Measurement of drug-induced physical and behavioral delays and abnormalities in animal studies: a general framework.
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Animals↗
Biomedical subjects
S B Sparber
Publications and source records attributed to S B Sparber.
The serotonin2 antagonist ritanserin blocks quasi-morphine withdrawal at a time when mianserin is no longer effective.
A quasi-morphine withdrawal syndrome (QMWS), produced in opiate-naive rats with an injection of isobutylmethylxanthine (IBMX) and the opioid antagonist naloxone, allows one to study the expression of opiate withdrawal in the absence of the acute or chronic effects of opiates and the adaptive processes termed dependence. The allegedly selective and long-acting serotonin2 (5-HT2) antagonist ritanserin attenuated the QMWS-induced suppression of fixed ratio (FR) operant responding, which is a sensitive measure of the expression of a QMWS. When administered 30 min prior to precipitation of the QMWS, the lowest dose of ritanserin tested (0.158 mg/kg) was the most effective in blocking the expression of withdrawal; however, there was not complete reversal of the behavioral suppression. Acutely, the two higher doses of ritanserin tested (2.5 and 10 mg/kg) suppressed responding when given alone. This may have masked their ability to attenuate a QMWS. At a dose of 2.5 mg/kg, ritanserin completely blocked the QMWS-induced suppression of responding 24 h post-administration, at a time when its actions at other receptors (e.g., alpha 2) have dissipated. At an equivalent dose, the shorter-acting 5-HT2 antagonist mianserin was unable to attenuate the QMWS-induced suppression of FR operant responding 24 h post-administration. The 5-HT2 antagonists reportedly produce a paradoxical down-regulation of 5-HT2 binding sites upon chronic treatment, rather than the expected supersensitivity. Chronic treatment with ritanserin (2.5 mg/kg/day for 7 days), but not mianserin (same regimen), attenuated a QMWS 24 h after the final injection, thus supporting with a functional measure, the down-regulation of such binding sites by ritanserin.(ABSTRACT TRUNCATED AT 250 WORDS)
1-Methyl-3-isobutylxanthine↗
Delayed effects of amphetamine or phencyclidine: interaction of food deprivation, stress and dose.
Tritium-labelled phencyclidine (PCP) hydrochloride (12 mg/kg) was injected SC for six consecutive days into two groups of eight male rats maintained at 85% of their initial free-feeding weights. Eight days after the last injection, electric footshock raised fat levels of PCP 28% over nonshocked controls, and lowered blood levels 18%, but did not alter brain levels of the drug significantly. Thus, application of an acute stressor does result in redistribution of tissue stores of phencyclidine as predicted in the literature; however, the direction of the redistributions was to fat, rather than to brain. To explore the relation of a long-term stressor (one that eliminates adipose tissue as a sink for mobilized PCP), exploratory behavior was evaluated in male rats during six days of food deprivation commencing after six daily injections of PCP HCl (2 or 4 mg/kg, SC). Exploratory behavior of the 4 mg/kg dose group was abruptly altered, compared to saline controls, at six days of food deprivation, when the rats' body weights were about 70% of initial weights and when body fat would be severely reduced or depleted. To assess replicability and generalizability of this phenomenon, PCP HCl (4 or 8 mg/kg, SC) or dextroamphetamine sulfate (3.2 or 6.4 mg/kg, SC) was injected into male rats for six days and food deprivation followed afterward for nine consecutive days, or until similar body weight reductions as in the first experiment were achieved. Again, exploratory behavior was altered in comparison to saline controls in phencyclidine-treated rats (at the 4 mg/kg dose level) when rats reached about 70% of initial weights.(ABSTRACT TRUNCATED AT 250 WORDS)
Adipose Tissue↗
Food deprivation alters behavioral and plasma corticosterone responses to phencyclidine in rats.
