Local modulation by presynaptic receptors controls neuronal communication and behaviour.

Central nervous system neurons communicate via fast synaptic transmission mediated by ligand-gated ion channel (LGIC) receptors and slower neuromodulation mediated by G protein-coupled receptors (GPCRs). These receptors influence many neuronal functions, including presynaptic neurotransmitter release. Presynaptic LGIC and GPCR activation by locally released neurotransmitters influences neuronal communication in ways that modify effects of somatic action potentials. Although much is known about presynaptic receptors and their mechanisms of action, less is known about when and where these receptor actions alter release, especially in vivo. This Review focuses on emerging evidence for important local presynaptic receptor actions and ideas for future studies in this area.

Decreased Ventral Tegmental Area CB1R Signaling Reduces Sign Tracking and Shifts Cue-Outcome Dynamics in Rat Nucleus Accumbens.

Sign-tracking (ST) rats show enhanced cue sensitivity before drug experience that predicts greater discrete cue-induced drug seeking compared with goal-tracking or intermediate rats. Cue-evoked dopamine in the nucleus accumbens (NAc) is a neurobiological signature of sign-tracking behaviors. Here, we examine a critical regulator of the dopamine system, endocannabinoids, which bind the cannabinoid receptor-1 (CB1R) in the ventral tegmental area (VTA) to control cue-evoked striatal dopamine levels. We use cell type-specific optogenetics, intra-VTA pharmacology, and fiber photometry to test the hypothesis that VTA CB1R receptor signaling regulates NAc dopamine levels to control sign tracking. We trained male and female rats in a Pavlovian lever autoshaping (PLA) task to determine their tracking groups before testing the effect of VTA → NAc dopamine inhibition. We found that this circuit is critical for mediating the vigor of the ST response. Upstream of this circuit, intra-VTA infusions of rimonabant, a CB1R inverse agonist, during PLA decrease lever and increase food cup approach in sign-trackers. Using fiber photometry to measure fluorescent signals from a dopamine sensor, GRABDA (AAV9-hSyn-DA2m), we tested the effects of intra-VTA rimonabant on NAc dopamine dynamics during autoshaping in female rats. We found that intra-VTA rimonabant decreased sign-tracking behaviors, which was associated with increases in NAc shell, but not core, dopamine levels during reward delivery [unconditioned stimulus (US)]. Our results suggest that CB1R signaling in the VTA influences the balance between the conditioned stimulus-evoked and US-evoked dopamine responses in the NAc shell and biases behavioral responding to cues in sign-tracking rats.SIGNIFICANCE STATEMENT Substance use disorder (SUD) is a chronically relapsing psychological disorder that affects a subset of individuals who engage in drug use. Recent research suggests that there are individual behavioral and neurobiological differences before drug experience that predict SUD and relapse vulnerabilities. Here, we investigate how midbrain endocannabinoids regulate a brain pathway that is exclusively involved in driving cue-motivated behaviors of sign-tracking rats. This work contributes to our mechanistic understanding of individual vulnerabilities to cue-triggered natural reward seeking that have relevance for drug-motivated behaviors.

Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation?

The Cannabis sativa plant has been used to treat various physiological and psychiatric conditions for millennia. Current research is focused on isolating potentially therapeutic chemical constituents from the plant for use in the treatment of many central nervous system disorders. Of particular interest is the primary nonpsychoactive constituent cannabidiol (CBD). Unlike Δ(9)-tetrahydrocannabinol (THC), CBD does not act through the cannabinoid type 1 (CB1) receptor but has many other receptor targets that may play a role in psychiatric disorders. Here we review preclinical and clinical data outlining the therapeutic efficacy of CBD for the treatment of motivational disorders such as drug addiction, anxiety, and depression. Across studies, findings suggest promising treatment effects and potentially overlapping mechanisms of action for CBD in these disorders and indicate the need for further systematic investigation of the viability of CBD as a psychiatric pharmacotherapy.

Chronic Augmentation of Endocannabinoid Levels Persistently Increases Dopaminergic Encoding of Reward Cost and Motivation.

