Locomotor Sensitization Research Articles

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 0.3mg/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.

Decrease of glycogen synthase kinase 3β phosphorylation in the rat nucleus accumbens shell is necessary for amphetamineinduced conditioned locomotor activity.

Phosphorylation levels of glycogen synthase kinase 3β (GSK3β) negatively correlated with psychomotor stimulant-induced locomotor activity. Locomotor sensitization induced by psychomotor stimulants was previously shown to selectively accompany the decrease of GSK3β phosphorylation in the nucleus accumbens (NAcc) core, suggesting that intact GSK3β activity in this region is necessary for psychomotor stimulants to produce locomotor sensitization. Similarly, GSK3β in the NAcc was also implicated in mediating the conditioned effects formed by the associations of psychomotor stimulants. However, it remains undetermined whether GSK3β plays a differential role in the two sub-regions (core and shell) of the NAcc in the expression of drug-conditioned behaviors. In the present study, we found that GSK3β phosphorylation was significantly lower in the NAcc shell obtained from rats expressing amphetamine (AMPH)-induced conditioned locomotor activity. Further, we demonstrated that these effects were normalized by treatment with lithium chloride, a GSK3β inhibitor. These results suggest that the behavior produced by AMPH itself and a conditioned behavior formed by associations with AMPH are differentially mediated by the two sub-regions of the NAcc.

Susceptibility to express amphetamine locomotor sensitization correlates with dorsolateral striatum bursting activity and GABAergic synapses in the globus pallidus

Repeated psychostimulant administration results in behavioral sensitization, a process that is relevant in the early phases of drug addiction. Critically, behavioral sensitization is not observed in all subjects. Evidence shows that differential neuronal activity in the dorsolateral striatum (DLS) accompanies the expression of amphetamine (AMPH) locomotor sensitization. However, whether individual differences in DLS activity previous to AMPH administration can predict the expression of locomotor sensitization has not been assessed. Here, we examined DLS neuronal activity before and after repeated AMPH administration and related it to the susceptibility of rats to sensitize. For that, single-unit recordings on DLS medium spiny neurons (MSNs) were carried out in freely moving male Sprague Dawley rats during repeated AMPH administration. We also examined differences in neurostructure that could accompany sensitization. We quantified the density of the inhibitory postsynaptic marker gephyrin (Geph) in the entopeduncular nucleus (EP) and globus pallidus (GP). A higher burst firing and a lower percentage of correlation between MSNs post-Saline firing rate vs. locomotion predicted the expression of locomotor sensitization. Moreover, during the AMPH challenge, we observed that burst firing decreased in sensitized rats, in contrast to non-sensitized rats in which burst firing was maintained. Finally, a higher Geph density on GP but not EP was observed in non-sensitized rats after AMPH challenge. These results indicate that initial differences in DLS burst firing might underlie the susceptibility to express locomotor sensitization and suggest that the potentiation of dorsal striatum indirect pathway could be considered a protective mechanism to locomotor sensitization.

Exercise against cocaine sensitization in mice: a [18F]fallypride micro-PET study.

Wheel-running exercise in laboratory rodents (animal model useful to study the neurobiology of aerobic exercise) decreases behavioural markers of vulnerability to addictive properties of various drugs of abuse including cocaine. However, neurobiological mechanisms underpinning this protective effect are far from fully characterized. Here, 28-day-old female C57BL/6J mice were housed with (n = 48) or without (n = 48) a running wheel for 6 weeks before being tested for acute locomotor responsiveness and initiation of locomotor sensitization to intraperitoneal injections of 8 mg/kg cocaine. The long-term expression of sensitization took place 3 weeks after the last session. On the day after, all mice underwent a micro-PET imaging session with [18F]fallypride radiotracer (dopamine 2/3 receptors antagonist). Exercised mice were less sensitive to acute and sensitized cocaine hyperlocomotor effects, such attenuation being particularly well marked for long-term expression of sensitization (η2P = 0.262). Chronic administration of cocaine was associated with a clear-cut increase of [18F]fallypride binding potential in mouse striatum (η2P = 0.170) while wheel-running exercise was associated with a moderate decrease in dopamine 2/3 receptors density in striatum (η2P = 0.075), a mechanism that might contribute to protective properties of exercise against drugs of abuse vulnerability.

