Survey of transportation procedures, management practices, and health assessment related to quality, quantity, and value for market beef and dairy cows and bulls.

This survey consisted of data collected from 23 beef harvest plants to document transportation procedures, management practices, and health assessments of market beef and dairy cows and bulls (about n ≅ 7,000 animals). Gooseneck/bumper-pulled trailers were used more often to transport dairy cattle than beef cattle to market whereas tractor-trailers were used more often to transport beef cattle than dairy cattle. All loads (n = 103) met the American Meat Institute Foundation guidelines for spacing. Loads where more than 3% of the cattle slipped during unloading were observed in 27.3% of beef loads and 29.0% of the dairy loads. Beef loads had numerically greater usage of electrical prods (32.4%) versus dairy loads (15.4%) during unloading and were more likely to have a variety of driving aids used more aggressively on them. Fewer cattle had horns, brands, and mud/manure contamination on hides than in the previous survey in 1999. The predominant hide color for beef cows was black (44.2%) whereas the predominant color for dairy cows was the Holstein pattern (92.9%). Fewer cattle displayed evidence of bovine ocular neoplasia (2.9%) than in previous surveys in 1994 (8.5%) and 1999 (4.3%). Knots on live cattle were found less in the round (0.5%) and more in the shoulder region (4.6%) than in 1999 (1.4% and 0.4%, respectively). Dairy cows were more frequently lame in 2007 (48.7%) than 1999 (39.2%) whereas beef cows had numerically less lameness (16.3% vs. 26.6%, respectively). Most beef cows (62.3%) and dairy cows (68.9%) received midpoint body condition scores (3, 4, and 5 for beef; 2 and 3 for dairy). Beef cows had higher numerical percentages of no defects present (72.0%) versus dairy cows (63.0%) when evaluated for a variety of reproductive, health, or management conditions. Continued improvements in several key factors related to transportation, management, and health were observed in this survey, which could result in increased value in market beef and dairy cows and bulls.

Innovative retail merchandising strategies to accommodate for the growing trend of heavier carcass weights in the United States.

Three subprimals from beef carcasses, Average (mean=340.6kg) and Heavy weight (mean=461.6kg), were cut using Innovative versus Conventional cutting styles. Longer (P<0.05) processing times were required for the Heavy compared to Average and Innovative compared to Conventional. Total saleable yields were lower for the Innovative compared to Conventional for the top sirloin butt (P=0.0025) and ribeye (P<0.0001), but not for the strip loin (P=0.1416). However, yields were higher for the Heavy compared to Average for the ribeye (P=0.0054) and strip loin (P=0.0017), but not for the top sirloin butt (P=0.6797). Retail pricing increases for the Innovative compared to Conventional were 11.6% for top sirloin butt, 26.9% for ribeye, and 2.6% for strip loin. Retailers adopting innovative cutting styles to more effectively merchandise heavyweight beef must account for the decreased primary saleable yields and increased labor requirements through increased retail pricing.

In-home consumer and shear force evaluation of steaks from the M. serratus ventralis thoracis.

The M. serratus ventralis thoracis was obtained from US Select arm chucks (n=87) to investigate if this underutilized muscle can be used as a steak alternative. Muscles were assigned randomly into three treatment groups: (1) control; (2) blade tenderization; and (3) injection, containing salt, phosphate, and papain. Steaks were cut from each muscle for in-home consumer evaluation (n=136) and Warner-Bratzler shear (WBS) force determination. The WBS values for injected steaks (13.1N) were lower (P<0.05) than for blade-tenderized (18.4N) and control (19.9N) steaks. Tenderness ratings for the injected steaks were higher (P<0.05) compared to the other treatments when steaks were grilled, oven prepared or were cooked in a skillet; however, this improvement did not significantly influence overall like scores for steaks that were oven prepared or cooked in a skillet. For the most part, degree of doneness did not significantly impact consumer evaluations of steaks prepared by the various cooking methods. However, there was a treatment x degree of doneness interaction for grilled-cooked steaks where increased doneness for blade-tenderized and injected steaks resulted in increased palatability ratings, whereas increased doneness for control steaks generally resulted in lowered palatability ratings. Consumer ratings and WBS values for the M. serratus ventralis thoracis indicate that merchandising steaks from this muscle may be a viable option in the marketplace, especially if blade tenderization or injection processes are used for further enhancement.

