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We have previously reported that continuous cocaine administration functionally down regulates 5-HT3 receptors in the nucleus accumbens. The current experiments evaluated the duration of behavioral tolerance to cocaine and whether the duration of behavioral tolerance and 5-HT3 receptor down-regulation co-varied. Rats were withdrawn from a pretreatment regimen (40 mg/kg/per day cocaine or 0.9% saline for 14 days) for 1, 7 or 14 days. The rats were either sacrificed, and slices from the nucleus accumbens obtained, or were exposed to behavioral rating procedures. The results indicated that continuous cocaine administration significantly attenuated the ability of mCPBG to facilitate K+ -stimulated DA release on days 1 and 7, but not day 14, of withdrawal. Furthermore, continuous cocaine administration induced behavioral tolerance to a cocaine challenge on days 1 and 7, but not day 14, of withdrawal. These results suggest that continuous cocaine administration functionally down-regulates 5-HT3 receptors in the nucleus accumbens, and this functional down-regulation co-varies with the behavioral tolerance induced by continuous cocaine administration. Hence, a functional down-regulation of accumbens 5-HT3 receptors may represent a partial mechanism for the tolerance following continuous cocaine administration.

Using in vitro fast scan cyclic voltammetry, we measured cocaine potency for inhibiting dopamine uptake/clearance in accumbens slices 7 days after withdrawal from chronic cocaine pretreatments. Rats were pretreated with 40 mg/kg per day for 14 days, either via continuous osmotic minipumps or by once-daily injections. The cocaine potency was subsequently assessed for endogenous and exogenous dopamine applied via single-pulse electrical stimulation and caged-dopamine photolysis, respectively. Under baseline conditions, no differences in either endogenous or exogenous dopamine kinetics were observed in the two cocaine pretreatment groups. In contrast, the potency of bath-applied cocaine for inhibiting endogenous dopamine uptake was enhanced in the intermittent injection group with no change in the continuous infusion group. The selective increase in the cocaine potency following injections was also demonstrable for clearance of photo-applied DA. The enhanced cocaine potency in the accumbens slices following 7 days of withdrawal is consistent with the residual sensitization to cocaine-induced locomotion following daily cocaine injections. Behavioral tolerance following continuous infusion, on the other hand, may be mediated via a mechanism distinct from altered dopamine uptake.

The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during withdrawal from chronic cocaine administration, to block the expression of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg/per day cocaine for 14 days by either s.c. injections or osmotic minipumps, or 0.9% saline, administered via osmotic minipump. During the first 5 days of withdrawal from this pretreatment regimen, all rats received a daily s.c. injection of 0-1.0 mg/kg ondansetron. On day seven of withdrawal from the cocaine pretreatment (2 days after the final ondansetron injection) all subjects received a 15.0 mg/kg i.p. cocaine challenge. Their behavior was then rated according to the Ellinwood and Balster (1974) scale for 60 min. The results indicated that daily injections of ondansetron, on days 1-5 of withdrawal from the pretreatment regimen, had no significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron, on days 1-5 of withdrawal from intermittent cocaine administration, significantly blocked the expression of sensitization. In the continuous cocaine group, ondansetron injections, on days 1-5 of withdrawal from continuous cocaine administration, also blocked the expression of behavioral tolerance. The results therefore indicate that changes in 5-HT3 receptor function are associated with the expression of tolerance and sensitization, respectively.

Abecarnil is a metabolically stable beta-carboline that binds with high affinity and selectivity to central benzodiazepine receptors. The effects on cognitive and psychomotor skills of abecarnil (ZK 112-119), 2.5 mg and 5.0 mg, were compared with lorazepam 2.0 mg and placebo. Twenty-four healthy, young males participated in a double-blind, four-way Latin square design and performed batteries of behavioral tests at predrug and at 20, 40, 60, 80, 100, 120, 180, 240, 360 and 480 min after drug administration. Abecarnil 5.0 mg and lorazepam 2.0 mg displayed similar impairment profiles in tests of cognitive functions including memory encoding. Abecarnil 2.5 mg was substantially less impairing than lorazepam. Impairment levels of the abecarnil and lorazepam treatments peaked at 2-3 h after oral administration. The two abecarnil doses showed dose-dependent effects on the cognitive and psychomotor tasks. All three drug treatments were well tolerated by the subjects, with no one terminating early due to adverse events. The incidence of reported adverse events for abecarnil was dose-dependent. The most frequent, statistically significant adverse effects were drowsiness, lack of concentration and visual disturbance for abecarnil 5.0 mg; and lack of concentration and dizziness for lorazepam 2.0 mg. There were no significant differences in adverse incidence rates between abecarnil 2.5 mg and placebo.

The present experiment evaluated the ability of the 5-HT3 antagonist, ondansetron, administered during chronic cocaine administration, to block the development of sensitization and tolerance induced by the intermittent or continuous administration of cocaine, respectively. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either SC injections or osmotic minipumps, or 0.9% saline, administered by SC injection. During this chronic (cocaine) treatment, all rats received a daily SC injection of 0-1.0 mg/kg ondansetron. The rats were then withdrawn from the pretreatment regimen for 7 days. On day 7 of withdrawal from the cocaine pretreatment all subjects received a 15.0 mg/kg IP cocaine challenge, and their behavior was then rated according to the modified Ellinwood and Balster scale for 60 min. The results indicated that daily injections of ondansetron had no consistent or significant effect on the subsequent behavioral response to cocaine in the saline control subjects. In contrast, daily injections of ondansetron with cocaine significantly blocked the development of sensitization with an inverted U-shape dose-response curve. In the continuous cocaine group ondansetron injections also attenuated the development of behavioral tolerance. The results therefore indicate that 5-HT3 receptor stimulation during continuous and intermittent cocaine administration is an important link in the development of behavioral tolerance and sensitization.

Chronic daily injections of cocaine induce behavioral sensitization to subsequent cocaine challenge, while continuous infusion induces tolerance. Following a 7-day withdrawal period, we examined the effects of these two dosing regimens on: (1) baseline dopamine efflux and uptake following single-pulse electrical stimulation, (2) inhibition of uptake by cocaine; and (3) inhibition of efflux by autoreceptor activation. Cocaine (40 mg/kg per day) was administered to rats for 14 days either continuously by osmotic minipumps or intermittently by once-a-day injections. Minipumps containing saline were implanted in the control group. After 7 days of withdrawal, dopamine kinetics in the caudate was examined using in vitro fast-scan cyclic voltammetry. This technique provides very rapid measurements of dopamine in the extracellular space. Thus, when combined with endogenous dopamine efflux evoked by single-pulse, electrical stimulations, it was possible directly to measure the release and uptake components of the efflux. In the absence of pharmacological agents, no group differences were found in the amount of baseline dopamine released or in the uptake kinetics; the potency of bath-applied cocaine (0.03-60 microM) in inhibiting the uptake was also unaltered in either group. In contrast, the potency of quinpirole (an autoreceptor agonist, 5-250 nM) was significantly decreased and increased in the cocaine injection and pump groups, respectively. Thus, the cocaine administration regimen which produces sensitization results in a functional subsensitivity of release-modulating autoreceptors, while the tolerance-producing regimen results in autoreceptor supersensitivity.

Effects of aging on ethyl alcohol (EtOH) pharmacodynamics were examined over progressive dosing schedules (0.4, 0.6, 0.8, 1.0 g/kg) in groups of young (25.0 +/- 2.9 years), middle-aged (41.1 +/- 6.6 years), and young-elderly adults (60.9 +/- 2.6 years) using three computerized cognitive-neuromotor tasks: digit-symbol substitution (DSS), keypad reaction time (KRT), and subcritical tracking (SCT). Hysteresis curves of performance impairment (adjusted for pre-drug baseline) as a function of blood alcohol concentration (BAC) were examined for time-course effects, and regression analyses were performed to assess the contribution of age beyond that accounted for by BAC. Results reflected differences in the patterning but not magnitude of impairment for elderly subjects, with earlier decrements and more rapid acute tolerance observed for DSS, in conjunction with less pharmacodynamic sensitivity for SCT. Regression analyses furthermore indicated that age and impairment were negatively related, arguing against synergistic intoxication effects as a function of aging. Analyses specifically comparing performance at baseline versus legally intoxicating BACs (> 1.0 mg/ml) likewise reflected a lack of interactive effects involving the elderly. Elderly subjects nevertheless exhibited significantly lower baseline performance for DSS and KRT than young subjects and achieved higher BACs with equivalent doses. These latter findings support the exercise of caution by elderly individuals consuming EtOH prior to engaging in neuromotor pursuits such as driving.

This experiment examined alterations in the ability of the highly selective 5-HT3 receptor agonist, 1-(m-chlorophenyl)-biguanide (mCPBG), to induce dopamine (DA) overflow in caudate brain slices obtained from rats withdrawn from continuous or intermittent cocaine administration. Rats were pretreated with 40 mg/kg per day cocaine for 14 days by either subcutaneous injections or osmotic minipumps, and then withdrawn from this regimen for 7 days. Caudate brain slices were obtained, and perfused with artificial cerebrospinal fluid. Following an equilibration period, the slices were then perfused with 25, 50, or 100 microM mCPBG. The samples were assayed for DA content by HPLC with electrochemical detection. The results indicated that the pretreatment with intermittent cocaine did not consistently alter the ability of mCPBG to induce DA overflow, although there was a reduction in the amount of DA released by the highest concentration of mCPBG. In contrast, pretreatment with continuous cocaine administration consistently and significantly attenuated the ability of mCPBG to induce DA overflow. The DA overflow induced by mCPBG was partially dependent on extracellular Ca2+ in the perfusion medium for the saline control and intermittent administration subjects: elimination of Ca2+ from the medium significantly reduced, but did not eliminate, DA overflow for these two groups. In contrast, elimination of Ca2+ from the perfusion medium had a significant enhancing effect on mCPBG-induced DA overflow in the continuous administration rats. These results suggest that distinct temporal patterns of cocaine administration differentially alter the ability of a 5-HT3 agonist to increase extracellular DA levels, and that this effect may be related to an impairment of Ca(2+)-dependent release.(ABSTRACT TRUNCATED AT 250 WORDS)

Daily, intermittent, subcutaneous cocaine injections produce sensitization, while the continuous administration of cocaine produces tolerance to the behavioral effects of subsequent cocaine injections. The present experiments examined whether these behavioral differences are related to differences in the ability of cocaine to increase extracellular dopamine. Increases in perfusate DA, in response to different concentrations of cocaine, were measured in caudate-putamen slices obtained from rats withdrawn for 7 days from a 14-day treatment of either continuous or daily subcutaneous cocaine injections. Compared to saline controls, cocaine-induced DA efflux was increased in subjects receiving daily injections and markedly decreased in subjects receiving continuous cocaine. Thus, different temporal patterns of cocaine administration produce dramatically different alterations in DA neurotransmission. Such changes in dopamine release may be related to the withdrawal symptoms experienced by human cocaine abusers.

The differential sensitivity of young and elderly healthy adults to the impairment effects of benzodiazepines was assessed by tasks with several levels of difficulty. Using a double-blind procedure, single doses of placebo, alprazolam (0.75 and 1.5 mg) and triazolam (0.25 and 0.5 mg) were ingested orally by 10 young men, 9 young women, 7 elderly men, and 10 elderly women. Order of drug administration was determined by a random Latin square design. Different versions of the subcritical tracking and digit symbol substitution tasks were characterized by three difficulty levels. Assessments of task performance were conducted at varying intervals for 7 h after drug administration. Both drugs induced a rapid initial onset of impairment in the two age groups. Evidence of increased drug sensitivity in the elderly was provided by the more prolonged duration of the pharmacologic effect in the older than young subjects, especially for the harder versions of the SCT and DSS tasks. In summary, the data provide support for the hypothesis of an age-related decline in the adaptive capacity to inhibit adverse drug effects.

The contribution of differential absorption-distribution pharmacokinetics to drug activity can be partially determined by comparing simultaneous estimates of drug serum level with pharmacodynamic effects. In the present paper we have contrasted the effects of clinically equipotent doses of lorazepam, alprazolam, and diazepam on the performance of tracking and digit symbol substitution tasks. Eight young males were tested for 12 h after ingesting the drug. The three benzodiazepines and placebo were administered to each subject according to a balanced double-blind Latin square design. A model is presented that describes the relationship between drug concentration and the degree of impairment across time after the final peak effect. Exponential rate constants were determined for each drug using a Marquardt nonlinear fit of the pooled data. Basically, the constants relate offset serum drug values to the impairment curves at a time when serum-brain equilibrium is assumed to have occurred. The values indicate markedly rapid acute tolerance for alprazolam and diazepam but relatively little acute tolerance for lorazepam. Whether these constants reflect adaptation or differential association-dissociation receptor rate constants cannot be determined, but they do highlight the need to consider receptor kinetics as an important factor in benzodiazepine pharmacodynamics.

Acute tolerance, defined as a decreasing drug effect relative to drug-plasma levels (DPL) over a period of minutes to a few hours, is pronounced following single doses of diazepam or pentobarbital. Both of these lipid-soluble drugs produce an early peak behavioral impairment and subsequent rapid recovery component that is followed by a much slower blood-drug rise time. These pronounced early peak effects were not shared by alcohol, and contribute significantly to the lack of correlation between impairment and DPL.