Role of Organic Cation Transporter 3 and Plasma Membrane Monoamine Transporter in the Rewarding Properties and Locomotor Sensitizing Effects of Amphetamine in Male andFemale Mice.

A lack of effective treatment and sex-based disparities in psychostimulant addiction and overdose warrant further investigation into mechanisms underlying the abuse-related effects of amphetamine-like stimulants. Uptake-2 transporters such as organic cation transporter 3 (OCT3) and plasma membrane monoamine transporter (PMAT), lesser studied potential targets for the actions of stimulant drugs, are known to play a role in monoaminergic neurotransmission. Our goal was to examine the roles of OCT3 and PMAT in mediating amphetamine (1 mg/kg)-induced conditioned place preference (CPP) and sensitization to its locomotor stimulant effects, in males and females, using pharmacological, decynium-22 (D22; 0.1 mg/kg, a blocker of OCT3 and PMAT) and genetic (constitutive OCT3 and PMAT knockout (−/−) mice) approaches. Our results show that OCT3 is necessary for the development of CPP to amphetamine in males, whereas in females, PMAT is necessary for the ability of D22 to prevent the development of CPP to amphetamine. Both OCT3 and PMAT appear to be important for development of sensitization to the locomotor stimulant effect of amphetamine in females, and PMAT in males. Taken together, these findings support an important, sex-dependent role of OCT3 and PMAT in the rewarding and locomotor stimulant effects of amphetamine.

Adenosine Monophosphate-activated Protein Kinase (AMPK) in serotonin neurons mediates select behaviors during protracted withdrawal from morphine in mice

Serotonin neurotransmission has been implicated in behavior deficits that occur during protracted withdrawal from opioids. In addition, studies have highlighted multiple pathways whereby serotonin (5-HT) modulates energy homeostasis, however the underlying metabolic effects of opioid withdrawal have not been investigated. A key metabolic regulator that senses the energy status of the cell and regulates fuel availability is Adenosine Monophosphate-activated Protein Kinase (AMPK). To investigate the interaction between cellular metabolism and serotonin in modulating protracted abstinence from morphine, we depleted AMPK in serotonin neurons. Morphine exposure via drinking water generates dependence in these mice, and both wildtype and serotonergic AMPK knockout mice consume similar amounts of morphine with no changes in body weight. Serotonergic AMPK contributes to baseline differences in open field and social interaction behaviors and blocks abstinence induced reductions in immobility following morphine withdrawal in the tail suspension test. Lastly, morphine locomotor sensitization is blunted in mice lacking AMPK in serotonin neurons. Taken together, our results suggest serotonergic AMPK mediates both baseline and protracted morphine withdrawal-induced behaviors.

Effects of repeated treatment with the 5-HT1A and 5-HT1B agonists (R)-( +)-8-hydroxy-DPAT and CP-94253 on the locomotor activity and axillary temperatures of preweanling rats: evidence of tolerance and behavioral sensitization.