National Beef Market Basket Survey - 2006: External fat thickness measurements and separable component determinations for beef from US retail establishments.

A market basket survey for beef retail cut composition at the retail level (four stores each from two chains in each city) was conducted in 11 US cities from January to March 2006. Beef cuts (n=17,495) were measured for external fat thickness with cuts from the chuck (0.05cm), round (0.05cm), and miscellaneous (0.04cm) having less (P<0.05) fat than cuts from the loin (0.11cm) and rib (0.11cm). Beef cuts (n=1327) were separated physically into separable components with round cuts having more (P<0.05) separable lean (96.63%) than chuck cuts (86.81%) and miscellaneous cuts (86.18%), which had more (P<0.05) separable lean than loin cuts (84.53%) with rib cuts (69.34%) having the lowest (P<0.05) separable lean. Chemical fat from the separable lean differed (P<0.05) between each cut category: round cuts (3.71%), miscellaneous cuts (4.99%), loin cuts (5.60%), chuck cuts (6.90%), and rib cuts (8.61%). Ground beef samples (n=235), with declared lean/fat percentages ranging from 73/27 to 96/4, had overall chemical fat values of 13.41% and moisture values of 67.42%. This survey documents the current beef retail cut and ground beef composition, which is helpful to those who need this information for various dietary and marketing purposes.

National Beef Quality Audit-2005: survey of targeted cattle and carcass characteristics related to quality, quantity, and value of fed steers and heifers.

The National Beef Quality Audit-2005 assessed the current status of quality and consistency of US fed steers and heifers. Hide colors or breed type were black (56.3%), red (18.6%), Holstein (7.9%), gray (6.0%), yellow (4.9%), brown (3.0%), white (2.3%), and brindle (1.0%). Identification method and frequency were lot visual tags (63.2%), individual visual tags (38.7%), metal-clip tags (11.8%), electronic tags (3.5%), bar-coded tags (0.3%), by other means (2.5%), and without identification (9.7%). Brand frequencies were no (61.3%), 1 (35.1%), and 2 or more (3.6%), and brands were located on the butt (26.5%), side (7.4%), and shoulder (1.2%). There were 22.3% of cattle without horns, and the majority of those with horns (52.2%) were between 2.54 and 12.7 cm in length. Percentages of animals with mud or manure on specific body locations were none (25.8%), legs (61.4%), belly (55.9%), side (22.6%), and top-line (10.0%). Permanent incisor number and occurrence were zero (82.2%), 1 (5.2%), 2 (9.9%), 3 (0.4%), 4 (1.2%), 5 (0.1%), 6 (0.3%), 7 (0.0%), and 8 (0.7%). Most carcasses (64.8%) were not bruised, 25.8% had one bruise, and 9.4% had multiple bruises. Bruise location and incidence were round (10.6%), loin (32.6%), rib (19.5%), chuck (27.0%), and brisket, flank, and plate (10.3%). Condemnation item and incidence were liver (24.7%), lungs (11.5%), tripe (11.6%), heads (6.0%), tongues (9.7%), and carcasses (0.0%). Carcass evaluation revealed these traits and frequencies: steer (63.7%), heifer (36.2%), bullock (0.05%), and cow (0.04%) sex classes; dark-cutters (1.9%); A (97.1%), B (1.7%), and C or older (1.2%) overall maturities; and native (90.9%), dairy-type (8.3%), and Bos indicus (0.8%) estimated breed types. Mean USDA yield grade (YG) traits were USDA YG (2.9), HCW (359.9 kg), adjusted fat thickness (1.3 cm), LM area (86.4 cm(2)), and KPH (2.3%). The USDA YG were YG 1 (16.5%), YG 2 (36.3%), YG 3 (33.1%), YG 4 (11.8%), and YG 5 (2.3%). Mean USDA quality grade traits were USDA quality grade (Select(90)), marbling score (Small(32)), overall maturity (A(64)), lean maturity (A(57)), and skeletal maturity (A(68)). Marbling score distribution was Slightly Abundant or greater (2.7%), Moderate (4.3%), Modest (14.4%), Small (34.5%), Slight (41.2%), and Traces or less (2.9%). This information helps the beef industry measure progress and provides a benchmark for future educational and research activities.

