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 (/a/, /æ/, //, /U/, and /љ/). 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.     

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

Three adult baboons were trained using a psychophysical procedure to discriminate between different synthetic vowel sounds (/a/, /æ/, //, /U/, and /). Baboons pressed and held a lever down to produce a pulsed train of a single reference vowel that served as the standard stimulus. Animals were trained to release the lever only when this standard vowel sound changed to one of the four remaining comparison vowels. A lever release within 1.5 s of this change in vowel sounds was defined as a correct detection of the change from the standard vowel to one of the comparison vowels, and was reinforced. All baboons readily learned the vowel discriminations and detected vowel changes at the 90–100% correct performance level. Acute IM administration of cocaine prior to test sessions (0.00032–3.2 mg/kg) produced dose-dependent decrements in vowel discriminability. At the same time, cocaine shortened lever release latencies (reaction times) to the vowel stimuli in two of three baboons. The cocaine-induced decrements in vowel discriminability were correlated with the degree to which frequency differences occurred among the different vowels in that lower vowel discriminability scores were found for those vowels with smaller spectral differences from the standard vowel. Further, false alarm rates were not systematically affected by cocaine, indicating that the cocaine-induced decrements in vowel discrimination accuracy occurred in the absence of systematic changes in the reliability of the baboons' discrimination performances.     

Effects of d-methamphetamine on auditory and visual reaction times and detection thresholds in the baboon

Baboons were trained in both auditory and visual reaction time procedures to release a response lever in the presence of low-intensity stimuli. By varying the stimulus intensity from trial to trial, functions relating reaction time (elapsed time from stimulus onset to lever release) to stimulus intensity were established, and detection thresholds were measured. The effects of acute, IM injections of d-methamphetamine (0.001–1.0 mg/kg) were examined on these psychophysical performance baselines. Reaction times for acoustic stimuli generally were faster for higher drug doses, whereas reaction times for visual stimuli either lengthened or shortened, depending on both drug dose and individual differences among animals. Auditory thresholds were unaffected at all drug doses studied, whereas visual thresholds were generally elevated at doses of 0.1 mg/kg and above.     

Environmental context conditioning with ethanol reduces the aversive effects of ethanol in the acquisition of self-administration in rats

RATIONALE: Many recent theoretical approaches to drug-taking behavior feature a role for Pavlovian conditioning. Despite growing evidence for that role, the particular contributions of Pavlovian conditioning to self-administration are not clear. For example, few studies have addressed the effects of Pavlovian conditioning on the acquisition of self-administration. OBJECTIVES: The purpose of this study was to test the effect of Pavlovian conditioning with an environmental conditioned stimulus and an ethanol unconditioned stimulus on the acquisition of self-administration reinforced by ethanol. METHODS: Rats were either given ethanol by gastric gavage in a distinctive context or in their home cage. All animals were then trained to bar press on a variable interval schedule for a sweetened ethanol solution in the distinctive context. RESULTS: Animals that had received ethanol associated with the training context maintained a higher level of bar press behavior for ethanol as the reinforcing solution. This effect developed only after the first session and resulted from differences in response rates, but did not affect the rate of reinforcement. CONCLUSIONS: This study demonstrates that an environmental context signaling the effects of ethanol maintains a higher operant response rate when ethanol is used subsequently as a reinforcer. This finding replicates previous reports of Pavlovian conditioning effects on ethanol consumption. The specific pattern of results suggests that conditioned tolerance modifies the reinforcing impact of ethanol. Context conditioning with ethanol reduces the aversive impact of initial ethanol consumption and maintains the reinforcing value of the ethanol solution.     

The effects of phencyclidine and ketamine on sensory thresholds and reaction times in the baboon

Adult male baboons were trained on a reaction time procedure, and absolute thresholds and reaction times to both a 16.0 kHz pure tone and a white light were obtained. Acute IM injections of phencyclidine (0.0032 to 0.1 mg/kg) or ketamine (0.032 to 3.2 mg/kg) were given at the beginning of 2-hr test sessions. Phencyclidine had no effect on auditory thresholds, visual thresholds, or visual reaction times, but selectively elevated auditory reaction times. Ketamine, on the other hand, elevated auditory thresholds and both auditory and visual reaction times, while having no effect on visual thresholds. Ketamine was also less potent than phencyclidine in elevating auditory reaction times, and recovery from these impairments was evident during the two-hour test sessions for ketamine, but not for phencyclidine.     

The effects of chronic administration of ethanol on startle thresholds in rats

The thresholds for startle responses to electric shock were measured in adult male Wistar strain rats given ethanol daily in doses rising from 3 to 7 g/kg over a 30-day period, and in controls receiving equicaloric doses of sucrose. Tests made 23, 36, or 47 h after ethanol (i.e., during partial or complete ethanol withdrawal) gave threshold values significantly lower than those obtained with sucrose-treated controls. The difference became greater after longer ethanol treatment and larger doses. However, when threshold measurements were made under the acute influence of ethanol in the experimental group, the mean values were virtually equal to those of the sucrose controls. This normalization, by ethanol, of a disturbance produced by absence of ethanol in a chronically treated animal is indicative of physical dependence. Following termination of ethanol treatment there was a gradual return of startle thresholds almost to control values over a relatively short period, indicating that the changes underlying the hyperexcitability are readily reversible.     

Similar effects of ethanol and flumazenil on acquisition of a shuttle-box avoidance response during withdrawal from chronic ethanol treatment.

1. Acquisition of a two-way shuttle-box avoidance response is facilitated by ethanol. This facilitated acquisition of an avoidance response to ethanol was attenuated during withdrawal from chronic-ethanol diet intake (i.e. tolerance developed by ethanol). The deficit in the avoidance task after chronic ethanol treatment could be overcome by increasing the dose of ethanol. 2. Flumazenil, a benzodiazepine antagonist, also facilitated acquisition of the avoidance response in control rats. This response to flumazenil was significantly reduced during withdrawal from chronic-ethanol treatment. This reduced avoidance responding during withdrawal also could be overcome by increasing the dose of flumazenil. 3. The benzodiazepine-inverse agonist, RO 15-4513, produced a deficit in avoidance responding that was antagonized by both ethanol and flumazenil in a dose-related manner. 4. To determine whether flumazenil has the properties of a benzodiazepine agonist, it was established that, unlike the benzodiazepine chlordiazepoxide, flumazenil did not enhance the ethanol-induced deficit in the aerial righting reflex. Additionally, flumazenil blocked the action of chlordiazepoxide in this procedure, consistent with the benzodiazepine antagonist action of flumazenil. 5. Data collected are consistent with the hypothesis that an endogenous substance with the properties of a benzodiazepine-inverse agonist antagonizes the anticonflict actions of acutely administered ethanol during withdrawal from chronic-ethanol exposure.     

Acute ethanol effects on sensory/motor function in baboons with a history of chronic ethanol ingestion.

Baboons with a history of chronic, daily ethanol ingestion were subsequently studied under conditions that assessed the effects of acute oral self-administration of ethanol on auditory and visual threshold functions and reaction times. During the post-chronic experiment reported herein, the animals consumed specific amounts of ethanol twice weekly (0.1, 0.32, 1.0 or 1.3 g/kg), following which they immediately performed psychophysical tests designed to assess ethanol's effects on sensory thresholds and reaction times. Clear, dose-related increases in reaction times were observed following ethanol doses greater than 0.32 g/kg. Trends within individual threshold functions were consistent with systematic changes in auditory and visual threshold sensitivities of 1-3 dB at the high ethanol doses. Reaction time increases ranged from 25 to 180 ms above baseline levels at the highest dose (a 15% average increase). These general findings however, were in contrast to data obtained in the same animals under conditions of daily, chronic ethanol administration which characteristically showed greater sensory/motor effects of up to twice the magnitude of those observed with single doses.     

The effects of chlorpromazine and secobarbital on the reaction times of chronic schizophrenics

Summary Twelve male schizophrenics were given a simple visual reaction time test (RT) after single doses and chronic (11 days) administration of chlorpromazine and secobarbital. RT was tested under two conditions: irregular, in which preparatory intervals were presented randomly, and regular, in which the same preparatory intervals were given in consecutive order. Results under single doses indicated that secobarbital reduced intra-individual variability, while chlorpromazine did not significantly affect performance. Results under chronic administration indicated that neither drug had a significant effect on RT performance. These findings are different from those obtained by other investigators who have observed facilitation in schizophrenic psychomotor performance after chlorpromazine, and deficit in performance after barbiturates.This study is a revision of part of a dissertation submitted in partial fulfillment of the requirements for the degree Master of Arts, from the Catholic University of America, August 1957, by the senior author. Thanks are due Dr. John W, Stafford, who served as thesis advisor.This study was part of an N.I.M.H. research project run at St. Elizabeths Hospital, Washington, D.C., under the direction of the junior author, and reported elsewhere (Kornetsky, Pettit, Wynne, and Evarts 1959).This paper was presented in part at the 1958 meetings of the American Psychological Association.     

Assessment of effects of ethanol self-administration on social interactions in alcoholics

Five volunteer chronic alcoholics participated in an experiment in which the availability or non-availability of a daily ration of 12 ounces (360 ml) of 95-proof ethanol (133.68 g ethanol) was randomly determined. For all subjects, rates of social interaction were significantly higher on ethanol days than non-ethanol days. The study demonstrates the feasibility of using complex molar units of human behavior as dependent variables in behavioral pharmacology research.Supported by USPHS research grant AA-00179 from NIAAA.     

Cocaine self-administration in monkeys: effects on the acquisition and performance of response sequences

A three-component multiple schedule of intravenous cocaine self-administration (0.01-0.3 mg/kg), repeated acquisition and performance was used to examine the effects of self-administered cocaine on learning in rhesus monkeys. A 0.03 mg/kg infusion of cocaine maintained reliable self-administration without markedly decreasing overall response rate or increasing the percentage of errors in the acquisition and performance components in which food was presented. When saline was substituted for 0.03 mg/kg of cocaine, there was little or no effect on responding in the acquisition or performance components while the number of infusions and response rate in the self-administration component decreased. These effects occurred to a greater extent under a FR 90 schedule (Experiment 2) as compared to a FR 30 schedule (Experiment 1) of cocaine self administration. Substitution of higher infusion doses of cocaine also decreased response rate and the number of infusions in the self-administration components, and substantially decreased responding in the acquisition components; decreases in overall accuracy of responding were evident when responding in this schedule component occurred. Taken together, these data indicate that learning is generally more sensitive than performance to the disruptive effects of self-administered cocaine.     

Cocaine's effects on the discrimination of simple and complex auditory stimuli by baboons

The effects of cocaine on tone frequency discriminations by baboons were examined and compared with previous data for more complex acoustic stimuli (speech sounds) to see if cocaine's perceptual effects on these discriminations depends upon the type of stimulus employed (i.e., tones vs. speech sounds). Baboons pressed a lever to produce one repeating "standard" tone and released the lever only when one of four other "comparison" tones occasionally occurred in place of the standard tone. Cocaine's effects were assessed once or twice weekly by giving an intramuscular injection of cocaine hydrochloride (0.01-0.56 mg/kg) immediately prior to performing the task and by examining correct detections and reaction times for each tone following drug administration. Cocaine impaired tone discriminability, with greater impairments occurring for those tones that were more similar in frequency to the standard tone. Cocaine's perceptual effects occurred within 20-70 min following drug administration. Cocaine also impaired or facilitated the speed of responding to auditory stimuli, depending upon the drug dose and subject. The results demonstrate that cocaine can impair auditory discriminations involving simple tones, as well as speech sounds, and further supports the suggestion that cocaine's effects are focused on CNS mechanisms related to the use of pitch cues.     

The effects of age at the onset of drinking to intoxication and chronic ethanol self-administration in male rhesus macaques

Rationale

Consumption of alcohol begins during late adolescence in a majority of humans, and the greatest drinking occurs at 18–25 years then decreases with age.

Objectives

The present study measured the differences in ethanol intake in relation to age at the onset of ethanol access among nonhuman primates to control for self-selection in humans and isolate age effects on heavy drinking.

Methods

Male rhesus macaques were assigned first access to ethanol during late adolescence (n?=?8), young adulthood (n?=?8), or early middle age (n?=?11). The monkeys were induced to drink ethanol (4 %?w/v in water) in increasing doses (water then 0.5, 1.0, 1.5 g/kg ethanol) using a fixed-time (FT) 300-s schedule of food delivery, followed by 22 h/day concurrent access to ethanol and water for 12 months. Age-matched controls consumed isocaloric maltose–dextrin solution yoked to the late adolescents expected to be rapidly maturing (n?=?4).

Results

Young adult monkeys had the greatest daily ethanol intake and blood-ethanol concentration (BEC). Only late adolescents escalated their intake (ethanol, not water) during the second compared to the first 6 months of access. On average, plasma testosterone level was consistent with age differences in maturation and tended to increase throughout the experiment more for control than ethanol-drinking adolescent monkeys.

Conclusions

Young adulthood in nonhuman primates strongly disposes toward heavy drinking, which is independent of sociocultural factors present in humans. Ethanol drinking to intoxication during the critical period of late adolescence is associated with escalation to heavy drinking.     

