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Nicotine has both rewarding and aversive effects. In this issue of Neuron , Liu et al. show that nicotine aversion depends on both desensitization of high-affinity nicotinic acetylcholine receptors (nAChRs) that activate midbrain dopamine neurons and activation of low-affinity nAChRs that inhibit dopamine neurons via the laterodorsal tegmental nucleus (LDT). [ABSTRACT FROM AUTHOR]

Reward-associated stimuli can both evoke conditioned responses and acquire reinforcing properties in their own right, becoming avidly pursued. Such conditioned stimuli (CS) can guide reward-seeking behavior in adaptive (e.g., locating food) and maladaptive (e.g., binge eating) ways. The basolateral amygdala (BLA) regulates conditioned responses evoked by appetitive CS, but less is known about how the BLA contributes to the instrumental pursuit of CS. Here we studied the influence of BLA neuron activity on both behavioral effects. Water-restricted male rats learned to associate a light-tone cue (CS) with water delivery into a port. During these Pavlovian conditioning sessions, we paired CS presentations with photo-stimulation of channelrhodopsin-2 (ChR2)-expressing BLA neurons. BLA photostimulation potentiated CS-evoked port entries during conditioning, indicating enhanced conditioned approach and appetitive conditioning. Next, new rats received Pavlovian conditioning without photo-stimulation. These rats then received instrumental conditioning sessions where they could press an inactive lever or an active lever that produced CS presentation, without water delivery. Rats pressed more on the active versus inactive lever, and pairing CS presentation with BLA-ChR2 photo-stimulation intensified responding for the CS. This suggests that BLA-ChR2 photo-stimulation enhanced CS incentive value. In a separate experiment, rats did not reliably seifadminister BLA-ChR2 stimulations, suggesting that BLA neurons do not carry a primary reward signal. Last, intra-BLA infusions of D-amphetamine also intensified lever-pressing for the CS. The findings suggest that BLA-mediated activity facilitates CS control over behavior by enhancing both appetitive Pavlovian conditioning and instrumental pursuit of CS. [ABSTRACT FROM AUTHOR]

Reward-associated conditioned stimuli (CSs) can acquire predictive value, evoking conditioned approach behaviours that prepare animals to engage with forthcoming rewards. Such CSs can also acquire conditioned reinforcing value, becoming attractive and pursued. Through their conditioned effects, CSs can promote adaptive (e.g., locating food) but also maladaptive behaviours (e.g., drug use). Basolateral amygdala neurons projecting to the nucleus accumbens core (BLA→NAc core neurons) mediate the response to appetitive CSs, but the extent to which this involves effects on the predictive and/or conditioned reinforcing properties of CSs is unclear. Thus, we examined the effects of optogenetic stimulation of BLA→NAc core neurons on i) CS-triggered approach to the site of reward delivery, a Pavlovian conditioned approach response and ii) the instrumental pursuit of a CS, a measure of conditioned reinforcement. Water-restricted, adult male rats learned that a light-tone compound cue (the CS) predicts water delivery into a receptacle. Pairing optogenetic stimulation of BLA→NAc core neurons with CS presentation potentiated CS-triggered water receptacle visits. This suggests that activity in BLA→NAc core neurons promotes Pavlovian goal-approach behaviour. Next, rats could lever press for CS presentations, without water delivery. Optogenetic stimulation of BLA→NAc core neurons either during instrumental test sessions or during prior CS-water conditioning did not influence lever responding for the CS. This suggests that activity in BLA→NAc core neurons does not influence the instrumental pursuit of a water-paired CS. We conclude that activation of BLA→NAc core neurons promotes cue-induced control over behaviour by increasing conditioned goal-approach responses, without affecting the operant pursuit of reward cues. • Reward-predictive cues guide animals toward rewards such as water and food. • Reward cues can also become conditioned reinforcers of instrumental behaviour. • Stimulating basolateral amygdala-to-accumbens neurons promoted cued reward approach. • Stimulating these neurons did not influence instrumental pursuit of reward cues. • This identifies new roles for amygdala-to-accumbens neurons in appetitive learning. [ABSTRACT FROM AUTHOR]

