Role of dopamine D1 receptor in the modulation of memory consolidation by passive and self-administered heroin and associated conditioned stimuli.

It has been proposed that opiates modulate memory consolidation, but recent work has indicated that this effect may be mediated by how the drug is experienced (i.e., passive injections vs. self-administration). Because the dopamine (DA) D1 receptor is involved in processing of learning signals and attribution of salience to events experienced by an organism, two studies in male Sprague-Dawley rats tested the effect of blocking this receptor on modulation of memory consolidation by passive and self-administered heroin, in addition to conditioned memory modulation by heroin-paired cues. Using the object location memory task, Study 1 employed SCH23390 (0, 0.05, 0.10 mg/kg, SC) to modulate enhancement of memory consolidation induced by post-training injections of heroin (1 mg/kg, SC) as well as by exposure to the environment paired with heroin injections (6 pairings, 1 h each, 1 mg/kg). Study 2 was conducted in rats that could self-administer heroin (0.05 mg/kg/infusion, IV) and tested whether SCH23390 (0 and 0.1 mg/kg, SC) could prevent memory modulation induced by a change in schedule of self-administration (from fixed to variable ratio). It was found that while repeated passive injections of heroin retained their enhancing effect on memory, when self-administered, heroin enhanced consolidation of object location memory only at the beginning of self-administration and after a change in schedule. Importantly, SCH23390 blocked memory modulation by heroin when passively administered and when the drug was self-administered on a novel schedule. SCH23390 also blocked conditioned memory modulation induced by post-training exposure to heroin-paired cues. Taken together, these results suggest that modulation of memory consolidation by unconditioned and conditioned opiate reinforcers involve a D1-dependent mechanism of salience attribution linked to the anticipation of drug effects.

Enhancement of memory consolidation by an avoidance conditioned stimulus: Modulation by the D3 receptor.

Conditioned stimuli (CS) paired with foot-shock can enhance memory consolidation. Because the dopamine D3 receptor (D3R) has been implicated in mediating various responses to CSs, the current study explored its potential role in modulation of memory consolidation by an avoidance CS. Male Sprague-Dawley rats trained to avoid foot-shocks in a two-way signalled active avoidance task (8 sessions, 30 trials per session, 0.8 mA foot-shock) were pre-treated with the D3R antagonist NGB-2904 (Vehicle, 0.1 or 5 mg/kg) and exposed to the CS immediately after the sample phase of an object recognition memory task. Discrimination ratios were assessed 72 h later. Immediate, but not delayed (6 h), post-sample exposure to the CS enhanced object recognition memory and this effect was blocked by NGB-2904. Control experiments with the beta-noradrenergic receptor antagonist propranolol (10 or 20 mg/kg) and D2R antagonist pimozide (0.2 or 0.6 mg/kg) indicated that NGB-2904 targeted post-training memory consolidation. Exploring the pharmacological selectivity of the NGB-2904 effect, it was found that: 1) 5 mg/kg NGB-2904 blocked conditioned memory modulation produced by post-sample exposure to a "weak" CS (one day of avoidance training) and concurrent stimulation of catecholamine activity by 10 mg/kg bupropion; and 2) post-sample exposure to a "weak" CS and concurrent administration of the D3R agonist 7-OH-DPAT (1 mg/kg) enhanced consolidation of object memory. Finally, because 5 mg/kg NGB-2904 had no effect on modulation by avoidance training in the presence of foot-shocks, the findings herein support the hypothesis that the D3R plays an important role in modulation of memory consolidation by CSs.

The effects of passive and active administration of heroin, and associated conditioned stimuli, on consolidation of object memory.

Mode of administration (i.e., active vs passive) could influence the modulatory action that drugs of abuse exert on memory consolidation. Similarly, drug conditioned stimuli modulate memory consolidation and, therefore, acquisition and extinction of this conditioned response could also be influenced by mode of drug administration. Exploring these questions in male Sprague-Dawley rats, Study 1 assessed memory modulation by post-training 0, 0.3 and 1 mg/kg heroin injected subcutaneously in operant chambers (i.e., drug conditioned context). Study 2 asked a similar question but in rats trained to self-administer 0.05 mg/kg/infusion heroin intravenously, as well as in rats that received identical amounts of intravenous heroin but passively, using a yoked design. The period of heroin exposure was followed by repeated drug-free confinement in the conditioned context, and by sessions during which responses on the active lever had no scheduled consequences. Study 2 also included a cue-induced reinstatement session during which lever responses reactivated a light cue previously paired with intravenous heroin infusions. The post-training effects of injected/self-administered/yoked heroin, extinction and reinstatement sessions on memory consolidation were tested using the object location memory task. It was found that post-sample heroin enhanced memory in injected and yoked, but not self-administering, rats. However, post-sample exposure to the heroin cues (i.e., context or/and light cue) modulated memory equally in all groups. Taken together, these data support the conclusion that mode of administration impacts the cognitive consequences of exposure to drugs but not of environmental stimuli linked to their reinforcing effects.

Memory enhancing effects of nicotine, cocaine, and their conditioned stimuli; effects of beta-adrenergic and dopamine D2 receptor antagonists.

BACKGROUND: There is evidence that post-training exposure to nicotine, cocaine, and their conditioned stimuli (CS), enhance memory consolidation in rats. The present study assessed the effects of blocking noradrenergic and dopaminergic receptors on nicotine and cocaine unconditioned and conditioned memory modulation. METHODS: Males Sprague-Dawley rats tested on the spontaneous object recognition task received post-sample exposure to 0.4 mg/kg nicotine, 20 mg/kg cocaine, or their CSs, in combination with 5-10 mg/kg propranolol (PRO; beta-adrenergic antagonist) or 0.2-0.6 mg/kg pimozide (PIM; dopamine D2 receptor antagonist). The CSs were established by confining rats in a chamber (the CS +) after injections of 0.4 mg/kg nicotine, or 20 mg/kg cocaine, for 2 h and in another chamber (the CS -) after injections of vehicle, repeated over 10 days (5 drug/CS + and 5 vehicle/CS - pairings in total). Object memory was tested 72 h post sample in drug-free animals. RESULTS: Co-administration of PRO or PIM blocked the memory-enhancing effects of post-training injections of nicotine, cocaine, and, importantly, exposure to their CSs. CONCLUSIONS: These data suggest that nicotine, cocaine as well as their conditioned stimuli share actions on overlapping noradrenergic and dopaminergic systems to modulate memory consolidation.

An Agent-Based Model of School Closing in Under-Vacccinated Communities During Measles Outbreaks.

The winter 2014-15 measles outbreak in the US represents a significant crisis in the emergence of a functionally extirpated pathogen. Conclusively linking this outbreak to decreases in the measles/mumps/rubella (MMR) vaccination rate (driven by anti-vaccine sentiment) is critical to motivating MMR vaccination. We used the NOVA modeling platform to build a stochastic, spatially-structured, individual-based SEIR model of outbreaks, under the assumption that R0 ≈ 7 for measles. We show this implies that herd immunity requires vaccination coverage of greater than approximately 85%. We used a network structured version of our NOVA model that involved two communities, one at the relatively low coverage of 85% coverage and one at the higher coverage of 95%, both of which had 400-student schools embedded, as well as students occasionally visiting superspreading sites (e.g. high-density theme parks, cinemas, etc.). These two vaccination coverage levels are within the range of values occurring across California counties. Transmission rates at schools and superspreading sites were arbitrarily set to respectively 5 and 15 times background community rates. Simulations of our model demonstrate that a 'send unvaccinated students home' policy in low coverage counties is extremely effective at shutting down outbreaks of measles.