Phencyclidine (PCP) sensitivity of rats, whose body weights were maintained at 70% of free-feeding controls, was compared to drug sensitivity of the controls in terms of unconditioned (exploratory) behavior and plasma corticosterone levels. Low doses of PCP HCl [0 (saline vehicle), 0.3 or 0.9 mg/kg, SC] were given to food-deprived rats and to free-feeding controls 15 minutes before measuring unconditioned behavior for 90 minutes; then PCP in brain and corticosterone in plasma were assayed. An additional group (0.43 mg/kg) was established from the reduced-weight rats in order to compare with free-feeding rats given 0.3 mg/kg, the same absolute dose-a circumstance reflecting "street" usage in which doses are not adjusted for body weight differences among users. These low doses of PCP altered exploratory behaviors, but there did not appear to be an interaction between food-deprivational status and drug, with the possible exception of an altered effect of PCP upon habituation in the lighter animals. PCP elevated plasma corticosterone levels over saline controls only in the reduced-weight rats. The drug, possibly reflecting a tranquilizing action of the lowest dose, reduced corticosterone levels in free-feeding controls. Brain levels of drug were directly related to dose, and were elevated in the food-deprived animals 26-30% over those at the same per-weight dose levels in the free-feeding rats, in spite of being given lower absolute amounts of drug. In the 0.43 mg/kg reduced-weight dose group, given the same absolute dose as the 0.3 mg/kg free-feeding group, brain levels were doubled over the latter group, and exploratory behavior was correspondingly different from the free-feeding group.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Hyperthermia sensitizes rats to cocaine's proconvulsive effects and unmasks EEG evidence of kindling after chronic cocaine.
In phase I, 64 male and female Sprague-Dawley rat siblings from 8 litters were divided equally among 4 treatment groups; saline plus normothermia (S37), saline plus hyperthermia (S45), cocaine (30 mg/kg) plus normothermia (C37), and cocaine plus hyperthermia (C45) and treated daily from 45-60 days of age. Cocaine plus hyperthermia produced protracted, intense and often fatal convulsions, whereas animals from either treatment alone did not convulse. Subsequently, 12 males, representing all phase I treatment groups equally, were implanted with telemetric transmitters to monitor the EEG and core body temperature in phase II. Survivors of this second phase were exposed to one trial each of saline plus hyperthermia, cocaine plus normothermia, and cocaine plus hyperthermia, in that order. The data obtained suggests that 1) the telemetered EEG and temperature can be used to detect changes reflecting sensitization/kindling in the absence of behavioral expression (convulsions), 2) analysis of EEG power spectral bands and body temperature curves showed that a history of daily cocaine exposure seems to have contributed more than daily hyperthermia to subsequently observed seizure patterns and thermic responses, and, finally, 3) cocaine plus hyperthermia resulted in a shorter latency to convulse and a lower maximal EEG seizure voltage, while increasing the variety, severity and duration of its behavioral expression (convulsion).
Animals↗
Modification of quasi-morphine withdrawal with serotonin agonists and antagonists: evidence for a role of serotonin in the expression of opiate withdrawal.
Methylxanthines produce a quasi-morphine withdrawal syndrome (QMWS) in opiate naive rats. Additionally, methylxanthine-induced suppression of conditioned behavior in rats is reversed by the alpha 2 adrenergic agonist clonidine which also attenuates true opiate withdrawal and the QMWS. Therefore, the operant behavioral effects of 3-isobutyl-1-methylxanthine (IBMX) provide a model with which to study mechanisms involved in the expression of opiate withdrawal. In order to examine the role of serotonin (5-HT) in the rate-decreasing effects of IBMX on operant behavior, the 5-HT precursor 5-hydroxytryptophan, and 5-HT reuptake blocker fluoxetine were administered in combination with IBMX to rats performing a fixed-ratio 30 operant for food reinforcement. Both drugs failed to reverse the behavioral suppression caused by relatively low doses of IBMX, suggesting that elevated 5-HT neurotransmission contributes to, rather than attenuates, the QMWS. The relatively selective 5-HT2 antagonists mianserin and pirenperone blocked the IBMX-induced suppression, whereas the classic 5-HT antagonist methysergide had no effect. The results indicate that the operant behavioral effects of IBMX and possibly the QMWS may be mediated by serotonergic mechanisms.
1-Methyl-3-isobutylxanthine↗
Evidence of single dose opioid dependence in 12- to 14-day-old chicken embryos.