Drugs that stimulate 5-HT1A/1B receptors produce both tolerance and behavioral sensitization in adult rats and mice, yet it is unknown whether the same types of plasticity are evident during earlier ontogenetic periods. The purpose of this study was to determine whether repeated treatment with selective 5-HT1A and/or 5-HT1B agonists cause tolerance and/or sensitization in preweanling rats. In Experiments 1 and 2, male and female preweanling rats were given a single pretreatment injection of saline, the 5-HT1A agonist (R)-( +)-8-hydroxy-DPAT (8-OH-DPAT), or the 5-HT1B agonist CP-94253 on PD 20. After 48h, rats received a challenge injection of 8-OH-DPAT or CP-94253, respectively. In Experiment 3, rats were pretreated with saline or DPAT + CP on PD 20 and challenged with the same drug cocktail on PD 22. In Experiment 4, the tolerance- or sensitization-inducing properties of 8-OH-DPAT, CP-94253, or DPAT + CP were tested after a 4-day pretreatment regimen on PD 17-20. On the first pretreatment day, 8-OH-DPAT, CP-94253, and DPAT + CP increased locomotion and caused hypothermia. Repeated treatment with 8-OH-DPAT (2 or 8mg/kg) or DPAT + CP caused locomotor sensitization in preweanling rats. In contrast, tolerance to the hypothermic effects of 8-OH-DPAT (8mg/kg), CP-94253 (5-20mg/kg), or DPAT + CP was evident after repeated drug treatment. During the preweanling period, a single injection of a selective 5-HT1A or 5-HT1B agonist is capable of producing drug-induced plasticity. A pretreatment administration of 8-OH-DPAT causes both tolerance (hypothermia) and behavioral sensitization (locomotor activity) in preweanling rats, whereas repeated CP-94253 treatment results in tolerance.

Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior

Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+ were dependent on the Zn2+ transporter 3 (ZnT3), a neuronal Zn2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+ deficiency in mice resulted in decreased striatal Zn2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+ release and turnover/metabolism in the striatum, and that synaptically released Zn2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn2+ may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.

M-CF3-substituted diphenyl diselenide attenuates all phases of morphine-induced behavioral locomotor sensitization in mice

BackgroundBehavioral sensitization, thought to underlie some aspects of drug dependence, is typically measured as increased locomotion in response to repeated administration of a drug. The study aimed to investigate the (m-CF3-PhSe)2 effects on the acquisition, withdrawal, and re-exposure phases of morphine-induced behavioral locomotor sensitization. MethodsSwiss male mice were treated with saline or morphine at 10 mg/kg twice a day for 3 days; those of the morphine group were kept in the morphine withdrawal period (5 days). On day 9, mice were re-exposed to morphine. (m-CF3-PhSe)2 (10 mg/kg) or vehicle was administered at all phases of morphine protocol, and mice performed locomotor activity test. Oxidative stress markers and the levels of opioid, dopamine, and glutamate receptors were determined in samples of the cerebral cortex. (m-CF3-PhSe)2 administered at all phases of protocol attenuated morphine-induced locomotor sensitization. ResultsMice exposed to morphine showed reduced weight gain and increased locomotor activity, but (m-CF3-PhSe)2 treatment attenuates the weight gain and behavioral hyperlocomotion effects. (m-CF3-PhSe)2, independent of the administration phase, modulated the increase of opioidergic (MOR, DOR, KOR) and glutamatergic (NMDA 2A and 2B) protein contents and attenuated redox imbalance in the cerebral cortex of mice exposed to morphine. However, (m-CF3-PhSe)2 did not modulate cortical protein levels of dopaminergic (D1 and D2) receptors in the acquisition phase of morphine-induced locomotor sensitization protocol. Conclusion(m-CF3-PhSe)2 was effective against the behavioral and molecular alterations caused by morphine at all phases of locomotor sensitization.

Captopril and losartan attenuate behavioural sensitization in mice chronically exposed to toluene

Inhalants are consumed worldwide for recreational purposes. The main component found in many inhalants is toluene. One of the most deleterious behavioural effects caused by chronic exposure to inhalants is addiction. This response has been associated with activation of the mesolimbic dopaminergic pathway, and it is known that the renin angiotensin system plays a role in the modulation of this dopaminergic system. In the present work, we hypothesize that blockade of the RAS with angiotensin converting enzyme inhibitors or angiotensin II type 1 receptor blockers is able to attenuate the addictive response induced by toluene. We exposed mice to toluene for four weeks to induce locomotor sensitization. In the second phase of the work, captopril or losartan were administered for 20 days. Subsequently, the expression of behavioural sensitization was evaluated with a toluene challenge. To exclude false associations between the observed responses and treatments, motor coordination and blood pressure were analysed in animals treated with captopril or losartan. At the end of the behavioural studies, animal brains were harvested and Ang II/Ang-(1–7) and Ang-(1–7)/Ang II ratios were analysed in the nucleus accumbens (NAc) and prefrontal cortex (PFCx). The results showed that toluene induced behavioural sensitization, while captopril or losartan treatment attenuated the expression of this response. No significant differences were observed in motor coordination or blood pressure. Repeated toluene administration decreased Ang-(1–7)/Ang II ratio in the PFCx. On the other hand, treatment with captopril or losartan decreased the Ang II/Ang-(1–7) ratio and enhanced the Ang-(1–7)/Ang II ratio in the NAc. This work suggests that blockade of RAS attenuates the toluene-induced behavioural sensitization.