Performance of baboons under a repeated acquisition procedure during chronic oral exposure to atenolol and propranolol

Repeated acquisition behavioral performances of normotensive and renovascular hypertensive baboons were tested before, during, and following chronic oral dosing with the-adrenergic antagonists atenolol HC1 (2.6 mg/kg/day PO), andd,l propranolol HC1 (6.8 mg/kg twice daily PO) in separate studies. Each study administered active drug for 21 consecutive days preceded and followed by 14-day baseline and recovery periods, respectively. Animals pressed five keys in sequence for food reinforcement during daily experimental sessions which consisted of alternating acquisition (new sequence learning) and performance (previously learned) task components. Atenolol increased response latencies during acquisition in comparison to performance components, and during early portions of sessions. Propranolol also increased response latencies during acquisition components in early periods of sessions, but fewer dependent measures were affected, and the magnitude of increases in response latencies was smaller (12%±5 SEM) as compared with atenolol (47%±13). Test doses of phencyclidine HC1 (PCP) increased latencies to the same degree as atenolol. PCP markedly reduced accuracy, while atenolol or propranolol did not. Blood pressures remained stable under atenolol, and decreased by approximately 10–15 mmHg under propranolol. No differences between renovascular hypertensive and normotensive baboons were found as a function of drug conditions. Drug effects were not dependent on plasma propranolol concentration.     

Effects of GABAergic modulators on food and cocaine self-administration in baboons

Drugs that indirectly alter dopaminergic systems may alter the reinforcing effects of cocaine. The inhibitory neurotransmitter gamma-aminobutyric acid (GABA) has extensive neural connections in mesolimbic regions that appear to modulate dopamine. The current study evaluated the effects of GABA_B receptor agonists baclofen and CGP44532, the benzodiazepine agonist alprazolam, and the GABA reuptake inhibitor tiagabine on lever responding maintained by low dose cocaine injections (0.032 mg/kg) or by food pellet (1 g) delivery in baboons. The benzodiazepine antagonist flumazenil was tested as a negative control. Cocaine or food was available under a fixed ratio (FR 10) schedule of reinforcement during daily 2-h sessions. During baseline conditions, cocaine and pellets maintained similar numbers of reinforcers per session. Baclofen, CGP44532 and tiagabine dose-dependently reduced the number of cocaine injections, where as the benzodiazepine antagonist flumazenil did not. Baclofen, CGP44532 and tiagabine also produced dose-related decreases in food-maintained behavior. In contrast, the benzodiazepine agonist alprazolam, which positively modulates GABA_A receptors via the benzodiazepine site, produced decreases in cocaine self-injection, but not food-maintained behavior. Thus, the effects of alprazolam were specific for cocaine-maintained behavior, where as the effects of baclofen and CGP44532 were not.     

The effects of pentobarbital upon auditory and visual thresholds in the baboon

Adult male baboons were trained to perform a reaction time procedure, which required holding a lever depressed for varying time intervals and releasing it during a 1.5 sec test stimulus to receive food. The test stimulus was a 16 kHz tone for auditory threshold testing, and a white light for visual threshold testing. Stimulus intensities were randomly varied to determine detection thresholds, and the latency of each correct lever release was recorded as a measure of reaction time. Acute, IM injections of pentobarbital (1.0 to 17.0 mg/kg) were given at the beginning of 2-hr experimental sessions. Pentobarbital elevated the absolute visual threshold and increased both auditory and visual reaction times in a dose-related manner. Two of three baboons showed reaction time and visual threshold decrements at pentobarbital doses which produced no change in absolute auditory thresholds.     

Buprenorphine alters ethanol self-administration in rats: dose-response and time-dependent effects

