Self administration of oxycodone alters synaptic plasticity gene expression in the hippocampus differentially in male adolescent and adult mice.

Abuse and addiction to prescription opioids such as oxycodone (a short-acting Mu opioid receptor (MOP-r) agonist) in adolescence is a pressing public health issue. We have previously shown differences in oxycodone self-administration behaviors between adolescent and adult C57BL/6J mice and expression of striatal neurotransmitter receptor genes, in areas involved in reward. In this study, we aimed to determine whether oxycodone self-administration differentially affects genes regulating synaptic plasticity in the hippocampus of adolescent compared to adult mice, since the hippocampus may be involved in learning aspects associated with chronic drug self administration. Hippocampus was isolated for mRNA analysis from mice that had self administered oxycodone (0.25 mg/kg/infusion) 2h/day for 14 consecutive days or from yoked saline controls. Gene expression was analyzed with real-time polymerase chain reaction (PCR) using a commercially available "synaptic plasticity" PCR array containing 84 genes. We found that adolescent and adult control mice significantly differed in the expression of several genes in the absence of oxycodone exposure, including those coding for mitogen-activated protein kinase, calcium/calmodulin-dependent protein kinase II gamma subunit, glutamate receptor, ionotropic AMPA2 and metabotropic 5. Chronic oxycodone self administration increased proviral integration site 1 (Pim1) and thymoma viral proto-oncogene 1 mRNA levels compared to controls in both age groups. Both Pim1 and cadherin 2 mRNAs showed a significant combined effect of Drug Condition and Age × Drug Condition. Furthermore, the mRNA levels of both cadherin 2 and cAMP response element modulators showed an experiment-wise significant difference between oxycodone and saline control in adult but not in adolescent mice. Overall, this study demonstrates for the first time that chronic oxycodone self-administration differentially alters synaptic plasticity gene expression in the hippocampus of adolescent and adult mice.

Regional mRNA expression of GABAergic receptor subunits in brains of C57BL/6J and 129P3/J mice: strain and heroin effects.

C57BL/6J and 129 substrains of mice are known to differ in their basal levels of anxiety and behavioral response to drugs of abuse. We have previously shown strain differences in heroin-induced conditioned place preference (CPP) between C57BL/6J (C57) and 129P3/J (129) mice, and in the regional expression of several receptor and peptide mRNAs. In this study, we examined the contribution of the GABAergic system in the cortex, nucleus accumbens (NAc), caudate putamen (CPu) and the region containing the substantia nigra and ventral tegmental area (SN/VTA) to heroin reward by measuring mRNA levels of 7 of the most commonly expressed GABA-A receptor subunits, and both GABA-B receptor subunits, in these same mice following saline (control) or heroin administration in a CPP design. Using real-time PCR, we studied the effects of strain and heroin administration on GABA-A α1, α2, α3, ß2, and γ2 subunits, which typically constitute synaptic GABA-A receptors, GABA-A α4 and δ subunits, which typically constitute extrasynaptic GABA-A receptors, and GABA-B R1 and R2 subunits. In saline-treated animals, we found an experiment-wise significant strain difference in GABA-Aα2 mRNA expression in the SN/VTA. Point-wise significant strain differences were also observed in GABA-Aα2, GABA-Aα3, and GABA-Aα4 mRNA expression in the NAc, as well as GABA-BR2 mRNA expression in the NAc and CPu, and GABA-BR1 mRNA expression in the cortex. For all differences, 129 mice had higher mRNA expression compared to C57 animals, with the exception of GABA-BR1 mRNA in the cortex where we observed lower levels in 129 mice. Therefore, it may be possible that known behavioral differences between these two strains are, in part, due to differences in their GABAergic systems. While we did not find heroin dose-related changes in mRNA expression levels in C57 mice, we did observe dose-related differences in 129 mice. These results may relate to our earlier behavioral finding that 129 mice are hyporesponsive to the rewarding effects of heroin.

Reinforcement, stereotypy, and rule discovery.