Motivational deficits characterized by an unwillingness to overcome effortful costs are a common feature of neuropsychiatric and neurologic disorders that are insufficiently understood and treated. Dopamine (DA) signaling in the nucleus accumbens (NAc) facilitates goal-seeking, but how NAc DA release encodes motivationally salient stimuli to influence effortful investment is not clear. Using fast-scan cyclic voltammetry in male and female mice, we find that NAc DA release diametrically responds to cues signaling increasing cost of reward, while DA release to the reward itself is unaffected by its cost. Because endocannabinoid (eCB) signaling facilitates goal seeking and NAc DA release, we further investigated whether repeated augmentation of the eCB 2-arachidonoylglycerol with a low dose of a monoacylglycerol lipase (MAGL) inhibitor facilitates motivation and DA signaling without the development of tolerance. We find that chronic MAGL treatment stably facilitates goal seeking and DA encoding of prior reward cost, providing critical insight into the neurobiological mechanisms of a viable treatment for motivational deficits.SIGNIFICANCE STATEMENT Decades of work has established a fundamental role for dopamine neurotransmission in motivated behavior and cue-reward learning, but how dopaminergic encoding of cues associates with motivated action has remained unclear. Specifically, how dopamine neurons signal future and prior reward cost, and whether this can be modified to influence motivational set points is not known. The current study provides important insight into how dopamine neurons encode motivationally relevant stimuli to influence goal-directed action and supports cannabinoid-based therapies for treatment of motivational disorders.

Activation of the mGlu1 metabotropic glutamate receptor has antipsychotic-like effects and is required for efficacy of M4 muscarinic receptor allosteric modulators.

Recent clinical and preclinical studies suggest that selective activators of the M4 muscarinic acetylcholine receptor have potential as a novel treatment for schizophrenia. M4 activation inhibits striatal dopamine release by mobilizing endocannabinoids, providing a mechanism for local effects on dopamine signaling in the striatum but not in extrastriatal areas. G protein-coupled receptors (GPCRs) typically induce endocannabinoid release through activation of Gαq/11-type G proteins whereas M4 transduction occurs through Gαi/o-type G proteins. We now report that the ability of M4 to inhibit dopamine release and induce antipsychotic-like effects in animal models is dependent on co-activation of the Gαq/11-coupled mGlu1 subtype of metabotropic glutamate (mGlu) receptor. This is especially interesting in light of recent findings that multiple loss of function single nucleotide polymorphisms (SNPs) in the human gene encoding mGlu1 (GRM1) are associated with schizophrenia, and points to GRM1/mGlu1 as a gene within the "druggable genome" that could be targeted for the treatment of schizophrenia. Herein, we report that potentiation of mGlu1 signaling following thalamo-striatal stimulation is sufficient to inhibit striatal dopamine release, and that a novel mGlu1 positive allosteric modulator (PAM) exerts robust antipsychotic-like effects through an endocannabinoid-dependent mechanism. However, unlike M4, mGlu1 does not directly inhibit dopamine D1 receptor signaling and does not reduce motivational responding. Taken together, these findings highlight a novel mechanism of cross talk between mGlu1 and M4 and demonstrate that highly selective mGlu1 PAMs may provide a novel strategy for the treatment of positive symptoms associated with schizophrenia.

Glutamatergic input from the insula to the ventral bed nucleus of the stria terminalis controls reward-related behavior.

Individuals suffering from substance use disorder often experience relapse events that are attributed to drug craving. Insular cortex (IC) function is implicated in processing drug-predictive cues and is thought to be a critical substrate for drug craving, but the downstream neural circuit effectors of the IC that mediate reward processing are poorly described. Here, we uncover the functional connectivity of an IC projection to the ventral bed nucleus of the stria terminalis (vBNST), a portion of the extended amygdala that has been previously shown to modulate dopaminergic activity within the ventral tegmental area (VTA), and investigate the role of this pathway in reward-related behaviors. We utilized ex vivo slice electrophysiology and in vivo optogenetics to examine the functional connectivity of the IC-vBNST projection and bidirectionally control IC-vBNST terminals in various reward-related behavioral paradigms. We hypothesized that the IC recruits mesolimbic dopamine signaling by activating VTA-projecting, vBNST neurons. Using slice electrophysiology, we found that the IC sends a glutamatergic projection onto vBNST-VTA neurons. Photoactivation of IC-vBNST terminals was sufficient to reinforce behavior in a dopamine-dependent manner. Moreover, silencing the IC-vBNST projection was aversive and resulted in anxiety-like behavior without affecting food consumption. This work provides a potential mechanism by which the IC processes exteroceptive triggers that are predictive of reward.