Examination of the effect of three doses of pentobarbital on the comparative performance of a complex psychomotor task with two simple neuromotor tasks, i. e., standing steady and pendulum eye tracking, revealed a high correlation. These simple tasks could be used as measures of intoxication since they do not require extensive training. Examination of the complex task impairment blood level ratio revealed that impairment relative to blood level was much greater in the absorption phase. This changing ratio underscores the point that blood levels alone are not an adequate estimate of intoxication.

The use of a pharmacokinetic/pharmacodynamic/receptor binding model to predict the onset and duration of the pharmacological effect of diazepam was explored. The analysis examined the effects of diazepam (0.28 mg/kg) on the wheel-tracking and digit-symbol substitution performance of young healthy adults. Both free-plasma drug concentration and relative amount of diazepam bound to the benzodiazepine receptor were calculated and compared to the behavioral measures across time. Performance was more significant correlated with relative receptor occupancy (RRO) than with unbound plasma-drug levels. For both tasks hysteresis plots indicated greater similarity between time profiles of performance and RRO than between those of performance and blood concentration alone. These results provide support for the inclusion of both receptor binding kinetics and plasma pharmacokinetics as the bases for the prediction of the pharmacologic activity of diazepam.

Cats were trained to choose between two levels or an operant chamber using interoceptive cues provided by d-amphetamine or saline as the discriminative stimuli. Following training, stimulus generalization was observed to additional doses of d-amphetamine and cocaine. but not to morphine. Clozapine blocked the generalization of the drug discrimination response to d-amphetamine, but had no effect on generalization to cocaine. These data indicate that discriminative stimulus properties of psychomotor stimulants, previously described in rats, are similar in cats.

The augmentation of the rat stereotypy response with repeated amphetamine doses, put forward as a model of human amphetamine psychosis, was examined during concurrent reserpinization. The effects of reserpinization, amphetamine treatment, and amphetamine dose on four dependent variables representing the time course of stereotypy ratings after a post-treatment amphetamine dose, were tested by three-way MANOVA. An earlier onset of stereotypy , as occurred in nonreserpinized rats, was not detected in reserpinized rats, but an earlier offset of stereotypy with repeated amphetamine occurred in these rats when high amphetamine doses were used.

The pharmacological activity of quazepam, a BZ1 specific benzodiazepine, was compared to the effects of triazolam, a BZ1, BZ2 nonspecific benzodiazepine. Using a double-blind procedure, single oral doses of quazepam (15 or 30 mg), triazolam (0.5 or 1.0 mg) and placebo were administered to 21 healthy young men according to a random Latin square design balanced for order of drug administration. The drug effects on the performance of motor coordination and cognitive tasks were monitored for 7 h following drug ingestion. The results did not indicate any differential effects on cognitive-neuromotor performance for the BZ1 specific quazepam and 2-oxoquazepam compared with the BZ1, BZ2 nonspecific N-desalkylflurazepam metabolite. The impairment magnitude for 30 mg quazepam was closer to that of 0.5 mg triazolam. The onset of the initial drug effect was considerably slower for quazepam than for triazolam. The time course of the impairment profiles for the tasks was compared to pharmacokinetic data from previous studies and suggested that published pharmacokinetic rate constants explain only a limited portion of the impairment time course. In particular, the performance scores were already showing recovery from peak impairment 2 h post-drug ingestion, although quazepam's potent N-desalkylflurazepam metabolite has been found to maintain a maximum plateau level from 2 to 24 h.

Pharmacokinetics do not adequately reflect recovery from cognitive neuromotor impairment induced by most benzodiazepines. This paper examines across time the nature of the relationship of effect to serum concentration of three benzodiazepines. Using the same protocol lorazepam, alprazolam, diazepam and placebo were administered to eight healthy males at doses of 0.057, 0.029, 0.286 and 0.000 mg/kg, body weight, respectively for the first study and at 0.028, 0.014, 0.143 and 0.000 mg/kg, respectively, for the second study. After each dose administration multiple measurements were made over a period of 5.5-11.5 h using two different psychomotor performance tests. Serum drug concentrations were also measured. The profiles for diazepam and alprazolam effects demonstrate a stepwise decrement in the slopes of the concentration versus response curves across time, illustrating the rapid development of acute tolerance. In contrast, lorazepam induced a remarkably constant relationship between concentration and effect across testing intervals.