The effects of reinforced pretraining on subsequent rule discovery were examined with college students as subjects. Levels of behavioral stereotypy observed during reinforced and non-contingent pretraining were compared. During pretraining subjects received reinforcement if they pressed two keys in a particular sequence. During the problem session pressing each key four times was a necessary condition for reinforcement, but each problem had additional different requirements for reinforcement. Subjects were asked to solve the problems by discovering the rule that determined whether or not they received reinforcement. Levels of stereotyped responding during pretraining were equivalent for contingently and non-contingently trained subjects. During the problem session contingently pretrained, non-contingently pretrained, and naive subjects required equal numbers of trials to solve problems and solved the same number of problems. The results suggest that behavioral stereotypy observed in this experimental preparation may be due to repeated exposure to the task. Differences between the results observed in this study and that of Schwartz (1982) and implications for the use of reinforcement procedures in applied settings are discussed.

Instructions, multiple schedules, and extinction: Distinguishing rule-governed from schedule-controlled behavior.

Schedule sensitivity has usually been examined either through a multiple schedule or through changes in schedules after steady-state responding has been established. This study compared the effects of these two procedures when various instructions were given. Fifty-five college students responded in two 32-min sessions under a multiple fixed-ratio 18/differential-reinforcement-of-low-rate 6-s schedule, followed by one session of extinction. Some subjects received no instructions regarding the appropriate rates of responding, whereas others received instructions to respond slowly, rapidly, or both. Relative to the schedule in operation, the instructions were minimal, partially inaccurate, or accurate. When there was little schedule sensitivity in the multiple schedule, there was little in extinction. When apparently schedule-sensitive responding occurred in the multiple schedule, however, sensitivity in extinction occurred only if differential responding in the multiple schedule could not be due to rules supplied by the experimenter. This evidence shows that rule-governed behavior that occurs in the form of schedule-sensitive behavior may not in fact become schedule-sensitive even though it makes contact with the scheduled reinforcers.

Rule-governed behavior and sensitivity to changing consequences of responding.

Humans were presented with a task that required moving a light through a matrix. Button presses could produce light movements according to a multiple fixed-ratio 18/differential-reinforcement-of-low-rate 6-s schedule, with components alternating every 2 min. Moving the light through the maze earned points worth chances on money prizes. In Experiment 1 four conditions were assessed through between-subject comparisons: minimal instructions, instructions to press rapidly, instructions to press slowly, and instructions that sometimes rapid responding would work while at other times a slow rate would work best. Subjects responded in three successive sessions of 32 min each. The results suggested that instructions affected the nature of the contact made with the programmed consequences and thus subsequent performance. In some cases, responding seemed to result from added contingencies introduced by stating rules. In Experiment 2 the relative contribution of these two effects was assessed by presenting and then withdrawing two lights that had been paired with two specific instructions: "Go Fast" or "Go Slow." There were three conditions. In one condition, only the Go Fast light was on; in a second, only the Go Slow light was on; and in a third, the lights alternated each minute. In each condition, half the subjects had all instruction lights turned off after the first session. The results once again showed an effect of instructions on contact with the programmed consequences. However, responding sometimes continued in a manner consistent with added contingencies for rule-following even when the programmed consequences had been contacted and would have controlled a different type of responding in the absence of instructions. The relevance of added contingencies for rule-following in determining the effects of explicitly programmed consequences is emphasized.

Mentalism, behavior-behavior relations, and a behavior-analytic view of the purposes of science.

In a behavioral view, the purposes of science are primarily prediction and control. To the extent that a scientist embraces both of these as a unified and generally applicable criterion for science, certain philosophical and theoretical practices are counterproductive, including mentalism in both its metaphysical and metatheoretical forms. It is possible and often worthwhile to recast some mentalistic talk into an issue of behavior-behavior relations. When behavior-behavior relations are approached non-mechanistically, however, analysis cannot stop at the level of the relations themselves. Several analytic concepts common in the behavioral community share some of the dangers of mentalism if not employed properly, including such concepts as self-reinforcement, response-produced stimulation, and self-rules.

Effect of varying the duration of grain presentation on automaintenance.

In a series of three experiments the effects of variation in grain duration on automaintenance were evaluated. In the first experiment, key illumination was followed by grain only when pigeons did not peck the key. Each subject was exposed to 2-, 4-, and 8-second feeder durations in blocks of 10 sessions. Subjects pecked on a high percentage of trials at all feeder durations. The mean peck latency was shorter in the 8-second condition than in the two other conditions in five of six subjects. The conditional probability of pecking given successive keylight-grain pairings did not increase as the number of pairings increased. The second experiment was identical to the first, except that key pecking had no scheduled consequence. Under these conditions, all three subjects showed substantial responding. The recorded measures showed no systematic relationship to feeder duration in this study. In the third experiment, two different stimuli were followed by feeder presentations of either identical (2- or 8-second) or different (2- and 8-second) durations within each session. Subjects tended to respond sooner and with a higher overall rate in the presence of the stimulus associated with the longer feeder duration only when different feeder durations were presented within the same session. This result was confirmed by direct observation of the pigeons. The results of these experiments suggest that the effects of varying grain duration may be small, compared to the effects of varying other variables. The results also suggest that the location as well as the frequency of pecking may be an important measure in the analysis of factors controlling the pigeon's key peck.