Motivational Impairment is Accompanied by Corticoaccumbal Dysfunction in the BACHD-Tg5 Rat Model of Huntington's Disease.

Neuropsychiatric symptoms, such as avolition, apathy, and anhedonia, precede the onset of debilitating motor symptoms in Huntington's disease (HD), and their development may give insight into early disease progression and treatment. However, the neuronal and circuit mechanisms of premanifest HD pathophysiology are not well-understood. Here, using a transgenic rat model expressing the full-length human mutant HD gene, we find early and profound deficits in reward motivation in the absence of gross motor abnormalities. These deficits are accompanied by significant and progressive dysfunction in corticostriatal processing and communication among brain areas critical for reward-driven behavior. Together, our results define early corticostriatal dysfunction as a possible pathogenic contributor to psychiatric disturbances and may help identify potential pharmacotherapeutic targets for the treatment of HD.

An Interaction between Serotonin Receptor Signaling and Dopamine Enhances Goal-Directed Vigor and Persistence in Mice.

The functionally selective 5-HT2C receptor ligand SB242084 can increase motivation and have rapid onset anti-depressant-like effects. We sought to identify the specific behavioral effects of SB242084 treatment and elucidate the mechanism in female and male mice. Using a quantitative behavioral approach, we determined that SB242084 increases the vigor and persistence of goal-directed activity across different types of physical work, particularly when work requirements are demanding. We found this influence of SB242084 on effort, rather than reward to be reflected in striatal DA measured during behavior. Using in vivo fast scan cyclic voltammetry, we found that SB242084 has no effect on reward-related phasic DA release in the NAc. Using in vivo microdialysis to measure tonic changes in extracellular DA, we also found no changes in the NAc. In contrast, SB242084 treatment increases extracellular DA in the dorsomedial striatum, an area that plays a key role in response vigor. These findings have several implications. At the behavioral level, this work shows that the capacity to work in demanding situations can be increased, without a generalized increase in motor activity or reward value. At the circuit level, we identified a pathway restricted potentiation of DA release and showed that this was the reason for the increased response vigor. At the cellular level, we show that a specific serotonin receptor cross talks to the DA system. Together, this information provides promise for the development of treatments for apathy, a serious clinical condition that can afflict patients with psychiatric and neurological disorders.SIGNIFICANCE STATEMENT Motivated behaviors are modulated by reward value, effort demands, and cost-benefit computations. This information drives the decision to act, which action to select, and the intensity with which the selected action is performed. Because these behavioral processes are all regulated by DA signaling, it is very difficult to influence selected aspects of motivated behavior without affecting others. Here we identify a pharmacological treatment that increases the vigor and persistence of responding in mice, without increasing generalized activity or changing reactions to rewards. We show that the 5-HT2C-selective ligand boosts motivation by potentiating activity-dependent DA release in the dorsomedial striatum. These results reveal a novel strategy for treating patients with motivational deficits, avolition, or apathy.

Contributions of nucleus accumbens dopamine to cognitive flexibility.