Dry versus wet aging of beef: Retail cutting yields and consumer palatability evaluations of steaks from US Choice and US Select short loins.

Paired beef short loins from US Choice (n=48) and US Select (n=48) carcasses were assigned to be dry or wet aged for 14, 21, 28 or 35d. After aging, short loins were processed to determine retail yields and processing times. Upon completion of cutting tests, steaks were served to consumers to assess palatability characteristics. Retail cutting tests showed that dry-aged short loins had reduced yields and increased cutting times when compared to wet-aged short loins. Consumers were unable to determine differences between dry- and wet-aged steaks and for aging periods; however, USDA quality grade had a significant impact on consumer perception of palatability attributes.

Identifying muscle and processing combinations suitable for use as beef for fajitas.

Four different treatments-control, papain, blade tenderization, and papain+blade tenderization-were applied to sixty USDA Choice M. diaphragma pars costalis, M. transversus abdominis, M. obliquus abdominis internus, M. rhomboideus, M. trapezius, M. latissimus, and M. serratus ventralis. Trained (n=6) and consumer (n=81) panelists scored papain samples higher for most sensory traits. Treatment tended not to affect the palatability scores of the M. diaphragma pars costalis and M. serratus ventralis, which tended to receive higher scores in comparison to the other muscles. Consumers were willing to purchase the M. latissimus and M. serratus ventralis treated with papain+blade tenderization and papain, respectively, and these muscles performed well enough to be considered as alternatives in the beef fajita market.

Dry versus wet aging of beef: Retail cutting yields and consumer sensory attribute evaluations of steaks from ribeyes, strip loins, and top sirloins from two quality grade groups.

Top Choice (n=48) and Select (n=48) paired bone-in ribeye rolls, bone-in strip loins, and boneless top sirloin butts were assigned randomly to one of two aging treatments, dry or wet, and were aged for 14, 21, 28 or 35d. Cutting tests, performed to determine retail yields and processing times, showed dry-aged subprimals had lower total saleable yield percentages and increased processing times compared to wet-aged subprimals. Sensory and Warner-Bratzler shear evaluation was conducted to determine palatability characteristics. For the most part, aging treatment and aging period did not affect consumer sensory attributes. However, ribeye and top loin steaks from the Top Choice quality grade group received higher sensory ratings than their Select counterparts. For top sirloin steaks, no consumer sensory attributes were affected by aging treatment, aging period, or quality grade group.

Evaluation of the discriminative stimulus effects of the low-affinity N-methyl-D-aspartate channel blockers AR-R 13950AA and AR-R 16283AA in rats and rhesus monkeys.

Low-affinity channel-blocking -methyl-D-aspartate (NMDA) antagonists have been of interest for clinical development because they are purported to produce few phencyclidine (PCP)-like side-effects, particularly at therapeutic doses. In the current study, two low-affinity NMDA channel blockers, AR-R 13950AA and AR-R 16283AA, were evaluated for NMDA antagonist-associated behavioral effects. The drugs were tested in rats and rhesus monkeys trained to discriminate PCP from saline, using a standard two-lever drug discrimination paradigm, under a fixed-ratio (FR) schedule of food reinforcement. Both drugs were also tested in rats trained to discriminate NPC 17742, a competitive NMDA antagonist, from saline in a similar experimental procedure. In rats, both AR-R 13950AA and AR-R 16283AA resulted in intermediate levels of PCP-lever selection (up to 60%). Testing in NPC 17742-trained rats produced at most 30% NPC 17742-lever responding. In rhesus monkeys, AR-R 13950AA produced virtually no PCP-lever responding at any dose, while AR-R 16283AA produced a dose-dependent substitution for PCP in all four subjects. The results with AR-R 16283AA in monkeys suggest that, at doses above therapeutic levels, it may produce PCP-like intoxication in humans. Overall, the results suggest that, while there is some overlap of the discriminative stimulus effects produced by the AR-R compounds with those of PCP, there are also important differences.

GHB: a new and novel drug of abuse.