Antipsychotic treatment can produce a dopamine-supersensitive state, potentiating the response to dopamine receptor stimulation. In both schizophrenia patients and rats, this is linked to tolerance to ongoing antipsychotic treatment. In rodents, dopamine supersensitivity is often confirmed by an exaggerated psychomotor response to d -amphetamine after discontinuation of antipsychotic exposure. Here we examined in rats the dopaminergic mechanisms mediating this enhanced behavioural response, as this could uncover pathophysiological processes underlying the expression of antipsychotic-evoked dopamine supersensitivity. Rats received 0.5 mg/kg/day haloperidol via osmotic minipump for 2 weeks, before treatment was discontinued. After cessation of antipsychotic treatment, rats showed a supersensitive psychomotor response to the D2 agonist quinpirole, but not to the D1 partial agonist SKF38393 or the dopamine reuptake blocker GBR12783. Furthermore, acute D1 receptor blockade (using SCH39166) decreased the exaggerated psychomotor response to d -amphetamine in haloperidol-pretreated rats, whereas acute D2 receptor blockade (using sulpiride) enhanced it. Thus, after discontinuation of antipsychotic treatment, D1- and D2-mediated transmission differentially modulate the expression of a supersensitive response to d -amphetamine. This supersensitive behavioural response was accompanied by enhanced GSK3β activity and suppressed ERK1/2 activity in the nucleus accumbens (but not caudate-putamen), suggesting increased mesolimbic D2 transmission. Finally, after discontinuing haloperidol treatment, neither increasing ventral midbrain dopamine impulse flow nor infusing d -amphetamine into the cerebral ventricles triggered the expression of already established dopamine supersensitivity, suggesting that peripheral effects are required. Thus, while dopamine receptor-mediated signalling regulates the expression of antipsychotic-evoked dopamine supersensitivity, a simple increase in central dopamine neurotransmission is insufficient to trigger this supersensitivity. • Antipsychotic exposure can lead to a state of dopamine (DA) supersensitivity. • In rats, this DA supersensitivity potentiates d -amphetamine-induced locomotion. • We report that D2 transmission promotes DA supersensitivity and D1 transmission tempers it. • d -amphetamine's central effects are also insufficient to reveal DA supersensitivity. [ABSTRACT FROM AUTHOR]

Antipsychotic drugs temper psychotic symptoms by interacting with dopamine D2 receptors to reduce dopamine neurotransmission. Currently, the standard of care involves antipsychotic treatment protocols that achieve steady-state levels of medication. Maintaining patients on continuous treatment is thought to be necessary to keep them stabilised. However, continuous antipsychotic exposure increases the risk of adverse effects over time. These effects include metabolic and cardiovascular disorders, extrapyramidal complications, and dopamine receptor supersensitivity, the latter of which could potentially promote both treatment tolerance and psychosis relapse. In the present review, we describe evidence showing that continuous exposure to antipsychotic drugs can not only worsen long-term outcome, but—past acute phase treatment—it is also unnecessary to effectively manage schizophrenia symptoms. We also describe evidence that regular but extended dosing, allowing predictable periods of lower antipsychotic levels/D2 occupancy, is both safe and effective in patients, and it greatly reduces drug exposure overall. Studies in laboratory animals show that compared to continuous antipsychotic exposure, regular but extended dosing actually has superior antipsychotic-like efficacy, and it also substantially reduces the likelihood of both motor side effects and dopamine receptor supersensitivity. We propose that regular, but extended dosing should be considered in the long-term treatment of people with schizophrenia, because the available evidence suggests it can be just as effective as continuous treatment, while decreasing overall drug exposure and potentially reducing harmful side effects. [ABSTRACT FROM AUTHOR]