There is a compelling evidence that midbrain dopamine (DA) neurons and their projections to the ventral striatum provide a mechanism for motivating reward-seeking behavior, and for utilizing information about unexpected reward prediction errors (RPEs) to guide behavior based on current, rather than historical, outcomes. When this mechanism is compromised in addictions, it may produce patterns of maladaptive behavior that remain obdurate in the face of contrary information and even adverse consequences. Nonetheless, DAergic contributions to performance on behavioral tasks that rely on the ability to flexibly update stimulus-reward relationships remains incompletly understood. In the current study, we used a discrimination and reversal paradigm to monitor subsecond DA release in mouse NAc core (NAc) using in vivo fast-scan cyclic voltammetry (FSCV). We observed post-choice elevations in phasic NAc DA release; however, increased DA transients were only evident during early reversal when mice made responses at the newly rewarded stimulus. Based on this finding, we used in vivo optogenetic (eNpHR) photosilencing and (Channelrhodopsin2 [ChR2]) photostimulation to assess the effects of manipulating VTA-DAergic fibers in the NAc on reversal performance. Photosilencing the VTA â†’ NAc DAergic pathway during early reversal increased errors, while photostimulation did not demonstrably affect behavior. Taken together, these data provide additional evidence of the importance of NAc DA release as a neural substrate supporting adjustments in learned behavior after a switch in expected stimulus-reward contingencies. These findings have possible implications for furthering understanding the role of DA in persistent, maladaptive decision-making characterizing addictions.

Drug-Induced Alterations of Endocannabinoid-Mediated Plasticity in Brain Reward Regions.

The endocannabinoid (eCB) system has emerged as one of the most important mediators of physiological and pathological reward-related synaptic plasticity. eCBs are retrograde messengers that provide feedback inhibition, resulting in the suppression of neurotransmitter release at both excitatory and inhibitory synapses, and they serve a critical role in the spatiotemporal regulation of both short- and long-term synaptic plasticity that supports adaptive learning of reward-motivated behaviors. However, mechanisms of eCB-mediated synaptic plasticity in reward areas of the brain are impaired following exposure to drugs of abuse. Because of this, it is theorized that maladaptive eCB signaling may contribute to the development and maintenance of addiction-related behavior. Here we review various forms of eCB-mediated synaptic plasticity present in regions of the brain involved in reward and reinforcement and explore the potential physiological relevance of maladaptive eCB signaling to addiction vulnerability.

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease.

UNLABELLED: Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood. We therefore tested whether altered NAc dopamine release accompanies motivational deficits in the Q175 knock-in HD mouse model. Q175 mice express a CAG expansion of the human mutant huntingtin allele in the native mouse genome and gradually manifest symptoms late in life, closely mimicking the genotypic context and disease progression in human HD. Sub-second extracellular dopamine release dynamics were monitored using fast-scan cyclic voltammetry, whereas motivation was assessed using a progressive ratio reinforcement schedule. As the response ratio (lever presses per reward) escalated, Q175 mice exerted less effort to earn fewer rewards versus wild-type (WT). Moreover, dopamine released at reward delivery dynamically encoded increasing reward cost in WT but not Q175 mice. Deficits were specific to situations of high effortful demand as no difference was observed in locomotion, free feeding, hedonic processing, or reward seeking when the response requirement was low. This compromised dopaminergic encoding of reward delivery coincident with suppressed motivation to work for reward in Q175 mice provides novel, neurobiological insight into an established and clinically relevant endophenotype of prodromal HD. SIGNIFICANCE STATEMENT: Psychiatric impairments in Huntington's disease (HD) typically manifest early in disease progression, before motor deficits. However, the neurobiological factors contributing to psychiatric symptoms are poorly understood. We used a mouse HD model and assessed whether impaired dopamine release in the nucleus accumbens (NAc), a brain region critical to goal-directed behaviors, accompanies motivational deficits, one of the most common early HD symptoms. HD mice exhibited blunted motivation to work for food reward coincident with diminished dopamine release to reward receipt. Motivational and NAc dopaminergic deficits were not associated with gross motor deficits or impaired food seeking when effortful demands were low. This work identifies a specific prodromal HD phenotype associated with a prominent and previously unidentified neurobiological impairment.

Subsecond Regulation of Synaptically Released Dopamine by COMT in the Olfactory Bulb.