We have previously reported that chicken embryos injected with a single dose of methadone (Meth) on day 3, 7 or 11 of embryogenesis fail to show dependence on day 14, measured as a significant overshoot in motility above baseline after challenge with the opioid antagonist naloxone (Nx). Constant infusion of Meth from day 7 to 14 also failed to produce evidence of dependence on day 14. To address the question of whether the 14-day-old embryo is capable of expressing withdrawal, isobutylmethylxanthine (IBMX), a compound that produces quasi-opioid withdrawal, was injected directly into the embryo, resulting in a significant increase in motility. To determine whether the 14-day-old embryo could also express true opioid withdrawal, the embryos were injected with various doses of Meth or morphine (Morph), followed at different time intervals by injections of varying doses of Nx. A high dose of Morph followed 24 hours later by a low dose of Nx produced evidence of withdrawal, as did a low dose of Meth followed 1 hour later by a higher dose of Nx, U50488H, a selective kappa agonist, had no effect on motility in the 14-day-old embryo, suggesting that the decrease in motility seen after Meth was not mediated by a kappa receptor. Pretreatment with the irreversible mu antagonist, beta-funaltrexamine (B-FNA), blocked the decrease in motility seen after Meth and also prevented the overshoot in motility when Nx was given 1 hour post-Meth. We were also able to demonstrate dependence/withdrawal in the 12-day-old embryo, but higher doses of both Meth and Nx were required.(ABSTRACT TRUNCATED AT 250 WORDS)
1-Methyl-3-isobutylxanthine↗
Naloxone administration impairs autoshaped learning.
Effects of naloxone on acquisition of autoshaped behavior were investigated. Rats deprived to 85% of free-feeding weights were trained to touch a retractable lever; delivery of a food pellet occurred on every trial following lever retraction. The lever was retracted immediately if a touch occurred within 15 s, or automatically after 15 s. Analyses were conducted on number and latencies of touches of the extended lever, nose-pokes (touches) directed at the retracted lever during intertrial intervals (a measure less constrained by ceiling effects than extended lever touches), and unconditioned exploratory rearing activity, measured as touches of a metal strip mounted above the grid floor of the apparatus. In an initial experiment, male Sprague-Dawley rats were given saline or naloxone (2.0 mg/kg, ip) 5 min before a training session of 12 trials. Two days later they were tested, in the absence of drug, in a session of 36 (three blocks of 12) trials. Naloxone depressed training levels of lever responding, in addition to slowing acquisition rate. No effect of naloxone was observed on rearing activity. Previous work showed that injection of saline 5 min before behavioral testing increases the rate of autoshaping compared to injections 30 min before (Messing & Sparber, 1984). Thus, effects of naloxone on acquisition of lever-directed behaviors may have been confounded by behavioral depressant effects and/or by an injection effect such a short time before testing. In a second experiment naloxone (0.5 or 2.0 mg/kg) was injected after five of seven training sessions (12 trials each) to male and female rats. A 6-s delay of reinforcement was inserted between lever retraction and food delivery, slowing acquisition rates and providing the opportunity to test the effects of naloxone throughout a multiple-session task. The low dose retarded acquisition of extended lever touching in both sexes; both doses retarded acquisition of interim lever touching in males. Thus, in some circumstances, post-training naloxone administration may impair learning. The results support the notion that low doses of naloxone may have agonist activity.
Animals↗
Morphine blocks and naloxone enhances suppression of operant behavior by low doses of 3-isobutyl-1-methylxanthine.
Methylxanthines administered in high doses or in combination with the opiate antagonist naloxone produce symptoms resembling opiate withdrawal. Administration of isobutyl-1-methylxanthine (IBMX, 1.25-5.00 mg/kg) to rats which were performing a fixed-ratio 30 operant for food reinforcement caused a dose-dependent suppression of responding and a decrease in colonic temperature. Administration of behaviorally inactive doses of the opiate antagonist naloxone (1.25-5.00 mg/kg) 10 min after the beginning of the fixed-ratio 30 session significantly increased the behavioral effects of IBMX (1.25-5.00 mg/kg) injected 30 min before the session, with no consistent effect upon IBMX-induced hypothermia. The coadministration of behaviorally inactive doses of morphine (0.05-1.50 mg/kg) with IBMX (5.00 mg/kg) 30 min before the fixed-ratio 30 session antagonized the operant behavioral effects of IBMX. These results suggest that the operant behavioral effects of IBMX provide a model with which to examine the expression of opiate withdrawal without the confounding changes associated with the acute pharmacological actions of opiates.
1-Methyl-3-isobutylxanthine↗
Parallel changes in operant behavioral adaptation and hippocampal corticosterone binding in rats treated with trimethyltin.
