Cocaine's effects on speech sound identification and reaction times in baboons.

The effects of cocaine on speech sound discriminations was examined to determine whether cocaine's previously demonstrated effect in reducing speech sound discriminability was dependent upon either the type of stimuli employed (simple tones versus complex speech) or the procedure (stimulus detection versus stimulus discrimination). Because of demonstrated similarities in the way that baboons and humans discriminate speech, and in the way the CNS is thought to encode and process speech sounds in these two species, baboons were trained to perform a choice procedure to identify the occurrence of different synthetic vowel sounds (see text). Animals held down a lever and released the lever only when one of four target vowels sounded, and not when a fifth, standard vowel sounded. Acute IM administration of cocaine (0.0032-1.0 mg/kg) produced dose-dependent decreases in vowel discriminability that were mostly due to elevations in false alarms (i.e., releases to the standard vowel) following cocaine. Cocaine also shortened reaction times to the stimuli in two of three baboons, but to a much lesser extent than observed previously. These results suggest that cocaine may interfere with the ability of the CNS to process the acoustic cues in speech sounds, and that the effects of cocaine on reaction times may depend upon the complexity of the reaction time procedure employed.

Effects of cocaine and quinpirole on perceptual and motor functions in baboons.

The effects of cocaine and quinpirole were studied in baboons to determine whether quinpirole, a relatively selective D2/D3 dopamine agonist, produced effects similar to those of cocaine on perceptual and motor processes. To measure perceptual and motor function, three baboons were trained to discriminate differences between a standard vowel and four other synthetic vowels: response accuracy as well as response latencies, or "reaction times", were measured following drug administrations. Cocaine reduced reaction times in two baboons, and did not affect reaction times in a third; on the other hand, quinpirole lengthened reaction times in a dose-dependent manner in all baboons. Cocaine and quinpirole also differed in the time course to produce the maximal reaction time effect following drug administration. Cocaine and quinpirole did not differ consistently in their perceptual effects, as indicated by similar changes in d', a signal-detection index of discriminability. These distinct profiles of effects for cocaine and quinpirole suggest differing neurochemical actions for these two drugs.

A force-plate actometer for quantitating rodent behaviors: illustrative data on locomotion, rotation, spatial patterning, stereotypies, and tremor.

This report describes a new kind of actometer for recording the behavior of rodents or other small animals. The instrument, a force-plate actometer, uses a stiff, low-mass horizontal plate coupled to four supporting force transducers positioned at the corners of the plate. When an animal moves on the plate, its movements are sensed by the transducers whose signals are processed by computer to yield measurements of a wide range of behaviors or behavioral attributes, such as locomotor activity, rotation around the center, whole-body tremor, and amphetamine-induced stereotypies. Spatial resolution is less than 1 mm, and temporal resolution is 0.02 s. Sample data were presented comparing the locomotor activity of CD-1, BALB/c, and C57BL/6 mice before and after treatment with D-amphetamine sulfate. Rotational behavior was recorded in an amphetamine-treated rat that had sustained a unilateral 6-hydroxydopamine-induced lesion of the nigrostriatal system. In the C57BL/6 mouse, harmaline-induced tremor was quantified. With rats as subjects, the force-plate actometer was used to quantify amphetamine-induced stereotypies, to demonstrate the development of sensitization to amphetamine's effects, and to quantitate the consistent 11-12 Hz rhythmicities that underlie the sterotypies. The performance of the force-plate actometer was compared with that of a variety of instruments reported in the literature on behavioral instrumentation. Finally, potential applications in neuroscience research other than those illustrated in this report were discussed.

Motor and associative deficits in D2 dopamine receptor knockout mice.

Behavioral abnormalities produced by D2 dopamine receptor gene deletion in mice have been attributed either to resulting Parkinson-like features (i.e. response slowing and response initiation difficulties) or to behavioral deficits contributed by alleles of the originating 129Sv strain. Three strategies were used to address these conflicting hypotheses: (1) we used mice congenic at n10 backcross into the C57BL/6 line to minimize the 129Sv contribution; (2) we compared mice that were wild-type (+/+), heterozygous (+/-), or homozygous (-/-) for the D2 gene with the two most relevant inbred lines (129Sv and C57BL/6) and (3) we used both conventional and novel behavioral assessment methods. Behavioral attributes were expressed in terms of locomotor activity, wall rearing, rotarod performance, operant response acquisition, operant response performance, lick dynamics (force, rhythm), grip strength, and tremor in response to harmaline challenge. Results showed that, compared to controls, the -/- mice exhibited longer duration wall rears, retarded operant response acquisition, increased latencies to move from the operandum to the reward well, and exaggerated response to harmaline. Age was investigated as a variable (10-11 weeks versus 41-44 weeks of age) in the locomotor activity and wall rear assessments. A gene dosage effect (deficits in the +/- mice) on these two variables became apparent in the older mice. Taken together, the results showed that mice without the D2 gene exhibited Parkinson-like behavioral features that were not easily attributed to alleles contributed by the 129Sv strain, but were consistent with basal ganglia dysfunction.

Low grip strength, impaired tongue force and hyperactivity induced by overexpression of neurotrophin-3 in mouse skeletal muscle.

Transgenic mice overexpressing neurotrophin-3 (NT-3) in skeletal muscle (mlc/NT-3 mice) develop abnormal muscle spindles in skeletal muscle and display abnormal motor function in the form of gait and locomotive disturbances. The purpose of this work was to characterize the functional consequences of NT-3 overexpression in skeletal muscle with further behavioral assessments that permitted inferences about muscle weakness in the tongue or forelimbs as well as potential central nervous system (CNS) abnormalities compared to wild-type controls. Wild-type (n=12) and mlc/NT-3 (n=12) male mice were tested in five procedures (in chronological order): lick dynamics, locomotor activity, grid ataxia, go-no-go discrimination procedure, and grip strength. Relative to wild-type mice, the mlc/NT-3 mice exhibited lower tongue force, hyperactivity, slowed limb retrieval in the grid ataxia test, similar discrimination performance, and lower grip strength. Overall, the data suggest that chronically elevated levels of NT-3 in mouse skeletal muscle cause muscle weakness in the mlc/NT-3 mice. Surprisingly, mlc/NT-3 mice also exhibited significant hyperactivity, suggesting that NT-3 overexpression in the periphery may have caused abnormalities in the CNS that are related to the cortical processing of proprioceptive afferent information.

Perceptual and motor effects of morphine and buprenorphine in baboons.

The effects of morphine and buprenorphine on auditory perceptual discriminations and response latency ("reaction time") in baboons are compared. The task employed synthetic human vowel sounds that are readily generated in the laboratory, and closely approximate natural baboon "grunt" vocalizations [J. Acoust. Soc. Am. 101 (1997) 2951]. Baboons pressed a lever to produce one repeating "standard" vowel, and released the lever only when one of four other "comparison" vowels occasionally occurred in place of the standard vowel. The percentage of correct detections and median reaction time for each comparison were measured following intramuscular drug administrations of morphine (0.01-1.8 mg/kg) and buprenorphine (0.00032-0.032 mg/kg). Both morphine and buprenorphine impaired vowel discriminability, and greater impairments occurred for those comparison vowels that were more similar in formant structure to the standard vowel. Morphine increased reaction time in all baboons, and buprenorphine increased reaction time in two of three baboons. Morphine's perceptual effects occurred within 20-40 min following drug administration; buprenorphine's perceptual effects occurred 50-100 min following drug administration. Morphine and buprenorphine did not differ in the time course of their maximal reaction time effects. The results demonstrate that both morphine and buprenorphine can impair auditory discriminations involving human vowel sounds in baboons, as well as lengthen reaction times to the stimuli.

Haloperiodol-induced microcatalepsy differs in CD-1, BALB/c, and C57BL/6 mice.

The degree of arrest of movement (microcatalepsy) induced by haloperidol at doses equipotent for operant rate suppression was measured with computerized instrumentation. The inbred C57BL/6 mouse strain displayed more susceptibility to microcatalepsy than the CD-1 and BALB/c strains. In addition, the C57BL/6 strain exhibited a greater degree of sensitization to repeated dosing than did the other 2 strains. The results were consistent with the C57BL/6 mouse's hypodopaminergic profile reported in the literature but were at odds with results reported for conventional catalepsy testing. The C57BL/6 mouse may serve as a model for genetic vulnerability to extrapyramidal motor side effects and may be useful in quantifying the mild extrapyramidal motor side effects of atypical antipsychotic drugs.

Some functional characteristics of avoidance of timeout from response-dependent food presentation in rats.

Three male and three female rats were first trained to respond on a Random-Interval 15-s schedule on one (food) lever in a rodent operant conditioning chamber. They were then exposed to a condition in which food could only be obtained during a timein period which lasted 10 s or longer dependent upon whether or not subjects pressed another (avoidance) fever. If subjects did not press the other level during the 10-s timein, a 50-s timeout was presented during which food could not be obtained. Subjects first had the opportunity to avoid timeout presentation by pressing the avoidance level during timein or to escape the timeout by pressing the lever during timeout. A changeover delay of 2-s prevented food presentation immediately following avoidance lever-food lever sequences. All subjects pressed the avoidance lever to avoid or escape timeout, but only one of the subjects consistently pressed the avoidance lever when escape was no longer available. One more subject acquired consistent avoidance responding after reexposure to the avoidance/escape and avoidance only conditions. The four remaining subjects were then exposed to a signalled avoidance procedure in which a 5-s stimulus change preceded timeout presentation. Three of the subjects came to respond reliably on the avoidance lever when switched back to the unsignalled avoidance procedure. One of the subjects never acquired consistent avoidance responding. Functional control by the avoidance contingency was demonstrated during the final two experimental conditions in which the contingencies associated with the avoidance lever were systematically removed and reintroduced.

Effects of chlordiazepoxide and cocaine on concurrent food and avoidance-of-timeout schedules.

Five rats were trained on a concurrent schedule in which responses on one lever produced a food pellet on a random-interval 30-s schedule during 10 s of food availability associated with distinctive exteroceptive stimuli. Responses on another lever postponed for 20 s the presentation of a 50-s timeout, during which all stimuli were extinguished and the schedule contingencies on the food lever were suspended. The response rates maintained by the random-interval schedule exceeded those maintained by the avoidance contingency, but both provided a stable baseline to assess the behavioral effects of different drugs. Low doses of cocaine hydrochloride (1 and 3 mg/kg) did not affect food-reinforced responding or avoidance response rates. Intermediate doses (5.6, 10, and 13 mg/kg) produced a dose-dependent decrease in food-maintained and avoidance response rates, and both types of responding were virtually eliminated after administration of the highest doses (17 and 30 mg/kg) of cocaine. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased food-maintained and avoidance response rates, and both rates decreased systematically after 10 and 30 mg/kg of this drug. The effects of cocaine and chlordiazepoxide on response rates maintained by avoidance of timeout from food presentation were unlike those reported when subjects responded to avoid shock presentation. The results of this experiment thus provide evidence to suggest that the effects of drug administration on avoidance behavior may be a function of the nature of the consequent event to be avoided.

Drug discrimination: stimulus control during repeated testing in extinction.

Rats were trained, under a two-lever drug-discrimination procedure, to respond differentially depending upon whether lorazepam (1.0 mg/kg) or no injection had been administered before the session. Responses on the appropriate lever produced a food pellet under a modified fixed-ratio (FR) 10 schedule, in which the 10 responses had to be emitted consecutively. In reinforcement tests, completing an FR 10 on either lever produced a pellet. In extinction tests, stimulus changes paired with reinforcement occurred but no pellet was delivered. Training sessions were conducted between test sessions. Each of four extinction phases consisted of six tests preceded by one stimulus (e.g., lorazepam). Repeated exposures to extinction reduced response rates for all rats, but stimulus control, as inferred from either percentage of total responses or percentage of total FR 10s on the drug-appropriate lever, remained high. The percentage of total FR 10s measure was less subject to skewing under low-rate conditions than was the percentage of total responses measure and provided an evaluation of stimulus control in terms of meeting the consecutive response contingency. These results demonstrate a level of independence between response rate and stimulus control in drug discrimination, which has positive implications for the validity of interpreting discriminative effects of novel test conditions in well-trained animals, even when overall response rates are low.

Key pecking during extinction after intermittent or continuous reinforcement as a function of the number of reinforcers delivered during training.

Key pecking by 7 pigeons was established and maintained on a multiple variable-ratio variable-ratio (VR) schedule of food presentation. The schedule in one of the components was then changed to fixed-ratio (FR) 1 for a predetermined number of reinforcers. Both components were then changed to extinction (i.e., multiple extinction, extinction). This sequence was repeated a different number of times for each pigeon to determine the relation between the number of reinforcers delivered during each component of the multiple VR FR 1 schedule and the number of responses during extinction. For most pigeons, there were fewer responses during extinction in the presence of a stimulus recently correlated with FR 1, regardless of the number of reinforcers received. The ratio of the total responses in extinction in the former VR component to the total responses in the former FR 1 component increased as the number of reinforcers delivered during each component of the multiple schedule increased. Within-subject replications of the partial-reinforcement extinction effect generally occurred, and there were no overall reductions in the number of responses in extinction with repeated exposures to extinction.

Prenatal methyl mercury exposure in relation to neurodevelopment and behavior at 19 years of age in the Seychelles Child Development Study.

BACKGROUND: Fish are important sources of protein and contain a variety of nutrients, such as n-3 long-chain polyunsaturated fatty acids (PUFA), essential for normal brain development. Nevertheless, all fish also contain methyl mercury (MeHg), a known neurotoxicant in adequate dosage. Our studies of the Seychelles Child Development Study (SCDS) Main Cohort enrolled in 1989-1990 (n=779) have found no consistent pattern of adverse MeHg effects at exposures achieved by daily fish consumption. Rather, we have observed evidence of improved performance on some cognitive endpoints as prenatal MeHg exposure increases in the range studied. These observations cannot be related to MeHg and may reflect the role of unmeasured covariates such as essential nutrients present in fish. To determine if these associations persist into young adulthood, we examined the relationship between prenatal MeHg exposure, recent PUFA exposure and subjects' neurodevelopment and behavior at 19 years of age. METHODS: We examined 533 participants using the following test battery: the Profile of Mood States-Bipolar (POMS-Bi); Finger Tapping; Kaufman Brief Intelligence Test (K-BIT); measures of Fine Motor Control and Complex Perceptual Motor Control; and Visual Spatial Contrast Sensitivity. We collected the following covariates: maternal IQ, family life course stressors, socioeconomic status, and subjects' recent postnatal MeHg, sex, and computer use. Primary analyses (based on N=392-475) examined covariate-adjusted associations in multiple linear regression models with prenatal MeHg as the primary exposure measure. Secondary analyses additionally adjusted for total n-6 and fish-related n-3 PUFA measured in the subjects' serum at the 19-year examination. RESULTS: Study participants had a mean prenatal MeHg exposure of 6.9 ppm, and a mean recent postnatal exposure of 10.3 ppm. There were no adverse associations between prenatal MeHg and any of the measured endpoints. For recent postnatal MeHg exposure, however, adverse associations were observed for Finger Tapping (non-dominant hand) among women and for the K-BIT Matrices for both sexes, with or without adjustment for PUFA. CONCLUSION: Our findings continue to provide no evidence for an adverse effect of prenatal MeHg exposure on development in a cohort that consumes fish daily. Observations for postnatal MeHg exposure will need to be confirmed using more comprehensive exposure measures.

Digital measurement of operant disk press force maintained in CD-1, BALB/c, and C57BL/6 mice.

Force of disk press responses by inbred (C57BL/6 and BALB/c) and outbred (CD-1) mice were measured with a PC/DOS-based system, which allowed for continuous measurement of pressing, as well as for control of reinforcer presentation on the basis of response-force dimensions. Photobeam-based measurement of mouse entry into a hopper where reinforcers were presented provided additional information about anticipatory and consumatory behavior in relation to environmental stimuli leading up to reinforcer delivery. Disk pressing was generated and measured with the use of an analog-to-digital interface with all three mouse strains. The strains differed in the physical and temporal characteristics of the disk press, as well as in the behavioral chain leading to reinforcer presentation. These measurement methods appear well suited for quantitating functional behavioral differences occasioned by genetic variations in mice.