UNLABELLED: The efficacy of neurotransmission depends on multiple factors, including presynaptic vesicular release of transmitter, postsynaptic receptor populations and clearance/inactivation of the transmitter. In the olfactory bulb (OB), short axon cells (SACs) form an interglomerular circuit that uses GABA and dopamine (DA) as cotransmitters. Selective optical activation of SACs causes GABA and DA co-release, resulting in a fast, postsynaptic GABA inhibitory response and a slower G-protein-coupled DA rebound excitation. In most systems, vesicular release of DA is cleared by the dopamine transporter (DAT). However, in the OB, high levels of specific DA metabolites suggest that enzymatic catalysis by catechol-O-methyl-transferase (COMT) predominates over DAT re-uptake. To assess this possibility we measured the amount of the DA breakdown enzyme, COMT, present in the OB. Compared with the striatum, the brain structure richest in DA terminals, the OB contains 50% more COMT per unit of tissue. Furthermore, the OB has dramatically less DAT compared with striatum, supporting the idea that COMT enzymatic breakdown, rather than DAT recycling, is the predominant mechanism for DA clearance. To functionally assess COMT inactivation of vesicular release of DA we used fast-scan cyclic voltammetry and pharmacological blockade of COMT. In mice expressing ChR2 in tyrosine hydroxylase-containing neurons, optical activation of SACs evoked robust DA release in the glomerular layer. The COMT inhibitor, tolcapone, increased the DA signal ∼2-fold, whereas the DAT inhibitor GBR12909 had no effect. Together, these data indicate that the OB preferentially employs COMT enzymatic inactivation of vesicular release of DA. SIGNIFICANCE STATEMENT: In the olfactory bulb (OB), odors are encoded by glomerular activation patterns. Dopaminergic short axon neurons (SACs) form an extensive network of lateral connections that mediate cross talk among glomeruli, releasing GABA and DA onto sensory nerve terminals and postsynaptic neurons. DA neurons are ∼10-fold more numerous in OB than in ventral tegmental areas that innervate the striatum. We show that OB has abundant expression of the DA catalytic enzyme catechol-O-methyl-transferase (COMT), but negligible expression of the dopamine transporter. Using optogenetics and fast-scan cyclic voltammetry, we show that inhibition of COMT increases DA signals ∼2-fold. Thus, in contrast to the striatum, which has the brain's highest proportion of DAergic synapses, the DA catalytic pathway involving COMT predominates over re-uptake in OB.

Medial Orbitofrontal Neurons Preferentially Signal Cues Predicting Changes in Reward during Unblocking.

UNLABELLED: The orbitofrontal cortex (OFC) has been broadly implicated in the ability to use the current value of expected outcomes to guide behavior. Although value correlates have been prominently reported in lateral OFC, they are more often associated with more medial areas. Further, recent studies in primates have suggested a dissociation in which the lateral OFC is involved in credit assignment and representation of reward identity and more medial areas are critical to representing value. Previously, we used unblocking to test more specifically what information about outcomes is represented by OFC neurons in rats; consistent with the proposed dichotomy between the lateral and medial OFC, we found relatively little linear value coding in the lateral OFC (Lopatina et al., 2015). Here we have repeated this experiment, recording in the medial OFC, to test whether such value signals might be found there. Neurons were recorded in an unblocking task as rats learned about cues that signaled either more, less, or the same amount of reward. We found that medial OFC neurons acquired responses to these cues; however, these responses did not signal different reward values across cues. Surprisingly, we found that cells developed responses to cues predicting a change, particularly a decrease, in reward value. This is consistent with a special role for medial OFC in representing current value to support devaluation/revaluation sensitive changes in behavior. SIGNIFICANCE STATEMENT: This study uniquely examines encoding in rodent mOFC at the single-unit level in response to cues that predict more, less, or no change in reward in rats during training in a Pavlovian unblocking task, finding more cells responding to change-predictive cues and stronger activity in response to cues predictive of less reward.

Chronic lithium treatment rectifies maladaptive dopamine release in the nucleus accumbens.

