Biology subjects

Samaha, A.-N.

Publications and source records attributed to Samaha, A.-N..

13 recordsLinked to original sources

bioRxiv2025

Basolateral Amygdala Projections to the Prelimbic Cortex Suppress the Motivational Value of Reward-Associated Cues

Reward-associated cues drive reward-seeking behaviours, with different cue types taking on distinct associative meanings. In instrumental settings, discriminative stimuli (DSs) signal when a response will produce reward, while conditioned stimuli (CSs) are paired with reward delivery after responding. Basolateral amygdala (BLA) projections are known to mediate CS-guided reward seeking, but their role in DS-guided behaviour remains unclear despite DSs being uniquely effective in triggering reward seeking. Here, we used optogenetic stimulation of BLA projections to the nucleus accumbens (NAc) core or prelimbic cortex (PrL) to probe their causal involvement in DS- and CS-guided sucrose seeking. Female and male rats learned to lever press during DS+ trials to obtain sucrose paired with a CS+, and to withhold responding during DS-trials where sucrose was unavailable. We then assessed sucrose seeking evoked by response-independent DS+ and CS+ presentations, without sucrose. The DS+ prompted the greatest increases in lever pressing, acting as a strong Pavlovian conditioned excitor. Cue-paired photostimulation of BLA[->]NAc core or BLA[->]PrL projections did not alter this effect. In a test of instrumental responding for conditioned reinforcement, rats lever pressed most for DS+ and CS+ presentations, with no effect of cue-type, indicating that the two cues gained comparable conditioned reinforcing value. While cue-paired photostimulation of BLA[->]NAc core neurons had no impact, photostimulation of BLA[->]PrL projections suppressed instrumental responding for both the DS+ and CS+. These findings reveal the BLA[->]PrL pathway as a key regulator that constrains control over behaviour by reward-associated cues, making them less desirable and reducing their motivational effects.

neuroscience↗

bioRxiv2025

Activation of Infralimbic cortex neurons projecting to the nucleus accumbens shell suppresses discriminative stimulus-triggered relapse to cocaine seeking in rats

Cocaine addiction is marked by high relapse rates, often triggered by drug-associated cues. These cues can be conditioned stimuli (CSs), which occur after drug intake and are paired with drug effects, and discriminative stimuli (DSs), which signal drug availability, regardless of ongoing drug-seeking behaviour. While projections from the infralimbic cortex (IL) to the nucleus accumbens (NAc) shell are known to regulate CS-induced cocaine relapse, their role in DS-triggered relapse is not known. To investigate this, we examined how activating IL[->]NAc shell projections influences relapse driven by DSs and CSs during abstinence from intermittent cocaine use. Female Sprague-Dawley rats received viral-mediated gene expression of excitatory designer receptors exclusively activated by designer drugs in the IL. Rats then self-administered cocaine during 12 intermittent-access sessions (5-min cocaine ON/25-min cocaine OFF, 4h/day). A discrete light (DS+) signalled drug-available periods, while a different light (DS-) signalled drug non-availability. During each DS+ period, cocaine infusions were paired with a compound light-tone (CS+). Four weeks later, rats were tested for cue-induced cocaine seeking following response-independent presentation of DS+, CS+ or both. Immediately prior to testing, rats received intra-NAc shell clozapine N-oxide or aCSF to activate IL terminals. DS+ alone and DS+/CS+ combined triggered greater cocaine seeking than did the CS+. Activation of IL[->]NAc shell projections suppressed relapse behaviour in DS+ and DS+/CS+ conditions. These findings highlight the distinct and powerful influence of DSs on relapse and identify the IL[->]NAc shell circuit as a promising target for relapse prevention.