Rats were given water vehicle or trimethyltin (TMT; 3.0, 6.0 or 7.5 mg/kg, p.o.). Lever responding for food was measured 3 months later, in a test in which the fixed ratio requirement was doubled daily (FR1-128). Response rates for all groups were inverted U-shaped functions of FR values. However, the effect of increasing ratio values was attenuated in the 6.0 mg/kg group, which responded less than controls when control rates were maximal (at FR16 and FR32). In contrast, rats given the high dose responded at higher rates (at FR4 and FR64). [3H]Corticosterone binding to hippocampal cytosolic protein was maximally reduced for the group given 6.0 mg TMT/kg. The greatest reduction in hippocampal weight resulted from injection of 7.5 mg TMT/kg, but a smaller reduction in [3H]corticosterone binding (i.e. 22%) was observed for this group. In the absence of an effect of 3.0 mg TMT/kg upon weight of hippocampus, there also was a reduction in steroid binding, indicating the sensitivity of this parameter for TMT toxicity. The results support the notion that hippocampal corticosteroid receptors are important for behavioral adaptation, and rats given moderate doses of TMT may be useful for studying functions of corticosterone receptors.
Animals↗
Reversal of a trimethyltin-induced learning deficit by desglycinamide-8-arginine vasopressin.
Trimethyltin (TMT) is an organometal neurotoxin which produces lesions primarily in the limbic system. Selectivity seems to depend upon the dose, but the hippocampus and related entorhinal cortical structures, of importance for learning and memory, are most often described as target sites. We have previously demonstrated that subjects treated with a moderate dose of TMT prior to acquisition sessions, are unable to learn a forward autoshaping task with a 6 sec delay of reinforcement, but are capable of acquiring the same task when no delay of reinforcement is used. These data suggested that the performance deficit is one of learning (i.e. consolidation) rather than of memory (i.e. storage), retrieval, or sensorimotor impairment. To more rigorously test this hypothesis, we determined if performance of a task already learned would be impaired by the neurotoxin. Adult male Long Evans rats were given 10 acquisition sessions of 24 trials, following which TMT (6.0 mg/kg, p.o.) was administered. One month later, these rats performed the lever-touching behavior as well as controls, despite the fact that the same dose of TMT interfered with learning if given one month prior to acquisition sessions, thus confirming our hypothesis. In a second experiment we determined if the peptide analog of vasopressin, desglycinamide-8-arginine vasopressin (DGAVP), could reverse a learning deficit in a population of non-learners. Rats were treated with TMT or water vehicle one month prior to autoshaping. TMT significantly retarded acquisition. After 10 sessions of 12 trials each, non-learners (i.e. rats treated with TMT that failed to associate the lever with delivery of a reinforcer) were administered saline or DGAVP (7.5 micrograms/kg, s.c.) 1 hr before sessions 11-13; treatment was discontinued prior to sessions 14 and 15. Peptide treated subjects showed evidence of acquisition and exhibited higher levels of lever-directed behavior than saline treated nonlearners. Performance was maintained after DGAVP treatment was discontinued, indicating that the learning-enhancing action of DGAVP was not transient or state-dependent.
Animals↗
Evidence for antiserotonergic properties of yohimbine.
Yohimbine (YOH) is a widely used pharmacological tool employed to produce a selective blockade of alpha 2-adrenergic receptors. In the present study operant behavior was used as a biobehavioral assay to determine the activity of YOH at serotonergic receptors, as indicated by its ability to antagonize the behavioral effects of a serotonergic agonist, lysergic acid diethylamide (LSD). Rats were trained to respond on a Fixed Ratio 15 schedule for food reinforcement. YOH (0.5-5.0 mg/kg) or vehicle and LSD (50 micrograms/kg) were administered (IP) 30 min and immediately prior, respectively, to the 30-min operant session. In a separate study, the ability of YOH (0.5-2.5 mg/kg) to antagonize a higher dose of LSD (100 micrograms/kg) was examined. Relatively low doses of YOH (0.5-1.0 mg/kg) were able to partially, but significantly antagonize the LSD-induced suppression and typical hallucinogen-induced disruption of schedule-controlled responding. These results suggest that YOH, even at moderate doses, may act nonselectively as an antagonist at 5-HT receptors, in addition to its antagonist action at alpha 2-adrenergic receptors. This study demonstrates the utility of operant behavior as a biobehavioral assay to study the receptor mediated action of drugs.