Dynamic dichotomy of accumbal population activity underlies cocaine sensitization.

Locomotor sensitization (LS) is an early behavioral adaptation to addictive drugs, driven by the increase of dopamine in the Nucleus Accumbens (NAc). However, the effect on accumbal population activity remains elusive. Here, we used single-cell calcium imaging in mice to record the activity of dopamine-1-receptor (D1R) and dopamine-2-receptor (D2R) expressing spiny projection neurons (SPNs) during cocaine LS. Acute exposure to cocaine elevated D1R SPN activity and reduced D2R SPN activity, albeit with high variability between neurons. During LS, the number of D1R and D2R neurons responding in opposite directions increased. Moreover, preventing LS by inhibition of the ERK signaling pathway decreased the number of cocaine responsive D1R SPNs, but had little effect on D2R SPNs. These results indicate that accumbal population dichotomy is dynamic and contains a subgroup of D1R SPNs that eventually drives LS. Insights into the drug-related activity dynamics provides a foundation for understanding the circuit-level addiction pathogenesis.

English

Nalbuphine, a semi-synthetic opioid drug, is a kappa (κ) agonist/ mu (μ) partial agonist. It is clinically used for moderate to severe pain. It produces the analgesic effect largely by binding to kappa opioid receptors. The present study was designed to investigate locomotor sensitization as well reinforcing effects of different doses (5, 10 and 20 mg/kg) of nalbuphine in rats. Potential analgesic and hyperalgesic effects after single and repeated administration respectively were also monitored. Reinforcing effects were monitored in a conditioned place preference (CPP) paradigm and associated changes in motor activity were monitored during a drug conditioning phase. The hot plate test was used to monitor nociceptive response. The present study showed that low (5 mg/kg) and high (20 mg/kg) doses of nalbuphine were reinforcing, while the moderate dose (10 mg/kg) had no reinforcing effect in the CPP paradigm. All doses were analgesic after the first administration and on repeated administration hyperalgesia did not develop to any dose. Analgesic effects still occurred at moderate doses of nalbuphine. Sensitization-like effects were produced following moderate and high doses of nalbuphine. These findings suggested that a moderate dose of nalbuphine did not produce reinforcing effects and hyperalgesia so this dose can be used safely for treating pain.

Does nicotine exposure during adolescence modify the course of schizophrenia-like symptoms? Behavioral analysis in a phencyclidine-induced mice model.

The first symptoms of schizophrenia (SCHZ) are usually observed during adolescence, a developmental period during which first exposure to psychoactive drugs also occurs. These epidemiological findings point to adolescence as critical for nicotine addiction and SCHZ comorbidity, however it is not clear whether exposure to nicotine during this period has a detrimental impact on the development of SCHZ symptoms since there is a lack of studies that investigate the interactions between these conditions during this period of development. To elucidate the impact of a short course of nicotine exposure across the spectrum of SCHZ-like symptoms, we used a phencyclidine-induced adolescent mice model of SCHZ (2.5mg/Kg, s.c., daily, postnatal day (PN) 38-PN52; 10mg/Kg on PN53), combined with an established model of nicotine minipump infusions (24mg/Kg/day, PN37-44). Behavioral assessment began 4 days after the end of nicotine exposure (PN48) using the following tests: open field to assess the hyperlocomotion phenotype; novel object recognition, a declarative memory task; three-chamber sociability, to verify social interaction and prepulse inhibition, a measure of sensorimotor gating. Phencyclidine exposure evoked deficits in all analyzed behaviors. Nicotine history reduced the magnitude of phencyclidine-evoked hyperlocomotion and impeded the development of locomotor sensitization. It also mitigated the deficient sociability elicited by phencyclidine. In contrast, memory and sensorimotor gating deficits evoked by phencyclidine were neither improved nor worsened by nicotine history. In conclusion, our results show for the first time that nicotine history, restricted to a short period during adolescence, does not worsen SCHZ-like symptoms evoked by a phencyclidine-induced mice model.

Chemogenetic modulation reveals distinct roles of the subthalamic nucleus and its afferents in the regulation of locomotor sensitization to amphetamine in rats.

The subthalamic nucleus (STN) is a key node in cortico-basal-ganglia thalamic circuits, guiding behavioral output through its position as an excitatory relay of the striatal indirect pathway and its direct connections with the cortex. There have been conflicting results regarding the role of the STN in addiction-related behavior to psychostimulants, and little is known with respect to the role of STN afferents. To address this, we used viral vectors to express DREADDs (Designer Receptors Exclusively Activated by Designer Drugs) in the STN of rats in order to bidirectionally manipulate STN activity during the induction of amphetamine sensitization. In addition, we used a Cre-recombinase dependent Gi/o-coupled DREADD approach to transiently inhibit afferents from ventral pallidum (a subcomponent of the striatal indirect pathway) or the prelimbic cortex (a subcomponent of the cortico-STN hyperdirect pathway). Despite inducing mild hyperactivity in non-drug controls, stimulation of STN neurons with Gq-DREADDs blocked the development and persistence of amphetamine sensitization as well as conditioned responding. In contrast, inhibition of STN neurons with Gi/o-DREADDs enhanced the induction of sensitization without altering its persistence or conditioned responding. Chemogenetic inhibition of afferents from ventral pallidum had no effect on amphetamine sensitization but blocked conditioned responding whereas chemogenetic inhibition of afferents from prelimbic cortex attenuated the persistence of sensitization as well as conditioned responding. These results suggest the STN and its afferents play complex roles in the regulation of amphetamine sensitization and highlight the need for further characterization of how integration of inputs within STN guide behavior.

Prepulse inhibition can predict the motivational effects of cocaine in female mice exposed to maternal separation

The prepulse inhibition (PPI) of the startle response can identify the rodents that are more sensitive to the effects of cocaine. Mice with a lower PPI presented a higher vulnerability to the effects of cocaine and a higher susceptibility to developing a substance use disorder (SUD). Maternal separation with early weaning (MSEW) is a relevant animal model to induce motivational alterations throughout life. Nevertheless, only a few studies on females exist, even though they are more vulnerable to stress- and cocaine-related problems. Hence, the aim of the present study was to evaluate the ability of PPI to identify females with a greater vulnerability to the long-term consequences of early stress on the motivational effects of cocaine. Female mice underwent MSEW and were classified according to their high or low PPI. They were then assessed in the cocaine-induced locomotor sensitization test, the conditioned place preference paradigm or the operant self-administration paradigm. Additionally, they were also evaluated in the passive avoidance task, the tail-suspension and the splash tests. The results revealed that the females with lower PPI presented higher consequences of MSEW on the effects of cocaine and showed an increase in anhedonia-like behaviours. Our findings support that a PPI deficit could represent a biomarker of vulnerability to the effects of cocaine induced by MSEW.

Potential Ago2/miR-3068-5p Cascades in the Nucleus Accumbens Contribute to Methamphetamine-Induced Locomotor Sensitization of Mice.