Chronic lithium treatment effectively reduces behavioral phenotypes of mania in humans and rodents. The mechanisms by which lithium exerts these actions are poorly understood. Pre-clinical and clinical evidence have implicated increased mesolimbic dopamine (DA) neurotransmission with mania. We used fast-scan cyclic voltammetry to characterize changes in extracellular DA concentrations in the nucleus accumbens (NAc) core evoked by 20 and 60 Hz electrical stimulation of the ventral tegmental area (VTA) in C57BL6/J mice treated either acutely or chronically with lithium. The effects of chronic lithium treatment on the availability of DA for release were assessed by depleting readily releasable DA using short inter-train intervals, or administering d-amphetamine acutely to mobilize readily releasable DA. Chronic, but not acute, lithium treatment decreased the amplitude of DA responses in the NAc following 60 Hz pulse train stimulation. Neither lithium treatment altered the kinetics of DA release or reuptake. Chronic treatment did not impact the progressive reduction in the amplitude of DA responses when, using 20 or 60 Hz pulse trains, the VTA was stimulated every 6 s to deplete DA. Specifically, the amplitude of DA responses to 60 Hz pulse trains was initially reduced compared to control mice, but by the fifth pulse train, there was no longer a treatment effect. However, chronic lithium treatment attenuated d-amphetamine-induced increases in DA responses to 20 Hz pulse trains stimulation. Our data suggest that long-term administration of lithium may ameliorate mania phenotypes by normalizing the readily releasable DA pool in VTA axon terminals in the NAc. Read the Editorial Highlight for this article on Page 520.

Amphetamine elevates nucleus accumbens dopamine via an action potential-dependent mechanism that is modulated by endocannabinoids.

The reinforcing effects of abused drugs are mediated by their ability to elevate nucleus accumbens dopamine. Amphetamine (AMPH) was historically thought to increase dopamine by an action potential-independent, non-exocytotic type of release called efflux, involving reversal of dopamine transporter function and driven by vesicular dopamine depletion. Growing evidence suggests that AMPH also acts by an action potential-dependent mechanism. Indeed, fast-scan cyclic voltammetry demonstrates that AMPH activates dopamine transients, reward-related phasic signals generated by burst firing of dopamine neurons and dependent on intact vesicular dopamine. Not established for AMPH but indicating a shared mechanism, endocannabinoids facilitate this activation of dopamine transients by broad classes of abused drugs. Here, using fast-scan cyclic voltammetry coupled to pharmacological manipulations in awake rats, we investigated the action potential and endocannabinoid dependence of AMPH-induced elevations in nucleus accumbens dopamine. AMPH increased the frequency, amplitude and duration of transients, which were observed riding on top of slower dopamine increases. Surprisingly, silencing dopamine neuron firing abolished all AMPH-induced dopamine elevations, identifying an action potential-dependent origin. Blocking cannabinoid type 1 receptors prevented AMPH from increasing transient frequency, similar to reported effects on other abused drugs, but not from increasing transient duration and inhibiting dopamine uptake. Thus, AMPH elevates nucleus accumbens dopamine by eliciting transients via cannabinoid type 1 receptors and promoting the summation of temporally coincident transients, made more numerous, larger and wider by AMPH. Collectively, these findings are inconsistent with AMPH eliciting action potential-independent dopamine efflux and vesicular dopamine depletion, and support endocannabinoids facilitating phasic dopamine signalling as a common action in drug reinforcement.

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters.

Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine's antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine's side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1-D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine's enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 µM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect.

ΔFosB induction in striatal medium spiny neuron subtypes in response to chronic pharmacological, emotional, and optogenetic stimuli.

The transcription factor, ΔFosB, is robustly and persistently induced in striatum by several chronic stimuli, such as drugs of abuse, antipsychotic drugs, natural rewards, and stress. However, very few studies have examined the degree of ΔFosB induction in the two striatal medium spiny neuron (MSN) subtypes. We make use of fluorescent reporter BAC transgenic mice to evaluate induction of ΔFosB in dopamine receptor 1 (D1) enriched and dopamine receptor 2 (D2) enriched MSNs in ventral striatum, nucleus accumbens (NAc) shell and core, and in dorsal striatum (dStr) after chronic exposure to several drugs of abuse including cocaine, ethanol, Δ(9)-tetrahydrocannabinol, and opiates; the antipsychotic drug, haloperidol; juvenile enrichment; sucrose drinking; calorie restriction; the serotonin selective reuptake inhibitor antidepressant, fluoxetine; and social defeat stress. Our findings demonstrate that chronic exposure to many stimuli induces ΔFosB in an MSN-subtype selective pattern across all three striatal regions. To explore the circuit-mediated induction of ΔFosB in striatum, we use optogenetics to enhance activity in limbic brain regions that send synaptic inputs to NAc; these regions include the ventral tegmental area and several glutamatergic afferent regions: medial prefrontal cortex, amygdala, and ventral hippocampus. These optogenetic conditions lead to highly distinct patterns of ΔFosB induction in MSN subtypes in NAc core and shell. Together, these findings establish selective patterns of ΔFosB induction in striatal MSN subtypes in response to chronic stimuli and provide novel insight into the circuit-level mechanisms of ΔFosB induction in striatum.

Effect of CB1 receptor blockade on food-reinforced responding and associated nucleus accumbens neuronal activity in rats.

Studies have shown that disruption of cannabinoid receptor signaling reduces operant responses for rewards; yet it is unknown whether changes in neural activity at dopamine terminal regions such as the nucleus accumbens (NAc) underlie these behavioral effects. To study the neural correlates that accompany the disruption of endogenous cannabinoid (eCB) signaling in a food-motivated task, we recorded the neural activity and local field potentials (LFPs) from the NAc. A within-subject design was used for recordings as rats engaged in lever-pressing behavior for sucrose chocolate-flavored pellets delivered during responding in a progressive ratio (PR) schedule of reinforcement. Rats were food restricted to 85 ± 5% of their free body weight and trained under a PR until a stable breakpoint was observed (12 sessions ± 3). Once performance was stable, recordings were made under baseline, vehicle, and following administration of the cannabinoid inverse agonist rimonabant (150 µg/kg, i.v). NAc neurons encoded reward-predictive cues as well as food reward delivery. Rimonabant administration robustly reduced breakpoints in all rats tested, as previously reported. We found that this reduction is accompanied by a profound attenuation in the strength and coordination of specific event-related spiking activity. Moreover, rimonabant decreased LFP gamma power at 80 Hz (high gamma) at reward delivery and gamma power at 50 Hz (low gamma) at cue onset. Together the present results indicate that the eCB system sculpts neural activity patterns that accompany PR performance and reward consumption.

Subsecond dopamine release in the nucleus accumbens predicts conditioned punishment and its successful avoidance.

The mesolimbic dopamine system is believed to be a pathway that processes rewarding information. While previous studies have also implicated a general role for dopamine in punishment and its avoidance, the precise nature of subsecond dopamine release during these phenomena remains unknown. Here, we used fast-scan cyclic voltammetry to investigate whether subsecond dopamine release events in the nucleus accumbens encode cues predicting the avoidance of punishment during behavior maintained in a signaled footshock avoidance procedure. In this task, rats could initiate an avoidance response by pressing a lever within a warning period, preventing footshock. Alternatively, once footshocks commenced, animals could initiate an escape response by pressing the lever, terminating footshock. This design allowed us to assess subsecond dopamine release events during the presentation of a warning signal, safety periods, and two distinct behavioral responses. We found that release consistently increased upon presentation of the warning signal in a manner that reliably predicted successful punishment avoidance. We also observed subsecond dopamine release during the safety period, as occurs following the receipt of reward. Conversely, we observed a decrease in release at the warning signal during escape responses. Because of this finding, we next assessed dopamine release in a conditioned fear model. As seen during escape responses, we observed a time-locked decrease in dopamine release upon presentation of a cue conditioned to inescapable footshock. Together, these data show that subsecond fluctuations in mesolimbic dopamine release predict when rats will successfully avoid punishment and differentially encode cues related to aversive outcomes.

Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function.

Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28-49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.