherein mice unlocked a running wheel with nose pokes. Using pharmacological tools and conditional mutants for cannabinoid type-1 (CB1) receptors, we provide evidence that CB1 receptors located on GABAergic neurons are both necessary and sufficient to positively control running motivation. Conversely, this receptor population proved dispensable for the modulation of running duration per rewarded sequence. Although the ECS mediated the motivation for another reward, namely palatable food, such a regulation was independent from CB1 receptors on GABAergic neurons. In addition, we report that the lack of CB1 receptors on GABAergic neurons decreases the preference for running over palatable food when mice were proposed an exclusive choice between the two rewards. Beyond providing a paradigm that enables motivation processes for exercise to be dissected either singly or in concurrence, this study is the first to our knowledge to identify a neurobiological mechanism that might contribute to sedentary behavior.

Specific alterations of extracellular endocannabinoid levels in the nucleus accumbens by ethanol, heroin, and cocaine self-administration.

Ethanol and opiate self-administration are sensitive to manipulations of cannabinoid CB1 receptor function and, from this, a role for the endogenous cannabinoid system in the modulation of drug reward has been hypothesized. However, direct in vivo evidence of drug-induced alterations in brain endocannabinoid (eCB) formation has been lacking. To address this issue, we explored the effect of drug self-administration on interstitial eCB levels in the nucleus accumbens (NAc) shell using in vivo microdialysis. Ethanol, heroin, and cocaine were compared because the rewarding properties of ethanol and heroin are reduced by CB1 receptor inactivation, whereas cocaine reward is less sensitive to these manipulations. Ethanol self-administration significantly increased dialysate 2-arachidonoylglycerol (2-AG) levels with no concomitant change in dialysate anandamide (AEA) concentrations. Conversely, heroin self-administration significantly increased dialysate AEA levels, and induced a subtle but significant decrease in dialysate 2-AG levels. In each case, the relative change in dialysate eCB content was significantly correlated with the amount of drug consumed. In contrast, cocaine self-administration did not alter dialysate levels of either AEA or 2-AG. Local infusion of the CB1 antagonist SR 141716A into the NAc significantly reduced ethanol, but not cocaine, self-administration. Together with our previous observation that intra-NAc SR 141716A reduces heroin self-administration, these data provide novel in vivo support for an eCB involvement in the motivational properties of ethanol and heroin but not cocaine. Furthermore, the selective effects of ethanol and heroin on interstitial 2-AG and AEA provide new insight into the distinct neurochemical profiles produced by these two abused substances.

Attentional capacities prior to drug exposure predict motivation to self-administer nicotine.

RATIONALE: Nicotine can enhance attention and attribution of incentive salience to nicotine-associated stimuli. However, it is not clear whether inter-individual differences in attentional capacities prior to any exposure could play a role in vulnerability to nicotine self-administration. We further explored this vulnerability through pre-existing inter-individual differences in attention to a reward-predictive cue in drug-free animals. METHODS: A cued version of the Fixed Consecutive Number schedule (FCN16cue) of reinforcement task was used to assess attention. This task consists in completing a long chain of sequential lever presses to obtain a reward, and examines the rats' ability to pay attention to a cue light that signals its availability. Rats were then trained to self-administer nicotine intravenously (30 µg/kg/0.1 mL). Drug-taking and seeking behaviors were investigated. RESULTS: Our results showed important inter-individual differences in response for nicotine during the progressive ratio schedule of reinforcement. By comparing rats in the lower and upper quartiles of the mean breaking point, we showed that high-motivated rats were also more sensitive to the reinforcing properties of nicotine than low-motivated ones. We found that while both groups did not differ in premature responding in the FCN16cue task, high-motivated rats were more efficient in taking the cue light into account than low-motivated rats as shown by a higher proportion of optimal chains, indicating a higher level of attention to the reward-predictive cue. Moreover, it was positively correlated with higher motivation for nicotine, a hallmark of nicotine addiction. CONCLUSIONS: These results suggest that higher attention to reward-associated cues prior to drug taking predicts vulnerability to nicotine-reinforcing properties.

Memories of Opiate Withdrawal Emotional States Correlate with Specific Gamma Oscillations in the Nucleus Accumbens.

Affective memories associated with the negative emotional state experienced during opiate withdrawal are central in maintaining drug taking, seeking, and relapse. Nucleus accumbens (NAC) is a key structure for both acute withdrawal and withdrawal memories reactivation, but the NAC neuron coding properties underpinning the expression of these memories remain largely unknown. Here we aimed at deciphering the role of NAC neurons in the encoding and retrieval of opiate withdrawal memory. Chronic single neuron and local field potentials recordings were performed in morphine-dependent rats and placebo controls. Animals were subjected to an unbiased conditioned placed aversion protocol with one compartment (CS+) paired with naloxone-precipitated withdrawal, a second compartment with saline injection (CS-), and a third being neutral (no pairing). After conditioning, animals displayed a typical place aversion for CS+ and developed a preference for CS- characteristic of safety learning. We found that distinct NAC neurons code for CS+ or CS-. Both populations also displayed highly specific oscillatory dynamics, CS+ and CS- neurons, respectively, following 80 Hz (G80) and 60 Hz (G60) local field potential gamma rhythms. Finally, we found that the balance between G60 and G80 rhythms strongly correlated both with the ongoing behavior of the animal and the strength of the conditioning. We demonstrate here that the aversive and preferred environments are underpinned by distinct groups of NAC neurons as well as specific oscillatory dynamics. This suggest that G60/G80 interplay-established through the conditioning process-serves as a robust and versatile mechanism for a fine coding of the environment emotional weight.

NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis.

Anxiety is controlled by multiple neuronal circuits that share robust and reciprocal connections with the bed nucleus of the stria terminalis (BNST), a key structure controlling negative emotional states. However, it remains unknown how the BNST integrates diverse inputs to modulate anxiety. In this study, we evaluated the contribution of infralimbic cortex (ILCx) and ventral subiculum/CA1 (vSUB/CA1) inputs in regulating BNST activity at the single-cell level. Using trans-synaptic tracing from single-electroporated neurons and in vivo recordings, we show that vSUB/CA1 stimulation promotes opposite forms of in vivo plasticity at the single-cell level in the anteromedial part of the BNST (amBNST). We find that an NMDA-receptor-dependent homosynaptic long-term potentiation is instrumental for anxiolysis. These findings suggest that the vSUB/CA1-driven LTP in the amBNST is involved in eliciting an appropriate response to anxiogenic context and dysfunction of this compensatory mechanism may underlie pathologic anxiety states.

Cannabinoid modulation of opiate reinforcement through the ventral striatopallidal pathway.

Recent evidence indicates that cannabinoid-1 (CB1) receptors play a role in the mediation of opiate reward, though the neural mechanisms for this process have not been characterized. The present experiments investigated the influence of CB1 receptors in the ventral striatopallidal system on opiate-induced neurochemical events and opiate self-administration behavior in rats. Acute morphine administration (3 mg/kg) significantly reduced ventral pallidal GABA efflux in a manner similar to that produced by heroin self-administration. This neurochemical effect was reversed by doses of the selective CB1 antagonist SR 141716A (Rimonabant; 1 and 3 mg/kg) that also significantly reduce opiate reward. Morphine-induced increases in nucleus accumbens dopamine levels were unaltered by SR 141716A. Intravenous heroin self-administration (0.02 mg/infusion) was significantly reduced by intra-accumbens, but not intraventral pallidal SR 141716A infusions (1 and 3 microg/side), implicating nucleus accumbens CB1 receptors in the modulation of opiate reinforcement. In contrast, SR14716A did not alter cocaine self-administration (0.125 mg/inf), cocaine-induced (10 mg/kg) decrements in ventral pallidal GABA efflux or cocaine-induced increases in accumbens dopamine. This is consistent with evidence that selective inactivation of CB1 receptors reduces opiate-, but not psychostimulant-maintained self-administration. The CB1 receptor agonist WIN 55,212-2 (5 mg/kg) reduced pallidal GABA efflux in a manner similar to morphine, and this effect was reversed by the opiate receptor antagonist naloxone. Collectively these findings suggest that CB1 receptors modulate opiate reward through the ventral striatopallidal projection and that the modulation of this projection system may be involved in the reciprocal behavioral effects between cannabinoids, and opioids.

Ventral Subiculum Stimulation Promotes Persistent Hyperactivity of Dopamine Neurons and Facilitates Behavioral Effects of Cocaine.

The ventral subiculum (vSUB) plays a key role in addiction, and identifying the neuronal circuits and synaptic mechanisms by which vSUB alters the excitability of dopamine neurons is a necessary step to understand the motor changes induced by cocaine. Here, we report that high-frequency stimulation of the vSUB (HFSvSUB) over-activates ventral tegmental area (VTA) dopamine neurons in vivo and triggers long-lasting modifications of synaptic transmission measured ex vivo. This potentiation is caused by NMDA-dependent plastic changes occurring in the bed nucleus of the stria terminalis (BNST). Finally, we report that the modification of the BNST-VTA neural circuits induced by HFSvSUB potentiates locomotor activity induced by a sub-threshold dose of cocaine. Our findings unravel a neuronal circuit encoding behavioral effects of cocaine in rats and highlight the importance of adaptive modifications in the BNST, a structure that influences motivated behavior as well as maladaptive behaviors associated with addiction.

Inhibition of 5-HT neurotransmission increases clonidine protective effects on naloxone-induced conditioned place aversion in morphine-dependent rats.

Previous pharmacological studies have implicated serotonergic brain systems in opiate-withdrawal-precipitated conditioned place aversion. To assess this hypothesis, we tested the effects of either (i). a near-total 5,7-dihydroxytryptamine-induced lesion (90% depletion) or (ii). an acute serotonin (5-HT) inhibition induced by the specific stimulation of 5-HT1A autoreceptors (8-OHDPAT 5-100 microg/kg), on naloxone-induced conditioned place aversion in morphine-dependent rats. Morphine dependence was induced by the implantation of morphine slow-release pellets. The protective properties of clonidine (an alpha-2 adrenergic agonist classically given for opiate detoxification) were also tested after inhibition of 5-HT transmission. Serotonergic lesions in morphine-dependent rats failed to alter naloxone-induced conditioned place aversion but increased the sensitivity to the protective effects of clonidine. Acute neuropharmacological blockade of serotonin transmission also potentiated the clonidine effects on naloxone-induced conditioned place aversion. When combined with the 5-HT1A agonist 8-OHDPAT, clonidine was also found to be more potent. Further understanding of this serotonin/noradrenaline interaction might help devise new therapeutic treatments for the acute opiate withdrawal syndrome.