Dysregulation of microRNA (miRNA) biogenesis is involved in drug addiction. Argonaute2 (Ago2), a specific splicing protein involved in the generation of miRNA, was found to be dysregulated in the nucleus accumbens (NAc) of methamphetamine (METH)-sensitized mice in our previous study. Here, we determined whether Ago2 in the NAc regulates METH sensitization in mice and identified Ago2-dependent miRNAs involved in this process. We found a gradual reduction in Ago2 expression in the NAc following repeated METH use. METH-induced hyperlocomotor activity in mice was strengthened by knocking down NAc neuronal levels of Ago2 but reduced by overexpressing Ago2 in NAc neurons. Surprisingly, miR-3068-5p was upregulated following overexpression of Ago2 and downregulated by silencing Ago2 in the NAc. Knocking down miR-3068-5p, serving as an Ago2-dependent miRNA, strengthened the METH sensitization responses in mice. These findings demonstrated that dysregulated Ago2 in neurons in the NAc is capable of regulating METH sensitization and suggested a potential role of Ago2-dependent miR-3068-5p in METH sensitization.

Morphine reward effects and morphine behavioral sensitization: The adventitious association of morphine activation of brain reward effects with ongoing spontaneous activity

The development of sensitization is one of the hallmarks of addictive drugs such as morphine. We administered morphine (10 mg/kg; MOR) to induce locomotor sensitization and ERK activation in the VTA and NAc. In the first experiment, four groups of rats received five daily 30 min sessions in an open-field, and locomotion was measured. For the first four sessions, one group received MOR pre-test (MOR-P); a second group received vehicle pre-test (MOR-UP) and MOR 30 min post-test; the remaining 2 groups received vehicle (VEH) pre-test. On the fifth session, the MOR-P, MOR-UP, and one VEH group received MOR pre-test and the remaining VEH group received VEH. Sensitization emerged in the first 5 min and progressed over to the second and third 5 min blocks only in the MOR-P group. For the second experiment, 4 groups received MOR and 4 groups VEH, and were then returned to their home cage and after 5, 15, 30 or 60 min post-injection, were euthanized for ERK measurements in VTA and NAc. ERK activation increased and peaked at 5 min post injection in the MOR group and then declined to VEH levels by 30 min. Another two groups received either MOR or VEH immediately before a 5 min arena test and ERK was measured immediately post-test. MOR had no effect on locomotion but increased ERK in the VTA and NAc. The peak ERK activation in VTA reflected activation of reward systems by morphine that reinforced locomotor behavior and with repeated treatments, induced a sensitization effect.

Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.

Effects of the selective dopamine D3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice

Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0–10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6–56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.

Dopamine D1 receptor-expressing neurons activity is essential for locomotor and sensitizing effects of a single injection of cocaine.

Dopamine D1 receptors play an important role in the effects of cocaine. Here, we investigated the role of neurons which express these receptors (D1-neurons) in the acute locomotor effects of cocaine and the locomotor sensitization observed after a second injection of this drug, using the previously established two-injection protocol of sensitization. We inhibited D1-neurons using double transgenic mice conditionally expressing the inhibitory Gi-coupled designer receptor exclusively activated by designer drugs (Gi-DREADD) in D1-neurons. Chemogenetic inhibition of D1-neurons by a low dose of clozapine (0.1 mg/kg) decreased the cocaine-induced expression of Fos in striatal neurons. It diminished the basal locomotor activity and acute hyper-locomotion induced by cocaine (20 mg/kg). Clozapine 0.1 mg/kg had no effect by itself and did not alter cocaine effects in wild-type mice. Inhibition of D1-neurons during the first cocaine administration prevented the sensitization of the locomotor response in response to a second cocaine administration 10 days later. On Day 11, inhibition of D1-neurons by clozapine stimulation of Gi-DREADD blocked cocaine-induced locomotion including in sensitized mice, whereas on Day 12, in the absence of clozapine and D1-neurons inhibition, all mice displayed a sensitized response to cocaine. These results show that chemogenetic inhibition of D1-neurons decreases spontaneous and cocaine-induced locomotor activity. It prevents sensitization induction and blocks sensitized locomotion in a two-injection protocol of sensitization but does not reverse established sensitization. Our study further supports the central role of D1-neurons in mediating the acute locomotor effects of cocaine and its sensitization.