Chad M. Galuska

Behavioral Effects of a Synthetic Agonist Selective for Nociceptin/Orphanin FQ Peptide Receptors in Monkeys

Behavioral effects of a nonpeptidic NOP (nociceptin/orphanin FQ Peptide) receptor agonist, Ro 64-6198, have not been studied in primate species. The aim of the study was to verify the receptor mechanism underlying the behavioral effects of Ro 64-6198 and to systematically compare behavioral effects of Ro 64–6198 with those of a μ-opioid receptor agonist, alfentanil, in monkeys. Both Ro 64-6198 (0.001–0.06 mg/kg, s.c.) and alfentanil (0.001–0.06 mg/kg, s.c.) produced antinociception against an acute noxious stimulus (50°C water) and capsaicin-induced allodynia. An NOP receptor antagonist, J-113397 (0.01–0.1 mg/kg, s.c.), dose-dependently produced rightward shifts of the dose–response curve of Ro 64-6198-induced antinociception. The apparent pA2 value of J-113397 was 8.0. Antagonist studies using J-113397 and naltrexone revealed that Ro 64-6198 produced NOP receptor-mediated antinociception independent of μ-opioid receptors. In addition, alfentanil dose-dependently produced respiratory depression and itch/scratching responses, but antinociceptive doses of Ro 64-6198 did not produce such effects. More important, Ro 64-6198 did not produce reinforcing effects comparable with those of alfentanil, cocaine, or methohexital under self-administration procedures in monkeys. These results provide the first functional evidence that the activation of NOP receptors produces antinociception without reinforcing effects in primates. Non-peptidic NOP receptor agonists may have therapeutic value as novel analgesics without abuse liability in humans.

Effects of the trace amine-associated receptor 1 agonist RO5263397 on abuse-related effects of cocaine in rats.

Animal knockout studies suggest that trace amine-associated receptor (TAAR) 1 is involved in behavioral effects of psychostimulants such as cocaine. Recently, several highly selective TAAR 1 agonists have been discovered. However, little is known of the impact of TAAR 1 agonists on abuse-related effects of cocaine. Here, we report the effects of a TAAR 1 agonist RO5263397 on several abuse-related behavioral effects of cocaine in rats. RO5263397 was evaluated for its effects on cocaine-induced behavioral sensitization, conditioned place preference (CPP), cue- and cocaine prime-induced reinstatement of cocaine-seeking behavior, and cocaine self-administration using behavioral economic analysis. RO5263397 reduced the expression of cocaine behavioral sensitization, cue- and cocaine prime-induced reinstatement of cocaine seeking, and expression but not development of cocaine CPP. Behavioral economic analysis showed that RO5263397 increased the elasticity of the cocaine demand curve, but did not change cocaine consumption at minimal prices. Taken together, this is the first systematic assessment of a TAAR 1 agonist on a range of behavioral effects of cocaine, showing that RO5263397 was efficacious in reducing cocaine-mediated behaviors. Collectively, these data uncover essential neuromodulatory roles of TAAR 1 on cocaine abuse, and suggest that TAAR 1 may represent a novel drug target for the treatment of cocaine addiction.

A comparison of economic demand and conditioned-cued reinstatement of methamphetamine-seeking or food-seeking in rats.

This study examined whether continued access to methamphetamine or food reinforcement changed economic demand for both. The relationship between demand elasticity and cue-induced reinstatement was also determined. Male Long–Evans rats were lever pressed under increasing fixed-ratio requirements for either food pellets or methamphetamine (20 &mgr;g/50 &mgr;l infusion). For two groups, demand curves were obtained before and after continued access (12 days, 2-h sessions) to the reinforcer under a fixed-ratio 3 schedule. A third group was given continued access to methamphetamine between determinations of food demand and a fourth group abstained from methamphetamine between determinations. All groups underwent extinction sessions, followed by a cue-induced reinstatement test. Although food demand was less elastic than methamphetamine demand, continued access to methamphetamine shifted the methamphetamine demand curve upward and the food demand curve downward. In some rats, methamphetamine demand also became less elastic. Continued access to food had no effect on food demand. Reinstatement was higher after continued access to methamphetamine relative to food. For methamphetamine, elasticity and reinstatement measures were correlated. Continued access to methamphetamine, but not food, alters demand in ways suggestive of methamphetamine accruing reinforcing strength. Demand elasticity thus provides a useful measure of abuse liability that may predict future relapse to renewed drug-seeking and drug use.