neuroscience↗

bioRxiv2023

Uncertain, intermittent access to reward promotes increased reward pursuit

Self-administration procedures have been developed to model the intermittency of cocaine use in humans. These procedures involve intermittent, predictable access to cocaine during daily self-administration sessions. However, human drug use often involves intermittent and unpredictable patterns of drug access. Here, we introduce a new procedure to study the effects of unpredictable, intermittent access (UIntA) to a reinforcer, and we compare this procedure to two existing ones that provide predictable reinforcer availability; continuous (ContA) or intermittent (IntA) access. Three groups of rats self-administered water or a 5% sucrose solution in daily hour-long sessions. UIntA rats had alternating periods of reinforcer ON and OFF of unpredictable duration (1, 5 or 9 min/period). During reinforcer ON periods, reinforcer quantities were also unpredictable (0, 0.1 or 0.2 ml of solution) and were available under a variable ratio 3 schedule of reinforcement (1-6 responses). Both IntA and ContA rats had access to a fixed volume of water or sucrose (0.1 ml), under a fixed ratio 3 schedule of reinforcement. IntA rats had alternating and predictable 5-min reinforcer ON and OFF periods, while ContA rats had 60 minutes of reinforcer access during each session. Following 14 daily self-administration sessions, we found that UIntA rats had the highest rates of responding for water or sucrose reward under progressive ratio and extinction conditions, and the highest levels of cue-induced reinstatement of sucrose seeking. Thus, uncertain, intermittent access to reward promotes increased reward-seeking and -taking behaviours. This has implications for modeling addiction and other disorders of increased reward seeking.

neuroscience↗

bioRxiv2022

Metabotropic glutamate group II receptor activation in the dorsal striatum suppresses the motivation for cocaine in rats

After a history of intermittent cocaine intake, rats develop patterns of drug use characteristic of addiction. The dorsal striatum is involved in the increased pursuit of cocaine after intermittent drug self-administration experience. Within the dorsal striatum, chronic cocaine use changes metabotropic glutamate type II receptor (mGlu2/3) density and function. We examined the extent to which activity at these receptors mediates responding for cocaine after intermittent cocaine use. In Experiment 1, male Wistar rats (n = 11) self-administered 0.25 mg/kg/infusion cocaine during 10 daily intermittent access (IntA) sessions (5 min ON/25 min OFF, for 5 h/session). We then examined the effects of intra-dorsal striatum infusions of the mGlu2/3 receptor agonist LY379268 (0, 1, and 3 g/hemisphere) on cocaine self-administration under a progressive ratio schedule of reinforcement. We observed a non-significant tendency for LY379268 to reduce responding for cocaine. In Experiment 2, we used a larger sample of male (n = 11) and female (n = 10) rats. Across 10 IntA sessions, the sexes showed similar levels of cocaine intake. Across the sexes, locomotion significantly increased over sessions, suggesting that rats developed psychomotor sensitization to self-administered cocaine. After 10 IntA sessions, intra-dorsal striatum LY379268 significantly reduced breakpoints achieved for cocaine, active lever presses, and cocaine infusions earned under progressive ratio. LY379268 had no effects on locomotion or inactive lever presses, indicating no motor effects. These results suggest that mGlu2/3 receptor activation in the dorsal striatum suppresses incentive motivation for cocaine, and this holds promise for anti-addiction therapeutics.

neuroscience↗

bioRxiv2022

Does vendor breeding colony influence sign- and goal-tracking in Pavlovian conditioned approach? A preregistered empirical replication

Vendor differences are thought to affect Pavlovian conditioning in rats. After observing possible differences in sign-tracking and goal-tracking behaviour with rats from different breeding colonies, we performed an empirical replication of the effect. 40 male Long-Evans rats from Charles River colonies K72 and R06 received 11 Pavlovian conditioned approach training sessions (or "autoshaping"), with a lever as the conditioned stimulus (CS) and 10% sucrose as the unconditioned stimulus (US). Each 58-min session consisted of 12 CS-US trials. Paired rats (n = 15/colony) received the US following lever retraction. Unpaired control rats (n = 5/colony) received sucrose during the inter-trial interval. Next, we evaluated the conditioned reinforcing properties of the CS, by determining whether rats would learn to nose-poke into a new, active (vs. inactive) port to receive CS presentations alone (no sucrose). Preregistered confirmatory analyses showed that during autoshaping sessions, Paired rats made significantly more CS-triggered entries into the sucrose port (i.e., goal-tracking) and lever activations (sign-tracking) than Unpaired rats did, demonstrating acquisition of the CS-US association. Confirmatory analyses showed no effects of breeding colony on autoshaping. During conditioned reinforcement testing, analysis of data from Paired rats alone showed significantly more active vs. inactive nosepokes, suggesting that in these rats, the lever CS acquired incentive motivational properties. Analysing Paired rats alone also showed that K72 rats had higher Pavlovian Conditioned Approach scores than R06 rats did. Thus, breeding colony can affect outcome in Pavlovian conditioned approach studies, and animal breeding source should be considered as a covariate in such work.

neuroscience↗

bioRxiv2021

D-amphetamine maintenance therapy reduces cocaine use in female rats

Currently, there are no approved medications to treat cocaine addiction. In this context, d-amphetamine maintenance therapy is a promising pharmacological strategy to reduce cocaine use. In both male rats and human cocaine users, d-amphetamine treatment reduces cocaine taking and seeking. However, this has not been examined systematically in female animals, even though cocaine addiction afflicts both women and men, and the sexes can differ in their response to cocaine. Here, we determined how d-amphetamine maintenance therapy during cocaine self-administration influences cocaine use in female rats. In experiment 1, two groups of female rats received 14 intermittent access (IntA) cocaine self-administration sessions. One group received concomitant d-amphetamine maintenance treatment (COC + A rats; 5 mg/kg/day, via minipump), the other group did not (COC rats). After discontinuing d-amphetamine treatment, we measured responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed reinstatement of drug seeking. In experiment 2, we assessed the effects of d-amphetamine maintenance on these measures in already cocaine-experienced rats. To this end, rats first received 14 IntA cocaine self-administration sessions without d-amphetamine. They then received 14 more sessions now either with (COC/COC + A rats) or without (COC/COC rats) concomitant d-amphetamine treatment. In both experiments, d-amphetamine treatment did not influence cocaine-primed reinstatement of cocaine seeking. However, after d-amphetamine treatment, rats responded less for cocaine both under progressive ratio and extinction conditions. Thus, d-amphetamine treatment can both prevent and reverse increases in the motivation to take and seek cocaine in female animals.

neuroscience↗

bioRxiv2021

Optogenetic activation of basolateral amygdala projections to nucleus accumbens core promotes cue-induced expectation of reward but not instrumental pursuit of cues

Reward-associated conditioned stimuli (CS) can acquire predictive value, evoking conditioned approach behaviors that prepare animals to engage with forthcoming rewards. Such CS can also acquire conditioned reinforcing value, becoming attractive and pursued. Through their predictive and conditioned reinforcing properties, CS can promote adaptive (e.g., locating food) but also maladaptive responses (e.g., drug use). Basolateral amygdala neurons projecting to the nucleus accumbens core (BLA[->]NAc core neurons) mediate the response to appetitive CS, but the extent to which this involves effects on the predictive and/or conditioned reinforcing properties of CS is unclear. Thus, we examined the effects of optogenetic stimulation of BLA[->]NAc core neurons on conditioned approach behavior and on the instrumental pursuit of a CS, the latter a measure of conditioned reinforcement. Water-restricted, adult male rats learned that a light-tone compound cue (CS) predicts water delivery. Pairing optogenetic stimulation of BLA[->]NAc core neurons with CS presentation potentiated conditioned approach behavior, and did so even under extinction conditions, when water was omitted. This suggests that BLA[->]NAc core neurons promote cue-induced expectation of rewards. Rats also received instrumental conditioning sessions during which they could lever press for CS presentations, without water delivery. Optogenetic stimulation of BLA[->]NAc core neurons either during these instrumental test sessions or during prior CS-water conditioning did not influence lever responding for the CS. This suggests that BLA[->]NAc core neurons do not influence the conditioned reinforcing effects of CS. We conclude that BLA[->]NAc core neurons promote cue-induced control over behavior by increasing cue-triggered anticipation of rewards, without influencing cue wanting. SIGNIFICANCE STATEMENTEnvironmental cues associated with rewards guide animals toward rewards essential for survival such as food. Reward-associated cues can also evoke maladaptive responses such as in addiction. Reward cues guide behavior in two major ways. First, they evoke approach toward imminent rewards, preparing animals to engage with these rewards. Second, cues can become attractive themselves, such that animals will learn new behaviors simply to obtain them. Here we show that activation of basolateral amygdala neurons projecting to the nucleus accumbens core increases cue-induced approach to the location of reward, without influencing the pursuit of reward cues. Thus, these amygdala-to-accumbens neurons promote cue-induced expectation of reward, without changing the attractiveness of cues.

neuroscience↗

bioRxiv2021

Metabotropic group II glutamate receptors mediate cue-triggered increases in incentive motivation for reward

RationaleReward-associated cues can acquire incentive motivational properties and invigorate reward-seeking actions via Pavlovian-to-instrumental transfer (PIT). Glutamatergic neurotransmission mediates the appetitive effects of reward-associated cues. We characterized the expression of PIT and its mediation by metabotropic group II glutamate (mGlu2/3) receptor activity in female and male rats. ObjectivesAcross the sexes, we used PIT procedures to determine i) cue-triggered increases in incentive motivation for water reward (Experiment 1), ii) the respective influences of the mGlu2/3 receptor agonist LY379268 and reward devaluation by satiation on this effect (Experiment 2). MethodsWater-restricted male and female Sprague-Dawley rats learned to lever press for water. Separately, they learned that one of two auditory stimuli predicts free water (CS+ vs CS-). On PIT test days, the CS+ and CS- were presented non-contingently, and we measured effects on lever pressing under extinction (no water). In Experiment 1, we characterized PIT across the sexes. In Experiment 2, we measured PIT after systemic LY379268 administration (0, 0.3 and 1 mg/kg), and water satiation, respectively. ResultsFemale and male rats showed similar PIT, with CS+ but not CS- presentations potentiating water-seeking behaviour. LY379268 (1 mg/kg) attenuated CS+ evoked increases in both water-associated lever pressing and conditioned approach to the water port. Reward devaluation attenuated both water-seeking and CS+ evoked conditioned approach behaviour. ConclusionsThe sexes show similar cue-triggered increases in reward wanting, and water devaluation suppresses both water seeking and cue-triggered anticipation of water reward. Finally, across the sexes, mGlu2/3 receptor activity mediates cue-triggered increases in reward wanting.

pharmacology and toxicology↗

bioRxiv2021

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

RationaleReward-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. ObjectivesIn 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. MethodsWater-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 g/hemisphere) before testing. ResultsAcross 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. ConclusionsmGlu2/3 receptor activity in the BLA mediates CS-triggered potentiation of incentive motivation for reward, suppressing both CS-induced increases in instrumental pursuit of the reward and anticipatory approach behaviour.

neuroscience↗

bioRxiv2020

Where and how does d-amphetamine act to reveal 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 GSK3{beta} 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 antipsychotic-evoked 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. HIGHLIGHTSO_LIAntipsychotic exposure can lead to a state of dopamine (DA) supersensitivity C_LIO_LIIn rats, this DA supersensitivity potentiates d-amphetamine-induced locomotion C_LIO_LIWe report that D2 transmission promotes DA supersensitivity and D1 transmission tempers it C_LIO_LID-amphetamines central effects are also insufficient to reveal DA supersensitivity C_LI

pharmacology and toxicology↗

bioRxiv2020

Amphetamine Maintenance Therapy During Intermittent Cocaine Self-Administration in Rats: Reduction of Addiction-like Behavior is Associated with Attenuation of Psychomotor and Dopamine Sensitization

BackgroundD-amphetamine maintenance therapy shows promise as a treatment for people with cocaine addiction. Preclinical studies using Long Access (LgA) cocaine self-administration procedures suggest D-amphetamine may act by preventing tolerance to cocaines effects at the dopamine transporter (DAT). However, Intermittent Access (IntA) cocaine self-administration better reflects human patterns of use, is especially effective in promoting addiction-relevant behaviors, and instead of tolerance, produces psychomotor, incentive, and neural sensitization. We asked, therefore, how D-amphetamine maintenance during IntA influences cocaine use and cocaines potency at the DAT. MethodsMale rats self-administered cocaine intermittently (5 minutes ON, 25 minutes OFF x 10) for 14 sessions, with or without concomitant D-amphetamine (5 mg/kg/day via s.c. osmotic minipump). In Experiment 1, psychomotor sensitization, responding for cocaine under a progressive ratio schedule, responding under extinction and cocaine-primed relapse were assessed. In Experiment 2, rats self-administered cocaine or saline intermittently, with or without D-amphetamine, and the ability of cocaine to inhibit dopamine uptake in the nucleus accumbens core was assessed using fast scan cyclic voltammetry ex vivo. ResultsIntA cocaine self-administration produced psychomotor sensitization, strong motivation to take and seek cocaine, and it increased cocaines potency at the DAT. The co-administration of D-amphetamine suppressed both the psychomotor sensitization and high motivation for cocaine produced by IntA experience, and also reversed sensitization of cocaines actions at the DAT, leaving baseline DAT function unchanged. ConclusionsTreatment with D-amphetamine might reduce cocaine use by preventing sensitization-related changes in cocaine potency at the DAT, consistent with an incentive-sensitization view of addiction.

neuroscience↗

bioRxiv2019

The basolateral nucleus of the amygdala regulates both the predictive and incentive motivational properties of reward cues

Reward-associated stimuli can acquire both predictive and incentive motivational properties. These conditioned stimuli (CS) can then guide reward-seeking behaviour in adaptive (e.g., locating food) and maladaptive (e.g., binge eating) ways. The basolateral amygdala (BLA) contributes to learning of the predictive value of CS, but less is known about BLA contributions to the incentive motivational properties of appetitive CS. Here we studied the influence of BLA neuron activity on both the predictive and incentive motivational effects of CS. Water-restricted male rats learned to associate a light-tone cue (CS) with water delivery into a port. We assessed the predictive value to the CS by measuring CS-evoked port entries during Pavlovian conditioning. We assessed CS-evoked incentive motivation by measuring lever-pressing for the CS during instrumental responding sessions. During Pavlovian conditioning, we paired CS presentations with photo-stimulation of channelrhodopsin-2 (ChR2)-expressing BLA neurons. This potentiated CS-evoked port entries during conditioning, but suppressed subsequent lever-pressing for the CS. This indicates increased conditioned responding to the CS, but an apparent decrease in incentive motivation for that CS. However, in rats previously naive to photo-stimulation, pairing BLA-ChR2 stimulations during lever-pressing for the CS intensified responding, indicating enhanced motivation for the CS. Rats did not self-administer BLA-ChR2 stimulations, suggesting that BLA activation does not carry a primary reward signal. Lastly, intra-BLA infusions of d-amphetamine also intensified lever-pressing for the CS. These converging findings suggest that BLA mediated-activity enhances both the predictive and incentive motivational properties of CS, allowing BLA-dependent circuits to guide behaviour in the presence of reward-associated cues.\n\nSIGNIFICANCE STATEMENTCues paired with rewards can guide animals to valuable resources such as food. Cues can also promote dysfunctional reward-seeking behaviour, as in over-eating. Reward-paired cues influence reward seeking through two major mechanisms. First, reward-paired cues are predictive and thus evoke anticipation of future 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 the predictive and motivational effects of reward-paired cues. The basolateral amygdala therefore facilitates cue-induced control over behaviour by both increasing anticipation for impending rewards and making reward cues more attractive.

animal behavior and cognition↗

bioRxiv2018

Sex differences in cocaine self-administration behaviour under Long Access versus Intermittent Access conditions

A widely accepted rodent model to study cocaine addiction involves allowing animals continuous access to drug during long self-administration sessions ( Long-access or LgA). This produces continuously high brain concentrations of drug during each session. This might not model the pharmacokinetics of cocaine use in experienced human users, which are thought to involve intermittently spiking brain cocaine concentrations within and between bouts of use. Intermittent-access (IntA) cocaine self-administration models this spiking pattern in rats. IntA is also particularly effective in increasing incentive motivation for drug. Most IntA studies have been conducted in male rats. Both humans and non-human animals can show sex differences in all phases of the addiction process. We compared cocaine use in female and male rats that self-administered the drug (0.25 mg/kg/injection, i.v.) during 10 daily, 6-h LgA or IntA sessions. Cocaine intake was greatest under LgA, and female LgA rats escalated their intake. However, only IntA rats (both sexes) developed locomotor sensitization to self-administered cocaine and sensitization was greatest in the females. Five and 25 days after the last self-administration session, we quantified incentive motivation for cocaine by measuring breakpoints for the drug (0.083-0.75 mg/kg/injection) under progressive ratio. Breakpoints were similar in IntA and LgA rats. There were no sex differences in breakpoints under LgA. However, under IntA, females reached higher breakpoints for cocaine than males. Thus, LgA might be best suited to study sex differences in cocaine intake, while IntA might be best suited to study sex differences in incentive motivational processes in cocaine addiction.

neuroscience↗