Animals↗
Metabolism of methadone by chicken embryos prevents induction of chronic opioid-type dependence after a single injection: use of osmotic pumps for continuous infusion.
Unlike N-desmethyl-1-alpha-acetylmethadol (NLAAM), a single injection of methadone (METH), near domestic chicken embryos early during development, cannot induce and sustain opioid-type dependence in the older embryo (i.e., days 14-17 of development). Injection of [3H]-METH near the 14-day-old embryo, followed by differential extraction, indicated that significant quantities of unmetabolized METH gained entrance to the brain, peaking at about 1 hr and declining with a half-life of about 2.8 hr. Thus, it is probably not practical to use a single injection of this shorter-acting opioid for studying biobehavioral effects of sustained dependence and withdrawal during development in this species. Chronic infusion of METH for 7 days via an externalized Alza osmotic mini-pump resulted in significant, dose-dependent brain concentrations of [3H]-METH on day 14. Even though the opioid antagonist naloxone (Nx) was unable to induce withdrawal, manifest as a significant increase in embryonic motility above that of controls, it partially reversed the depressed motility caused by the chronic infusion of [3H]-METH. Since 7-day-old embryos exposed to NLAAM, at doses which can be demonstrated to produce dependence by precipitating withdrawal on day 17 of development, were also unable to express withdrawal on day 14, it is possible that either 14-day-old chicken embryos cannot yet fully respond with an adaptive process (i.e., dependence) or its expression (i.e., withdrawal).
Animals↗
Different methods for producing neonatal undernutrition in rats cause different brain changes in the face of equivalent somatic growth parameters.
Similar degrees of undernutrition were induced in neonatal rat pups using a modified Slob technique and a large-litter manipulation. From birth, large litters and Slob litters were comprised of 20 and 10 pups, respectively. On days 2, 4 and 6, half of the pups in the Slob group were cross-fostered to nonlactating foster aunts, while the remaining half of each litter (controls), as well as the large-litter rats were cross-fostered to a lactating dam. On day 10, undernourished Slob and large-litter pups showed similar body weight and body length deficits compared with controls, but differences between the two undernourished groups emerged when regional brain weight and nucleic acids and proteins were examined. The acute intermittent undernutrition of the modified Slob technique had more severe consequences than the large-litter manipulation for brain growth and development. Therefore, two methods of inducing early postnatal undernutrition may yield equivalent somatic effects, but very different brain growth parameters.
Animals↗
Dose-specific effects of trimethyltin poisoning on learning and hippocampal corticosterone binding.
The organometal neurotoxin trimethyltin (TMT) damages limbic forebrain, and impairs acquisition of lever-directed behaviors in an autoshaping task, in which a lever is presented according to a random time schedule, and rats learn to associate its presentation/retraction with food delivery (Cohen et al., 1987). This impairment is evident only if a sufficiently long delay of reinforcement is interposed between lever retraction (which occurs either automatically after 15 sec, or immediately upon a touch response) and food pellet delivery. Paradoxically, rats given a higher (7.5 mg/kg) dose show a smaller acquisition impairment, perhaps because they are generally more reactive to the lever than controls. These rats sustain a larger hippocampal lesion (measured by wet weight of the structure). The experiment reported here was done to investigate (1) an autoshaping deficit related to hippocampal weight loss, and (2) biochemical changes in hippocampus which might be related to behavioral impairments. Rats were treated with water vehicle or TMT four weeks before autoshaping using a 6 sec reinforcement delay. In addition to lever touching, touches of the food trough were measured. The timing of trough-touching behaviors within a trial was used as an indication of the strength of the association formed between the lever and the site of food delivery. Following autoshaping rats were adrenalectomized and killed for measurement of cytosolic [3H]corticosterone binding in hippocampus. As before, rats treated with 6.0 mg TMT/kg showed a deficit in acquisition of lever-directed behaviors. Also, as hypothesized, the proportion of total trough-directed behaviors made during the 6 sec reinforcement delay intervals (when reinforcement probability was high) diverged significantly from control values as learning progressed. These rats also showed a reduction in hippocampal weight compared with controls, but significant decreases in hippocampal steroid binding were observed only in groups given the low and median dose of TMT. Further, steroid binding was correlated with lever-directed behaviors. It thus appears that lever and trough behaviors can be used to simultaneously assess different aspects of impairment in associative learning which are accompanied by differential cell loss and biochemical deficit.