Effects of Daily Morphine Administration and Deprivation on Choice and Demand for Remifentanil and Cocaine in Rhesus Monkeys.

Choice procedures have indicated that the relative reinforcing effectiveness of opioid drugs increases during opioid withdrawal. The demand curve, an absolute measure of reinforcer value, has not been applied to this question. The present study assessed whether mild morphine withdrawal would increase demand for or choice of remifentanil or cocaine. Four rhesus monkeys chose between remifentanil and cocaine during daily sessions. Demand curves for both drugs were subsequently obtained. The effects of daily injections of 3.2 mg/kg morphine on both choice and demand for these drugs was assayed 3 and 20.5 hr after each morphine injection, and then during a postmorphine period. Three hours following morphine injections, choice of remifentanil over cocaine decreased and demand for remifentanil--but not cocaine--became more elastic. During morphine withdrawal (20.5 hr postinjection), choice of remifentanil increased and remifentanil demand became more inelastic in 3 of 4 monkeys. Cocaine demand also became more inelastic during this period. Four to five weeks following the morphine regimen, demand for both drugs was more inelastic relative to the initial determination. The results suggest that both the relative and absolute reinforcing effectiveness of remifentanil decreased following morphine administration and increased during morphine withdrawal. The absolute reinforcing effectiveness of cocaine also increased during morphine withdrawal. In addition, extended exposure to drug self-administration and/or exposure to the morphine regimen produced long-term increases in demand for both drugs.

Fixed-ratio schedules of cocaine self-administration in rhesus monkeys: joint control of responding by past and upcoming doses.

By manipulating a signaled upcoming cocaine dose, we investigated how the dose just received and the upcoming dose jointly controlled cocaine self-administration. Three rhesus monkeys self-administered cocaine according to a multiple schedule differing in dose following completion of a fixed-ratio response requirement. The larger dose (0.03 or 0.056 mg/kg) was 10-fold higher than the smaller dose (0.003 or 0.0056 mg/kg). Following each infusion, there was an equal probability that the next dose would be large or small. This resulted in four types of signaled transitions: from a small dose to a small dose, small to large, large to large, and large to small. Across conditions the response requirement was increased. At lower ratios, pauses were brief and run rates were controlled by the upcoming dose. At larger ratios, pauses were pronounced, and run rates suppressed, in transitions from a large to a small dose. The behavioral disruption engendered by this transition occurred with both dose combinations. The results suggest that negative discriminable shifts in drug availability disrupt ongoing responding.

The effect of prefeeding on fixed-ratio pausing is jointly determined by past and upcoming reinforcer magnitudes

Pausing within multiple fixed-ratio schedules differing in reinforcer magnitude is jointly controlled by both past and upcoming conditions of reinforcement. Abrupt shifts from a just-received large reinforcer to a signaled upcoming small reinforcer (i.e., a negative incentive shift) produce marked disruptions in responding, as indexed by extended pausing. The purpose of this experiment was to determine if reducing the level of food deprivation via prefeeding enhanced these disruptive effects. Five Long Evans rats lever-pressed according to a fixed-ratio schedule. Half of the components ended in a relatively large reinforcer (three 45-mg food pellets) and half ended in a relatively small reinforcer (one pellet). Components alternated irregularly, yielding four transitions between reinforcers: small-small, small-large, large-small (the negative incentive shift), and large-large. During five, 1-session prefeeding probes, rats were given 12 g of food in their home cages 1h prior to the start of the session. Under steady-state conditions, negative incentive shifts engendered the longest pausing. Prefeeding produced large absolute and relative increases in pausing during negative incentive shifts, and small increases in pausing in the other transitions. The results are interpreted within a resistance to change framework.

Effects of price and pellet type on food waste in mice.