Response-rate invariance in concurrent schedules: effects of different changeover contingencies.

In a two-key chamber, one key (the food key) was either red or green with different variable-interval schedules operating concurrently in each color and a second key (the changeover key) served to change the food-key color. Three pigeons were trained with either a 2-sec changeover delay or a 0-sec changeover delay and three birds with a fixed-ratio 2 on the changeover key instead of a changeover delay. The proportion of time spent in red approximated the proportion of reinforcers delivered in red for all birds. When the procedure was changed so that reinforcers were signalled in the green schedule, rates of reinforcement were unaltered, but the pigeons spent virtually the whole session in red. Changeovers to green were allowed only when a reinforcer was assigned by the schedule associated with green. For all pigeons with the fixed-ratio requirement on the changeover key or with a 0-sec changeover delay, the overall rate of red-key responses was higher during the signalling condition than during unsignalled, or baseline, condition. The present data question the generality of previous reports that the rate of one response is independent of the amount of time allocated to the alternative response.

Time allocation on concurrent schedules with asymmetrical response requirements.

Pigeons were trained on concurrent schedules in which key pecking was required by both schedules (concurrent variable-interval variable-interval schedules) and on concurrent schedules in which key pecking was required by only one of the schedules (concurrent variable-interval variable-time schedules). The distribution of reinforcements was systematically varied with both types of concurrent schedules. The distribution of time between the schedules depended on the reinforcement distribution and was independent of the symmetry of the response requirement. The relation between time and reinforcement distributions appears to be invariant over a wide range of manipulations of responding maintained by concurrent schedules.

Concurrent schedules of response-independent reinforcement: duration of a reinforcing stimulus.

Presentations of grain to three pigeons were determined by two response-independent schedules. Interpresentation intervals varied with a mean interval of 1.5 min for each schedule. Both were concurrently operative, but grain was presented by one only when the chamber was illuminated with blue light and by the other only during amber illumination. A response on a white key, the only key in the chamber, alternated the stimulus conditions and the effective schedule. Grain presentation durations associated with the illumination conditions were varied from 1.5 to 4.5 sec. The proportion of the total session time spent in an illumination condition closely approximated the relative grain presentation duration provided in that illumination. For two of the birds, the proportion of the total number of grain presentations obtained in an illumination condition was an increasng function of the presentation duration in that illumination.

Interresponse time duration in fixed-interval schedules of reinforcement: control by ordinal position and time since reinforcement.

The times between each of the first thirteen responses after reinforcement (the first twelve interresponse times) were determined for two pigeons whose pecking was reinforced on fixed-interval schedules of food reinforcement ranging from 0.5 min to 5 min. These interresponse times were classified with respect to their ordinal position in the sequence of responses and with respect to the time since the preceding reinforcement at which the initiating response occurred. The median interresponse time durations were essentially constant after the sixth response after reinforcement regardless of the time at which the interresponse time was initiated. The durations of the first few interresponse times after reinforcement decreased as the number of preceding responses increased and as the time since the preceding reinforcement increased.

Some effects of relative reinforcement rate and changeover delay in response-independent concurrent schedules of reinforcement.

Reinforcements were arranged independently of the pigeon's behavior by concurrent variable-interval schedules. The reinforcements arranged by one of the schedules occurred when the chamber was illuminated with amber light, and the reinforcements arranged by the other schedule occurred when the chamber was illuminated with blue light. Both schedules functioned concurrently, but reinforcers were delivered by each only in the presence of the appropriate stimulus condition. A response on a white key, the only key in the chamber, alternated the stimulus condition and the effective schedule. The results of this procedure were similar to those obtained with concurrent response-dependent variable-interval schedules of reinforcement. The proportion of the total session time spent in the presence of a schedule component approximated the proportion of the total number of reinforcements in the component. Changeover rate was a decreasing function of the changeover delay and of the difference between the relative rates of reinforcement for each pair of concurrent schedules.