Optogenetic activation of basolateral amygdala-to-nucleus accumbens core neurons promotes Pavlovian approach responses but not instrumental pursuit of reward cues.

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.

Dips in dopamine say "no" to nicotine.

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).

Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats.

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 GSK3ß 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.

Metabotropic group II glutamate receptors in the basolateral amygdala mediate cue-triggered increases in incentive motivation.

RATIONALE: Reward-associated cues can trigger incentive motivation for reward and invigorate reward-seeking behaviour via Pavlovian-to-instrumental transfer (PIT). Glutamate signaling within the basolateral amygdala (BLA) modulates cue-triggered increases in incentive motivation. However, the role of BLA metabotropic group II glutamate (mGlu2/3) receptors is largely unknown. OBJECTIVES: In Experiment 1, we characterized cue-triggered increases in incentive motivation for water reward using the PIT paradigm. In Experiment 2, we assessed the influence of intra-BLA microinjections of the mGlu2/3 receptor agonist LY379268 on this effect. METHODS: Water-restricted male Sprague-Dawley rats learned to press a lever for water. Separately, they learned to associate one of two auditory cues with free water. On test days, rats could lever press under extinction conditions (no water), with intermittent, non-contingent CS+ and CS- presentations. In Experiment 1, rats were tested under baseline conditions. In Experiment 2, rats received intra-BLA microinjections of LY379268 (0, 3 and 6 [Formula: see text]g/hemisphere) before testing. RESULTS: Across experiments, CS+, but not CS-, presentations increased water-associated lever pressing during testing, even though responding was reinforced neither by water nor the CS+. Intra-BLA LY379268 abolished both CS+ potentiated pressing on the water-associated lever and CS+ evoked conditioned approach to the site of water delivery. LY379268 did not influence locomotion or instrumental and Pavlovian response rates during intervals between CS presentations or during the CS-, indicating no motor effects. CONCLUSIONS: mGlu2/3 receptor activity in the BLA mediates cue-triggered potentiation of incentive motivation for reward, suppressing both cue-induced increases in instrumental pursuit of the reward and anticipatory approach behaviour.

Continuous versus extended antipsychotic dosing in schizophrenia: Less is more.

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.

Optogenetic Activation of the Basolateral Amygdala Promotes Both Appetitive Conditioning and the Instrumental Pursuit of Reward Cues.

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 photo-stimulation 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 self-administer 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.SIGNIFICANCE STATEMENT Cues paired with rewards can guide animals to valuable resources such as food. Cues can also promote dysfunctional reward-seeking behavior, as in overeating. Reward-paired cues influence reward seeking through two major mechanisms. First, reward-paired cues evoke conditioned anticipatory behaviors to prepare for impending rewards. Second, reward-paired cues are powerful motivators and they can evoke pursuit in their own right. Here we show that increasing neural activity in the basolateral amygdala enhances both conditioned anticipatory behaviors and pursuit of reward-paired cues. The basolateral amygdala therefore facilitates cue-induced control over behavior by both increasing anticipation of impending rewards and making reward cues more attractive.

Antipsychotic-evoked dopamine supersensitivity.

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'.

Role of the orbitofrontal cortex and the dorsal striatum in incentive motivation for cocaine.

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.

Neurotensin in the nucleus accumbens reverses dopamine supersensitivity evoked by antipsychotic treatment.

Long-term exposure to antipsychotics like haloperidol can increase sensitivity to dopamine agonist stimulation. This could contribute to treatment failure and increase relapse to psychosis. Chronic antipsychotic treatment elevates neurotensin levels in the nucleus accumbens (NAc), where the neuropeptide modulates dopamine function by signalling through NTS1 receptors. We hypothesized that increasing neurotensin activity in the NAc attenuates the expression of antipsychotic-induced dopamine supersensitivity, which is indicated by a potentiated psychomotor response to amphetamine. Rats received either continuous (CONT-HAL; achieved via subcutaneous osmotic minipump) or intermittent (INT-HAL; achieved via daily subcutaneous injection) haloperidol treatment for 16-17 days. Three to 5 days later, we injected neurotensin into the NAc and measured amphetamine-induced locomotion. Only CONT-HAL rats showed potentiated amphetamine-induced locomotion, indicating dopamine supersensitivity. Compared to intra-NAc saline, intra-NAc neurotensin suppressed amphetamine-induced locomotion in CONT-HAL rats, but not in INT-HAL or control rats. In a new cohort of CONT-HAL and INT-HAL rats, we measured striatal levels of proneurotensin mRNA and NTS1 receptors. The two treatments led to overlapping but also distinct neurochemical profiles. Neither treatment altered NTS1 receptor levels in the NAc, but both increased proneurotensin mRNA levels in the NAc core. In the caudate-putamen, only INT-HAL increased NTS1 receptor levels, while only CONT-HAL increased proneurotensin mRNA expression. Thus, antipsychotic-induced dopamine supersensitivity enhances the ability of neurotensin in the NAc to regulate dopamine-mediated behaviours, and this likely does not involve changes in local levels of NTS1 receptors or proneurotensin mRNA. We conclude that increasing neurotensin activity could be considered to attenuate antipsychotic-induced dopamine supersensitivity.

5-HT2 receptors modulate the expression of antipsychotic-induced dopamine supersensitivity.

Antipsychotic treatment can produce supersensitivity to dopamine receptor stimulation. This compromises the efficacy of ongoing treatment and increases the risk of relapse to psychosis upon treatment cessation. Serotonin 5-HT2 receptors modulate dopamine function and thereby influence dopamine-dependent responses. Here we evaluated the hypothesis that 5-HT2 receptors modulate the behavioural expression of antipsychotic-induced dopamine supersensitivity. To this end, we first treated rats with the antipsychotic haloperidol using a clinically relevant treatment regimen. We then assessed the effects of a 5-HT2 receptor antagonist (ritanserin; 0.01 and 0.1mg/kg) and of a 5-HT2A receptor antagonist (MDL100,907; 0.025-0.1mg/kg) on amphetamine-induced psychomotor activity. Antipsychotic-treated rats showed increased amphetamine-induced locomotion relative to antipsychotic-naïve rats, indicating a dopamine supersensitive state. At the highest dose tested (0.1mg/kg for both antagonists), both ritanserin and MDL100,907 suppressed amphetamine-induced locomotion in antipsychotic-treated rats, while having no effect on this behaviour in control rats. In parallel, antipsychotic treatment decreased 5-HT2A receptor density in the prelimbic cortex and nucleus accumbens core and increased 5-HT2A receptor density in the caudate-putamen. Thus, activation of either 5-HT2 receptors or of 5-HT2A receptors selectively is required for the full expression of antipsychotic-induced dopamine supersensitivity. In addition, antipsychotic-induced dopamine supersensitivity enhances the ability of 5-HT2/5-HT2A receptors to modulate dopamine-dependent behaviours. These effects are potentially linked to changes in 5-HT2A receptor density in the prefrontal cortex and the striatum. These observations raise the possibility that blockade of 5-HT2A receptors might overcome some of the behavioural manifestations of antipsychotic-induced dopamine supersensitivity.

The conditioning and extinction of fear in youths: what's sex got to do with it?

Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10-17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses.