Biology subjects

Samaha, A.

Publications and source records attributed to Samaha, A..

6 recordsLinked to original sources

bioRxiv2025

Intermittent Cocaine Use Patterns, Not Total Intake, Predict Cue-induced Drug Seeking in Rats

Background and purposeCocaine-associated cues trigger relapse to drug use in humans and animal models. In rats, long daily cocaine access (4-6 h vs. 1-2 h) increases drug self-administration and cue-induced cocaine seeking, suggesting that greater intake promotes relapse. However, prior studies used continuous-access paradigms, whereas human cocaine use is typically intermittent. Moreover, these studies used conditioned stimuli (CS), whereas discriminative stimuli (DS) are more effective in triggering increases in drug-seeking actions. Here, we used intermittent access (IntA) self-administration to examine how session length (Short-IntA: 2 h vs. Long-IntA: 4 h) affects CS- and DS-induced cocaine seeking. Experimental approachFemale rats self-administered cocaine intermittently during daily 2- or 4-h IntA sessions, with alternating DS+ (cocaine available; 5 min) and DS- (no cocaine; 25 min) periods. Lever pressing during DS+ delivered cocaine and a CS+; lever pressing during DS-delivered only a CS-. After four weeks of abstinence, rats received a cocaine-seeking test where all cues were presented response-independently, and lever presses - which had no consequence - measured cocaine seeking. Key resultsLong-IntA rats took twice more cocaine than did Short-IntA rats. Both groups later showed significant (DS+)-but not (CS+)-triggered cocaine seeking, with no group differences. Thus, total intake did not predict cue-induced relapse propensity. However, individual cocaine intake patterns did (hourly consumption, burst-like self-administration, and latency to first infusion). Conclusions and ImplicationsUnder intermittent-access conditions, individual cocaine-use patterns, not cumulative intake, predict vulnerability to cue-induced relapse. This highlights the importance of individual drug-taking profiles in relapse risk assessment.

animal behavior and cognition↗

bioRxiv2024

Triggered Temptations: A New Procedure to Compare Reward-Seeking Behaviour Induced by Discriminative and Conditioned Stimuli in Rats

RationaleEnvironmental cues guide animals towards resources vital for survival but can also drive maladaptive reward-seeking behaviours, as in gambling and eating disorders. While conditioned stimuli (CSs) are paired with reward delivery after reward-seeking actions, discriminative stimuli (DSs) signal reward availability independent of behaviour. ObjectiveWe introduce a procedure to compare CS and DS effects on reward-seeking behaviour, in the same subjects within a single session. MethodsFemale and male Sprague-Dawley rats learned to self-administer sucrose. During each session, DS+ trials signaled that lever pressing would produce sucrose paired with a CS+, and DS-trials signaled no sucrose and a CS-. Next, in the absence of sucrose, we assessed the ability of the cues to i) reinforce lever pressing and ii) increase sucrose seeking when presented response-independently. We also assessed the effects of the mGlu2/3 receptor agonist LY379268 and d-amphetamine on cue-induced sucrose seeking. ResultsBy the end of self-administration training, lever pressing peaked during DS+ trials and dropped during DS-trials. The DS+ was a conditioned reinforcer of sucrose seeking in both sexes, whereas the CS+ was more effective in males. Response-independent presentations of the DS+ invigorated sucrose seeking in both sexes, whereas the CS+ was effective only in males. LY379268 suppressed DS+-triggered sucrose seeking in females, with no effect in males. D-amphetamine enhanced sucrose seeking non-specifically across cue conditions in males, with no effect in females. ConclusionsOur new trial-based procedure can be used to identify unique and similar mechanisms underlying DS and CS influences on appetitive behaviour.

neuroscience↗

bioRxiv2024

Activation of Group II Metabotropic Glutamate Receptors in the Basolateral Amygdala Inhibits Reward Seeking Triggered by Discriminative Stimuli

Reward-associated cues are essential in guiding reward-seeking behaviours. These cues include conditioned stimuli (CSs) which occur following seeking actions and indicate reward delivery, and discriminative stimuli (DSs) which occur response-independently and signal reward availability. Metabotropic group II glutamate (mGlu2/3) receptors in the basolateral amygdala (BLA) modulate CS-guided reward seeking; however, their role in DS effects is unknown. We first developed a procedure to assess DS and CS effects on reward seeking in the same subjects within the same test session. Female and male rats first self-administered sucrose during sessions where discriminative stimuli signaled periods of sucrose availability (DS+) and unavailability (DS-). During DS+ presentations, active lever presses produced sucrose paired with a CS+. During DS-presentations, active lever presses produced a CS- and no sucrose. Across 14 sessions, rats learned to load up on sucrose during DS+ presentation and inhibit responding during DS-presentation. We then compared the effects of intra-BLA microinfusions of the mGlu2/3 receptor agonist LY379268 on cue-evoked sucrose seeking during an extinction test (no sucrose) where the DSs and CSs were presented response-independently. Before test, rats received intra-BLA microinjections of artificial cerebrospinal fluid (aCSF) or LY379268. Under aCSF, only the DS+ and DS+CS+ combined triggered increases in reward-seeking behaviour. The CS+ alone was ineffective. Intra-BLA LY379268 reduced sucrose seeking triggered by the DS+ and DS+CS+ combination. Thus, using a new procedure to test reward seeking induced by DSs and CSs, we show that BLA mGlu2/3 receptor activity mediates the conditioned incentive motivational effects of reward predictive DSs.

neuroscience↗

bioRxiv2024

Relapse after intermittent access to cocaine: Discriminative cues more effectively trigger drug seeking than do conditioned cues

When people with drug addiction encounter cues associated with drug use, this can trigger cravings and relapse. These cues can include conditioned stimuli (CSs) signaling drug delivery and discriminative stimuli (DSs) signaling drug availability. Compared to CS effects, DS effects are less explored in preclinical studies on cue-induced relapse. We compared CS and DS effects on reward seeking following abstinence from intermittent-access cocaine (or sucrose) self-administration. During 15-20 intermittent-access sessions, rats self-administered sucrose pellets or i.v. cocaine paired with a light-tone CS. Cocaine/sucrose was available for 5-min (signalled by a light; DS+) and unavailable for 25 min (signalled by different lighting conditions; DS-), and this cycled for 4 h/session. Following abstinence, we measured cocaine/sucrose seeking under extinction triggered by CS and DS presentation, and instrumental responding reinforced by these cues. Across intermittent-access sessions, rats increased lever pressing for cocaine or sucrose during DS+ periods and decreased responding during DS-periods. On days 2 and 21 of abstinence, only presentation of the DS+ or DS+ and CS combined elicited increased cocaine/sucrose-seeking behaviour (i.e., increased active lever presses). Additionally, presenting the DS-alongside the DS+ suppressed the increased cocaine-seeking behaviour otherwise produced by the DS+. Finally, on day 21 of abstinence, rats showed equivalent levels of lever pressing reinforced by the DS+, CS and by the DS+ and CS combined, suggesting comparable conditioned reinforcing value. After intermittent self-administration, cocaine-associated DSs and CSs acquire similar conditioned reinforcing properties, but DSs more effectively trigger increases in drug seeking.

animal behavior and cognition↗

bioRxiv2023

Intermittent Nicotine Access is as Effective as Continuous Access in Promoting Nicotine Seeking and Taking in Rats

Nicotine is a principal psychoactive agent in tobacco, contributing to tobaccos addictive potential. Preclinical studies on the effects of voluntary nicotine intake typically use self-administration procedures that provide continuous nicotine access during each self-administration session. However, many smokers consume cigarettes intermittently rather than continuously throughout each day. For drugs including cocaine and opioids, research in laboratory rats shows that intermittent intake can be more effective than continuous intake in producing patterns of drug use relevant to addiction. We asked, therefore, how intermittent versus continuous nicotine self-administration influences nicotine seeking and taking behaviours. Female and male rats had continuous (i.e., Long Access; LgA, 6 h/day) or intermittent (IntA; 12 min ON, 60 min OFF, for 6 h/day) access to intravenous nicotine (15 {micro}g/kg/infusion), for 12 daily sessions. We then assessed intake, responding for nicotine under a progressive ratio schedule of drug reinforcement and cue- and nicotine-induced reinstatement of drug seeking. We also estimated nicotine pharmacokinetic parameters during LgA and IntA self-administration. Overall, LgA rats took twice more nicotine than did IntA rats, yielding more sustained increases in estimated brain concentrations of the drug. However, the two groups showed similar motivation to seek and take nicotine, as measured using reinstatement and progressive ratio procedures, respectively. Thus, intermittent nicotine use is just as effective as continuous use in producing addiction-relevant behaviours, despite significantly less nicotine exposure. This has implications for modeling nicotine self-administration patterns in human smokers and resulting effects on brain and behaviour.

neuroscience↗

bioRxiv2020

Taking rapid and intermittent cocaine infusions enhances both incentive motivation for the drug and cocaine-induced gene regulation in corticostriatal regions

A goal in addiction research is to distinguish forms of neuroplasticity that are involved in the transition to addiction from those involved in mere drug taking. Animal models of drug self-administration are essential in this context. Here, we compared in male rats two cocaine self-administration procedures that differ in the extent to which they evoke addiction-like behaviours. We measured both incentive motivation for cocaine using progressive ratio procedures, and cocaine-induced c-fos mRNA expression, a marker of neuronal activity. Rats self-administered intravenous cocaine (0.25 mg/kg/infusion) for seven daily 6-hour sessions. One group had intermittent access (IntA; 6 minutes ON, 26 minutes OFF x 12) to rapid infusions (delivered over 5 seconds). This models the temporal kinetics of human cocaine use and produces robust addiction-like behaviour. The other group had Long access (LgA) to slower infusions (90 seconds). This produces high levels of intake without promoting robust addiction-like behaviour. LgA-90s rats took twice as much cocaine as IntA-5s rats did, but IntA-5s rats showed greater incentive motivation for the drug. Following a final self-administration session, we quantified c-fos mRNA expression in corticostriatal regions. Compared to LgA-90s rats, IntA-5s rats had more cocaine-induced c-fos mRNA in the orbitofrontal and prelimbic cortices and the caudate-putamen. Thus, a cocaine self-administration procedure (intermittent intake of rapid infusions) that promotes increased incentive motivation for the drug also enhances cocaine-induced gene regulation in corticostriatal regions. This suggests that increased drug-induced recruitment of these regions could contribute to the neural and behavioural plasticity underlying the transition to addiction.

neuroscience↗