All antipsychotic medications attenuate the symptoms of psychosis by interacting with dopamine D2 receptors and reducing dopamine-mediated neurotransmission. However, long-term antipsychotic treatment can produce neuroadaptations that are thought to lead to dopamine supersensitivity. In patients with schizophrenia, this dopamine supersensitivity could compromise treatment efficacy, promote relapse to psychosis and trigger movement disorders. Such effects have been seen in patients treated with either typical or atypical antipsychotics. In non-human animals, chronic exposure to antipsychotic medications, using clinically pertinent doses and modes of administration, can also evoke dopamine supersensitivity. This is indicated by an augmented behavioural response to dopamine agonists and tolerance to the antipsychotic-like effects of ongoing treatment. Here, we first describe antipsychotic-evoked dopamine supersensitivity in patients with schizophrenia and in laboratory animals. We then review approaches to prevent or reverse antipsychotic-evoked dopamine supersensitivity, based on preclinical animal studies. This evidence suggests that using atypical antipsychotics and regular but intermittent (versus continuous) antipsychotic dosing/D2 receptor occupancy is significantly less likely to produce dopamine supersensitivity. Lastly, we discuss potential neurobiological mechanisms. These include changes at the D2 receptor, but also other changes within and outside of the dopamine system. We conclude that in parallel to the search for new antipsychotic molecules, we need to better understand how different dosing regimens with currently used medications influence long-term outcome. There is also a pressing need to better characterize the development and expression of dopamine supersensitivity in humans. This will help determine the treatment strategies least likely to evoke dopamine supersensitivity. This article is part of the issue entitled 'Special Issue on Antipsychotics'. • Long-term antipsychotic treatment can evoke dopamine supersensitivity. • This might impair treatment efficacy and worsen psychosis in schizophrenia patients. • Dopamine supersensitivity is also linked to tolerance to antipsychotics in rats. • D2-related changes are seen but are not perfect dopamine supersensitivity markers. • Adequate dosing and treatment kinetics can prevent dopamine supersensitivity. [ABSTRACT FROM AUTHOR]

Drug addiction involves increased incentive motivation for drug. Intermittent access to cocaine (IntA; 5-6 minutes ON, 25-26 minutes OFF, for 5-6 hours/session) enhances motivation to take the drug. The orbitofrontal cortex (OFC) and the dorsal striatum (DS) are part of a corticolimbic circuit that encodes incentive value and regulates reward-directed behaviour. We predicted that inactivation of the OFC, DS or both suppresses incentive motivation for cocaine after IntA experience. Male Wistar rats had IntA to cocaine (0.25 mg/kg/infusion) for 10 sessions. The rats developed a 'loading' pattern of intake, taking most of their cocaine in the first minute of each drug-available period. They also developed psychomotor sensitization to self-administered cocaine. We then measured incentive motivation for cocaine using a progressive ratio schedule of reinforcement (PR). Before some PR sessions, rats received microinfusions of a baclofen/muscimol cocktail (0.3 and 0.03 nmol/hemisphere, respectively, or saline) to temporarily inactivate the OFC or DS, or to disconnect the two regions. None of these treatments changed spontaneous locomotion in cocaine-naïve rats. However, both baclofen/muscimol and saline infusions influenced cocaine self-administration behaviour. Infusing baclofen/muscimol or saline into the OFC or into the OFC and contralateral DS decreased responding for cocaine under PR, with baclofen/muscimol and saline having similar effects, except that only OFC-DS disconnection with baclofen/muscimol slowed the pace of cocaine intake. Baclofen/muscimol or saline into the DS also reduced responding for cocaine under PR, but baclofen/muscimol was more effective. We conclude that neuronal activity in the OFC and DS might regulate incentive motivation for cocaine., (Copyright © 2019 Elsevier B.V. All rights reserved.)