When laboratory mice are provided with free access to food, they often fragment their food such that it collects on the cage floor - wasted. An operant analysis of food waste, however, has not yet been conducted. The purpose of the present study was to evaluate the effect of response requirement and pellet type on food waste using a behavioral economic paradigm. Sixteen mice responded under a series of escalating fixed ratio schedules. Nose pokes were reinforced with either a grain-based pellet or a fiber-based pellet (diluted with non-digestible cellulose) across conditions. We found that mice spilled a greater percent of the total earned pellets at low response requirements. Additionally, mice spilled more fiber-based pellets relative to grain-based pellets. This difference was most pronounced when the fixed ratio requirement was low and was attenuated as the fixed ratio was increased, and this decrease in food waste across prices was well accounted for by an exponential model. Mice may have been extracting the calorically dense components of the fiber-based pellets only when the schedule of reinforcement was rich. When the schedule of reinforcement was lean, responding for a new pellet likely was a more functional behavior than fragmenting a pellet and discarding portions.

Effects of reinforcer magnitude on response acquisition with unsignaled delayed reinforcement

Sixteen rats received eight 1-h sessions of a tandem fixed-ratio 1 differential-reinforcement-of-other-behavior 30-s schedule with reinforcer magnitude at one or six food pellet(s) across groups of eight rats. The larger reinforcer magnitude established the lever press more effectively. First, mean schedule completions differed across groups, in terms of both their overall difference and in their increase across sessions. Second, whereas the larger reinforcer magnitude established reliable response acquisition in all eight rats by the end of the experiment, the smaller reinforcer magnitude only established reliable response acquisition in four of eight rats. The present results systematically replicate earlier findings obtaining more reliable response acquisition with unsignaled delayed reinforcement with greater food deprivation. Taken together, this work demonstrates the influence of motivational variables on response acquisition with unsignaled delayed reinforcement.

Response acquisition and fixed-ratio escalation based on interresponse times in rats.

The effectiveness of a fixed-ratio (FR) escalation procedure, developed by Pinkston and Branch (2004) and based on interresponse times (IRTs), was assessed during lever-press acquisition. Forty-nine experimentally naïve adult male Long Evans rats were deprived of food for 24 hr prior to an extended acquisition session. Before the start of the session, three food pellets were placed in the magazine. Otherwise, no magazine training, shaping, nor autoshaping procedure was employed. The first 20 presses each resulted in the delivery of a 45-mg food pellet. Then, the FR increased (2, 4, 8, 11, 16, 20, 25, 30) when each IRT in the ratio was less than 2 s during three consecutive ratios. Sessions lasted 13 hr or until 500 pellets were earned. On average, rats reached a terminal ratio of 11 (mean) or 16 (median) during the first session. Seven rats reached the maximum value of FR 30 and only one rat did not acquire the response. In most rats, a break-and-run pattern of responding characteristic of FR schedules began to develop in this acquisition session. Subsequently, the ratio-escalation procedure continued during daily 2-hr sessions. In these sessions, the starting ratio requirement was set at the terminal ratio reached in the previous session. Using this procedure, over half (26) of the rats reached the FR 30 requirement by the fourth session. These data demonstrate that a ratio-escalation procedure based on IRTs provides a time-efficient way of establishing ratio responding.

Effects of shifts in food reinforcement context on rats’ consumption of concurrently available water or sucrose solution

The purpose of this study was to investigate the effects of signaled transitions from relatively rich to lean conditions of food reinforcement on drinking concurrently available water or sucrose-sweetened water in rats. Past research demonstrated that these negative incentive shifts produce behavioral disruption in the form of extended pausing on fixed-ratio schedules. Four male Long-Evans rats operated on a two-component multiple fixed-ratio fixed-ratio schedule. In one manipulation, the ratio was held constant and the components arranged either a large six-pellet reinforcer (rich) or small one-pellet reinforcer (lean). In a second manipulation, the components both produced a one-pellet reinforcer but differed in terms of the ratio requirement, with the rich and lean conditions corresponding to relatively small and large ratios. In both manipulations, components were pseudorandomly presented to arrange four transitions signaled by retractable levers: lean-to-lean, lean-to-rich, rich-to-rich, and rich-to-lean (the negative incentive shift). During experimental conditions, a bottle with lickometer was inserted in the chamber, providing concurrent access either to tap water or a 10% sucrose solution. The negative incentive shift produced considerably more drinking than the other transitions in all rats during both manipulations. The level of drinking was not polydipsic; rather, it appears that the negative incentive shift enhanced the value of concurrently available reinforcers relative to food reinforcement.