Animals↗
Learning enhancement and behavioral arousal induced by yohimbine.
Learning of a food motivated delayed reinforcement autoshaping task was investigated in rats treated with water vehicle or the prototypical anxiogenic agent and alpha 2-adrenergic antagonist yohimbine (0.5 or 1.5 mg/kg, i.p. 30 min before behavioral testing). Unconditioned exploratory rearing activity was monitored concomitantly with acquisition of a lever touch response. The low dose of yohimbine enhanced learning, but it also increased unconditioned behavioral arousal. The high dose retarded acquisition, but when it was withdrawn the animals learned but exploratory activity increased beyond control levels prior to acquisition. Learning thus appeared to be related to the behavioral arousal produced by yohimbine, suggesting that learning enhancement by anxiogenic substances is not due to a direct effect on processes intrinsic to information storage and retrieval; rather, anxiogenic substances may be important modulators of vigilance and performance variables.
Animals↗
Selective learning impairment of delayed reinforcement autoshaped behavior caused by low doses of trimethyltin.
The organometal neurotoxin trimethyltin (TMT), induces impaired learning and memory for various tasks. However, administration is also associated with other "non-specific" behavioral changes which may be responsible for effects on conditioned behaviors. To determine if TMT treatment causes a specific learning impairment, three experiments were done using variations of a delay of reinforcement autoshaping task in which rats learn to associate the presentation and retraction of a lever with the delivery of a food pellet reinforcer. No significant effects of TMT treatment were found with a short (4 s) delay of reinforcement, indicating that rats were motivated and had the sensorimotor capacity for learning. When the delay was increased to 6 s, 3.0 or 6.0 mg TMT/kg produced dose-related reductions in behaviors directed towards the lever. Performance of a group given 7.5 mg TMT/kg, while still impaired relative to controls, appeared to be better than the performance of groups given lower doses. This paradoxical effect was investigated with a latent inhibition paradigm, in which rats were pre-exposed to the Skinner boxes for several sessions without delivery of food reinforcement. Control rats showed retardation of autoshaping when food reinforcement was subsequently introduced. Rats given 7.5 mg TMT/kg exhibited elevated levels of lever responding during pre-exposure and autoshaping sessions. The results indicate that 7.5 mg TMT/kg produces learning impairments which are confounded by hyperreactivity to the environment and an inability to suppress behavior toward irrelevant stimuli. In contrast, low doses of TMT cause learning impairments which are not confounded by hyperreactivity, and may prove to be useful models for studying specific associational dysfunctions.
Animals↗
Attenuation of isobutylmethylxanthine-induced suppression of operant behavior by pretreatment of rats with clonidine.
Administration of 3-isobutyl-1-methylxanthine (IBMX) to rats performing a FR30 operant for food reinforcement produces a dose-dependent suppression of behavior. Operant behavior suppressed by 5 mg IBMX/kg is attenuated by pretreatment, 30 min before the operant session, with the alpha 2 adrenergic agonist clonidine (5-30 micrograms/kg). Clonidine itself causes a dose-dependent reduction in FR30 responding prior to the administration of IBMX. However, doses of clonidine which also suppressed responding were not more effective than lower doses in attenuating the suppression of operant behavior caused by IBMX, perhaps due to postsynaptic or nonspecific actions of clonidine. Methylxanthines, alone or in combination with the opiate antagonist naloxone, produce signs of opiate withdrawal. This quasi-morphine withdrawal syndrome may be useful in studies of either the development or expression of opiate withdrawal. Since clonidine attenuates the rate-suppressant effect of IBMX, it is likely that a significant component of IBMX's behavioral effects are due to increases in NE neurotransmission. These results are similar to those obtained with true opiate withdrawal in rats, strengthening the idea that suppression of operant behavior by IBMX involves mechanisms in common with opiate withdrawal. It may be a useful way of objectively studying the expression of the withdrawal syndrome in the absence of opiates and/or a way of determining if a drug can selectively block withdrawal.
1-Methyl-3-isobutylxanthine↗