There has been increasing attention in the United States to problems of abuse of gamma-hydroxybutyrate (GHB), with some evidence for problems in other parts of the world as well. In vitro and animal research show that, while GHB shares some properties with abused central nervous system depressant drugs, it has unique aspects of its pharmacology as well, including actions at a specific neural receptor which probably mediates many of its effects. Abuse potential assessment of GHB using standard animal models has not yielded a picture of a highly abusable substance, but little human testing has yet been done. Very little systematic data exist on tolerance and dependence with GHB, but both have been seen in human users. Quantitative data on the prevalence of GHB abuse is incomplete, but various qualitative measures indicate that a mini-epidemic of abuse began in the late 1980s and continues to the present. GHB is often included with the group of 'club drugs', and can be used as an intoxicant. It also has been used as a growth promoter and sleep aid and has been implicated in cases of 'date rape', usually in combination with alcohol. Undoubtedly the easy availability of GHB and some of its precursors has contributed to its popularity. Recent changes in the control status of GHB in the US may reduce its availability with as yet unknown consequences for the scope of the public health problem. Drug abuse experts need to familiarize themselves with GHB as possibly representing a new type of drug abuse problem with some unique properties.

Evaluation of the reinforcing properties and phencyclidine-like discriminative stimulus effects of dextromethorphan and dextrorphan in rats and rhesus monkeys.

RATIONALE: Dextromethorphan (DXM) and its metabolite, dextrorphan (DXO) have neuroprotective and anticonvulsant properties through their activity as N-methyl-D-aspartate (NMDA) receptor channel blockers. Based on this receptor activity, coupled with reports of DXM abuse, both were evaluated for abuse potential and phencyclidine (PCP)-like behavioral effects in two animal models. OBJECTIVES AND METHODS: The discriminative stimulus properties of DXO and DXM were tested in rats (3-56 mg/kg DXM, i.p. and 2.2-40.9 mg/kg DXO, i.p.) and rhesus monkeys (0.3-10 mg/kg DXM, i.m. and 0.25-8.0 mg/kg DXO, i. m.) trained to discriminate PCP from saline using a standard two-lever drug-discrimination paradigm under a fixed-ratio (FR) schedule of food reinforcement. In a second set of experiments, i.v. self-administration of DXO (10-100 microg/kg/infusion) and DXM (10-1000 microg/kg/infusion) were tested under a FR schedule of reinforcement in monkeys trained to lever press for infusions of PCP during daily 1-h sessions. RESULTS: In rats, both DXM and DXO produced a dose-dependent substitution for PCP. When tested in monkeys, DXM yielded partial (1 monkey) and full (2 monkeys) substitution for PCP, while DXO substituted fully for PCP in all four subjects tested. In the self-administration study, in five of the six subjects, at least one dose of DXM served as a positive reinforcer, maintaining infusion rates above those for saline. For DXO, at least one dose maintained infusion numbers well above mean saline infusion numbers in all subjects. CONCLUSIONS: Taken together, these data show that DXM has some PCP-like effects in rats and monkeys, but that they are more reliably produced by its metabolite, DXO. Thus, high doses of DXM may have some PCP-like abuse potential in humans but this potential may be associated with, or enhanced by, metabolism of DXM to DXO.

Evaluation of the reinforcing and discriminative stimulus properties of the low-affinity N-methyl-D-aspartate channel blocker memantine.

Memantine (MEM) is currently in clinical use in Europe for the treatment of various neurological disorders. It is a low-affinity channel blocker of N-methyl-D-aspartate (NMDA) receptors whose voltage-dependent, rapid binding kinetics are believed to limit its phencyclidine (PCP)-like side effects. MEM, and its analog amantadine (AMA), which has also been demonstrated to have some NMDA antagonist activity, were evaluated for PCP-like behavioral effects. The discriminative stimulus properties of MEM and AMA were tested in monkeys and rats trained to discriminate PCP from saline using a standard two-lever drug discrimination paradigm under a fixed ratio (FR) schedule of food reinforcement. In rats, MEM resulted in a dose-dependent substitution for PCP; however, full substitution occurred only at response rate suppressing doses. AMA failed to substitute for PCP at any dose tested. For MEM, all four monkeys showed complete substitution for PCP at doses which did not greatly decrease rates of responding. Conversely, AMA occasioned little or no responding on the PCP-associated level in any of the subjects. Intravenous self-administration of MEM and AMA was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. MEM served as a reinforcer in all subjects at one or more doses tested. For two of the subjects, at least one dose of AMA maintained rates of self-administration above those for saline. For both MEM and AMA, maximal response rates were considerably lower than with PCP self-administration and both drugs were much less potent in monkeys than would be predicted from rodent studies. The data show that MEM shares discriminative stimulus effects with PCP under these testing conditions, whereas the chemically similar compound AMA does not. MEM also serves as a positive reinforcer in rhesus monkeys, whereas AMA can serve as a weak reinforcer in only some subjects. Both AMA and MEM are reported to function as NMDA antagonists, yet clear differences exist in their behavioral effects with MEM acting more like a PCP-like antagonist. In addition, despite the rapid channel kinetics of MEM's NMDA receptor blockade, it may have some PCP-like abuse potential in humans at doses above the normal therapeutic levels.