 Buprenorphine is a partial opioid agonist derived from thebaine and has high affinity for μ and κ opioid receptors. The present study investigated dose-response (0.03, 0.15, 0.3, 3 mg/kg) and time-dependent effects of buprenorphine (1.5 or 4 h post-treatment) on EtOH self-administration in outbred Sprague-Dawley rats. Freely feeding and drinking rats were trained to initiate EtOH self-administration for 1 h daily using the ascending concentration procedure, wherein they were provided with increasing concentrations of EtOH at 2, 5, 7, 9 and 11% (v/v), respectively. Water was concurrently available with each concentration. Animals were maintained on a given concentration of EtOH for 5 days. By day 21, animals began their stabilization on the 11% regimen and remained on this concentration throughout the remainder of the study. EtOH and water consumption were recorded daily at both 10- and 60-min intervals. At 1.5 h post-buprenorphine, all test doses greatly suppressed both EtOH and water intake at the 10-min interval. At the 60-min interval, all but the lowest dose (0.03 mg/kg) significantly suppressed EtOH intake, while only the highest dose (3 mg/kg) suppressed water intake. In contrast to the suppressant profile observed at 1.5 h post-buprenorphine, at 4 h post-buprenorphine the lower doses (0.03 and 0.15 mg/kg) significantly increased EtOH intake while the higher doses (0.3 and 3 mg/kg) continued to suppress intake. None of the doses of buprenorphine altered water intake 4 h post-buprenorphine. The results support previous research demonstrating the utility of low doses of buprenorphine in suppressing behavior rewarded by a non-opioid drug. Received: 11 September 1997 / Final version: 21 February 1998     

Effects of repeated withdrawal from chronic ethanol on oral self-administration of ethanol on a progressive ratio schedule

Male hooded Lister rats were trained using a sucrose-fading technique, to perform an operant lever press response to obtain ethanol. Initial training, using an FR4 schedule in which each reinforcement required four lever presses, included varying the concentration of ethanol in the liquid reinforcer. Changes in reinforcer concentration between 7 and 15% (vol/vol) had little effect on either numbers of lever pressing responses, or reinforcers obtained during the 3h session. Increasing the reinforcer concentration to 20% caused a decline in responding. The effects of varying reinforcer concentration (0-20% ethanol) were also studied in the same animals performing a progressive ratio schedule, in which the number of responses required to obtain a reinforcer was successively increased during the session. In these experiments the point at which rats ceased to respond (breaking point) was taken as a measure of their motivation to obtain ethanol. The function describing the relationship between ethanol concentration and number of responses, and number of reinforcers obtained in a session was an inverted U, with the maximum values occurring at an ethanol concentration of 10%. The value of the breaking point (highest ratio achieved) depended on the criterion used to define cessation of responding, but was between 15 and 22. Rats performing for ethanol showed higher breaking points than when responding for water, but there was no statistically reliable effect of ethanol concentration on the breaking point parameter. The effects of feeding the rats a liquid diet containing ethanol, and its subsequent withdrawal, on progressive ratio responding for 5% ethanol, were studied over four cycles of exposure and withdrawal. Intakes of ethanol of 11 g/kg/day had no effect on the animals' breaking point on the progressive ratio schedule, but withdrawal from the ethanol diet resulted in breaking points significantly higher than those in a control group pair-fed a nutritionally equivalent, ethanol-free diet. Although there was no further effect of repeated exposure and withdrawal on responding during the acute withdrawal phase, baseline levels of responding were elevated in the animals which had received multiple cycles of ethanol diet and withdrawal. These results are discussed in the context of the consequences of sensitization to repeated withdrawal from ethanol in dependent animals and humans.     

Effects of sweetened ethanol solutions on ethanol self-administration and blood ethanol levels

The enhancement of voluntary self-administration of ethanol by sucrose or saccharin was tested in conjunction with measurements of blood ethanol levels. Adult male rats were given access to both tap water and one of five solutions: 0.125% saccharin, 10% sucrose, ethanol, saccharin+ethanol, or sucrose+ethanol. The rats receiving the sucrose+ethanol solution drank consistently more ethanol (>5 g/kg/day) than did the rats receiving the saccharin+ethanol solution (<3 g/kg/day) or ethanol only (<2 g/kg/day). Both sweetened solutions produced higher ethanol consumption during these periods than ethanol alone. However, no significant differences in blood ethanol levels were found between the sucrose+ethanol and saccharin+ethanol conditions, when tested at different intervals on Day 44 or Day 45 of ethanol consumption. Following 45 days of consumption, no change in the bicuculline seizure threshold was observed in the ethanol-consuming rats compared to the controls. In a separate study using 90 naive rats, rats were gavaged with ethanol (1, 2, or 3 g/kg) containing either 10% sucrose (n=10 for each dose of ethanol), 0.125% saccharin (n=10 for each dose of ethanol), or ethanol alone (n=10 for each dose of ethanol), and blood was collected from the tip of the tail 30, 60, 180, 300, and 540 min later and analyzed for ethanol concentrations. Sucrose significantly decreased the resultant blood ethanol levels at several time points following gavage. These results indicate that sucrose can significantly alter blood ethanol levels and that chronic self-administration of a sweetened ethanol solution for 6 weeks does not produce ethanol dependence.