Phencyclidine-like discriminative stimulus effects of polyamine modulators of N-methyl-D-aspartate receptor activity in rats.

Excessive N-methyl-D-aspartate (NMDA) receptor activation has been implicated in many acute and chronic neuropathologies. NMDA antagonists might prove to be useful treatments, unfortunately, some can produce phencyclidine (PCP)-like side effects. The polyamine-site modulators, spermine (SPM) and spermidine (SPD), produce dose related biphasic modulation of NMDA channel currents while another polyamine, arcaine (ARC), produces only negative modulatory effects. The PCP-like effects of these compounds were tested in rats trained to discriminate PCP from saline in a standard two-lever drug discrimination paradigm under a fixed ratio schedule of food reinforcement. SPM, SPD and ARC occasioned little, if any, responding on the PCP-associated lever, even at response rate suppressing doses. The results provide further evidence that differences exist between the discriminative stimulus effects produced by drugs active at different sites on the NMDA receptor and suggest that the polyamine modulatory site should be a good target for development of NMDA antagonist medications with a reduced propensity for PCP-like acute behavioral effects.

Regulation of SNARE complex assembly by an N-terminal domain of the t-SNARE Sso1p.

The fusion of intracellular transport vesicles with their target membranes requires the assembly of SNARE proteins anchored in the apposed membranes. Here we use recombinant cytoplasmic domains of the yeast SNAREs involved in Golgi to plasma membrane trafficking to examine this assembly process in vitro. Binary complexes form between the target membrane SNAREs Sso1p and Sec9p; these binary complexes can subsequently bind to the vesicle SNARE Snc2p to form ternary complexes. Binary and ternary complex assembly are accompanied by large increases in alpha-helical structure, indicating that folding and complex formation are linked. Surprisingly, we find that binary complex formation is extremely slow, with a second-order rate constant of approximately 3 M(-1) s(-1). An N-terminal regulatory domain of Sso1p accounts for slow assembly, since in its absence complexes assemble 2,000-fold more rapidly. Once binary complexes form, ternary complex formation is rapid and is not affected by the presence of the regulatory domain. Our results imply that proteins that accelerate SNARE assembly in vivo act by relieving inhibition by this regulatory domain.

Diminished reproduction, failure to thrive, and altered immunologic function in a colony of T-cell receptor transgenic mice: possible role of Citrobacter rodentium.

Citrobacter rodentium from an undetermined source was detected in a breeding colony of T-cell receptor transgenic mice housed in a conventional mouse facility in which murine hepatitis virus had been endemic and Helicobacter spp. had been detected. Citrobacter rodentium, isolated from blood, spleen, and colon, correlated with a significant increase in mortality and morbidity in this breeding colony. Transgenic mice of all ages were affected by chronic debilitation, loss in reproductive efficiency, rectal prolapse, and acute death, resulting in the near loss of these noncommercially available strains. Several alterations in immunologic parameters were observed, including outgrowth of an unusual population of cells in the spleen and blood, reduction in ascites production, loss of the capacity of peritoneal exudate cells to serve as feeders for the cloning of long-term T-cell lines, and inhibition of antigen-specific cytotoxic T-cell activity. These altered immune functions also were apparent in commercially-derived nontransgenic mice cohoused with the infected colony and in overtly healthy transgenic and nontransgenic littermates. Citrobacter rodentium and murine hepatitis virus were eliminated ultimately on rederivation of the affected strains by embryo transfer. However, the rapid decrease in the health of the colony necessitated more immediate action. To reduce mortality and allow breeding to continue during rederivation of the transgenic lines, animals were treated with enrofloxacin and moved to a barrier facility. Antibiotic therapy significantly reduced morbidity and mortality, markedly increased litter size and frequency, and resulted in the normalization of many of the immunologic assays. The involvement of C. rodentium in altering viability of the colony and perturbing immunologic assays is suggested by correlation of the onset of the syndrome with the appearance of Citrobacter sp. and its resolution with the elimination of Citrobacter sp. from the colony. Whether infection with Citrobacter alone is causative or whether superinfection of murine hepatitis virus- and Helicobacter-infected mice is required remains to be determined.

Evaluation of the reinforcing and discriminative stimulus effects of the N-methyl-D-aspartate competitive antagonist NPC 17742 in rhesus monkeys.

The phencyclidine (PCP)-like effects of the N-methyl-D-aspartate (NMDA) competitive antagonist 2R,4R,5S-2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 17742) were evaluated in three behavioral tests in rhesus monkeys. The discriminative stimulus properties of NPC 17742 (2-24 mg/kg, i.m.) were tested in four rhesus monkeys trained to discriminate PCP from saline under a fixed-ratio (FR) 50 schedule of food reinforcement. In three of the monkeys, NPC 17742 showed complete substitution for PCP at doses which did not decrease rates of responding. Intravenous self-administration of NPC 17742 (50-800 micrograms/kg/infusion) was tested under a FR schedule of reinforcement in four monkeys trained to lever press for infusions of PCP. At least one dose of NPC 17742 functioned as a reinforcer in two of the monkeys. A second self-administration study, employing a 10 min fixed interval schedule of reinforcement, was performed in three monkeys trained to self-administer PCP during three daily sessions. Compared with PCP, NPC 17742 (0.4-1.6 mg/kg/infusion) maintained very low rates of responding; NPC 17742 could not be clearly established as a reinforcer in this procedure. The data show that NPC 17742 has some PCP-like behavioral effects, and may function as a weak reinforcer in some subjects under specific conditions. The results provide further evidence that both similarities and differences exist between the behavioral effects of PCP and competitive NMDA antagonists.

Dexfenfluramine lacks amphetamine-like abuse potential.

1. The amphetamine-like abuse potential of dexfenfluramine (dFEN) was evaluated using drug discrimination and self-administration procedures. 2. Male Fischer rats were trained to discriminate either dFEN (1.0 mg/kg) or d-amphetamine (dAMP; 1.0 mg/kg) from saline in a two-choice discrete-trial avoidance paradigm. 3. In dAMP-trained rats, dFEN (0.5-4.0 mg/kg) engendered almost exclusively saline-appropriate responding. In dFEN-trained rats, dAMP (1.0-4.0 mg/kg) engendered entirely saline-appropriate responding in 3 of 6 rats and intermediate levels of dFEN-appropriate responding in the remaining animals. 4. Potential reinforcing effects of dFEN were also evaluated in 3 male rhesus monkeys trained to self-administer cocaine (i.v.) during daily 60 min sessions under a fixed-ratio (FR)-10 schedule. 5. Various doses of dFEN (30-1000 micrograms/kg/infusion) and dAMP (10 micrograms/kg/infusion) were substituted for cocaine in 4 consecutive daily sessions. In all subjects, dFEN maintained rates of self-administration within the range of rates maintained by saline and considerably below those maintained by cocaine and dAMP. Furthermore, the within-session distribution of responding with dFEN resembled that produced by saline. 6. Taken together, these results strongly suggest that dFEN will not have amphetamine-like abuse potential in humans.

Behavioral pharmacology of two novel substituted quinoxalinedione glutamate antagonists.

Two novel quinoxalinedione glutamatergic antagonists, with in vitro selectivity for the glycine modulatory site on the N-methyl-d-aspartate (NMDA) receptor, were evaluated in a number of behavioral tests primarily designed to compare their effects to those of the noncompetitive NMDA antagonist phencyclidine (PCP). The compounds evaluated were 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) and 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021). In rats, both ACEA-1011 and ACEA-1021 were completely devoid of PCP-like discriminative stimulus effects, although behavioral activity, in the form of response rate suppression, was seen at the higher doses tested (6-25mg/kg, i.p.). ACEA-1011 and ACEA-1021 were also ineffective as antagonists of PCP discrimination in rats. ACEA-1021 failed to substitute in rhesus monkeys trained to discriminate PCP from sham injection, although in the monkeys minimal effects were observed on rates of responding even at the highest dose tested (10.2mg/kg, i.v.). ACEA-1021 also failed to produce ethanol-like discriminative stimulus effects in rats under test conditions where PCP has been shown to produce substantial levels of substitution for ethanol. Both ACEA-1011 and ACEA-1021 were also evaluated as antagonists of NMDA discrimination in rats. ACEA-1011 produced some decreases in NMDA-lever responding, with the largest effect at one intermediate dose (3mg/kg, i.p.). ACEA-1021 was ineffective as an antagonist of NMDA discrimination. Unlike results reported for PCP-like NMDA antagonists, neither ACEA-1011 nor ACEA-1021 disrupted prepulse inhibition of the acoustic startle reflex in rats. It was not possible to establish ACEA-1021 (10 or 15.6mg/kg) as a discriminative stimulus in rats. In conclusion, the novel glutamate antagonists ACEA-1011 and ACEA-1021 did not produce a profile of behavioral effects similar to that of PCP-like noncompetitive NMDA antagonists. These results are consistent with an emerging body of evidence showing differences in the behavioral effects of different classes of glutamate antagonists.

Evaluation of the reinforcing effects of eliprodil in rhesus monkeys and its discriminative stimulus effects in rats.

Two studies examined the abuse potential of the N-methyl-D-aspartate (NMDA) non-competitive antagonist eliprodil [(+/-)-alpha-(4-chlorophenyl)-4-[(fluorophenyl)methyl]-1- piperidineethanol] by evaluating its reinforcing effects in rhesus monkeys and its phencyclidine (PCP)-like discriminative stimulus effects in rats. The monkeys were trained to self-administer PCP i.v. under a fixed ratio 10 schedule of reinforcement. After the monkeys were trained, saline, vehicle and various doses of eliprodil were substituted for PCP. The rats were trained to discriminate 3 micrograms/kg PCP from saline using a standard two-lever discrimination procedure with correct-lever responding reinforced under a fixed ratio 10 schedule of food reinforcement. After acquiring the discrimination, the rats were tested with various doses of PCP, dizocilpine and eliprodil. The self-administration study showed that eliprodil did not have reinforcing effects, since it maintained injection rates comparable to the negative controls, saline and vehicle. In the discrimination study it was found that the higher doses of PCP and dizocilpine resulted in 100% PCP-associated lever responding, whereas eliprodil occasioned no responding on the PCP-associated lever. The results from these studies suggest that eliprodil has a low potential for abuse in humans as well as providing further evidence that eliprodil produces a profile of behavioral effects unlike the PCP-site selective NMDA antagonists.

Failure of Delta(9)-tetrahydrocannabinol and CP 55,940 to maintain intravenous self-administration under a fixed-interval schedule in rhesus monkeys.

The lack of procedures which can unequivocally demonstrate cannabinoid self-administration in animals has been an obstacle to the study of the neural basis for the reinforcing effects of this drug class. Because delta(9)-tetrahydrocannabinol (delta(9)-THC) produce a relatively slow-onset, long-lasting behavioral effect, a self-administration procedure with widely spaced drug deliveries was evaluated as an alternative to fixed-ratio schedules which typically require frequent, closely spaced injections to demonstrate reinforcing effects. Three adult male rhesus monkeys were surgically implanted with intravenous catheters and trained to self-administer phencyclidine (PCP) under a 10min fixed-interval schedule of reinforcement. Three injections were available each day, separated by 2h periods during which responding had no programmed consequences. In an attempt to link the effect of the drug with the response which produced it, each 20s injection was paired with a red light which remained illuminated for 10min. PCP (100µg/kg/injection) maintained steady rates of responding during each availability period, ranging from approximately 0.2 to 0.7 responses/s. During 7 day substitution periods, Delta(9)-THC (17-100µg/kg/injection) maintained low rates of responding which occasionally surpassed those during vehicle substitutions, but fell far below rates maintained by PCP. Substitution tests with the potent Delta(9)-THC analog CP 55,940 also resulted in low rates of responding. These results demonstrate that Delta(9)-THC is a poor reinforcer in animals, even under conditions where some of its unfavourable biodispositional properties are taken into consideration.