Amphetamine-induced withdrawal responding: effects of repeated drug administration

 The first purpose of this research was to assess withdrawal haloperidol-appropriate lever responding 24 h after a single administration of 0.35, 0.75, and 1.00 mg/kg amphetamine. Rats were trained to discriminate among 0.35 mg/kg amphetamine (AM), distilled water (DW), and 0.033 mg/kg haloperidol (HA) in a three-lever drug discrimination task. An increase in HA-appropriate lever responding occurred following the 1.00 mg/kg dose of AM but not after either of the lower doses. The second purpose was to determine the effect of repeated administration of 0.75 mg/kg AM. Two groups of animals were given five administrations of drug, one at an interdose interval (IDI) of 24 h and the other at an IDI of 48 h. Control animals were given injections of DW. Increased HA-appropriate lever responding occurred in both of the AM-treated groups. The magnitude of this effect tended to be less in the 48-h IDI group. Thus, even though HA-lever responding was not evident 24 h after a single administration of 0.75 mg/kg AM, it was produced by repeated administration of this dose, even at 48-h intervals. Received: 7 November 1996 / Final version: 25 April 1997     

Long-lasting rebound cue effects following single doses of nicotine and amphetamine: implications for understanding tolerance

RATIONALE: Previous drug-discrimination studies have, with the exception of nicotine (NIC), demonstrated tolerance to the cue effects of a broad range of drugs of abuse. Barrett et al. have shown that tolerance to a drug's cue properties reflects drug-induced rebound shifts in the discrimination baseline and not a weakened or less salient cue. OBJECTIVES: The objective of the present study was to use a discrimination task sensitive to bidirectional cue changes to characterize the interoceptive cues associated with both the primary and rebound cues produced by nicotine in an attempt to understand why a recent study by Shoaib et al. failed to observe tolerance to the nicotine cue. METHODS: Since dopamine (DA) has been implicated in mediating the NIC cue, rats were trained to discriminate between 0.25 mg/kg amphetamine (AMPH), an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) following acquisition. This procedure provided a behavioral baseline to assess NIC-related changes along a presumed continuum of DA-mediated cues. Following acquisition of the discrimination: (i) NIC substitution tests were conducted, (ii) rats were tested for lever choice at intervals from 2 h to 48 h following treatment with single doses of 0.25 mg/kg and 0.50 mg/kg NIC, and (iii) rats were challenged with test doses of NIC during a period of NIC rebound. RESULTS: (i) NIC substituted for AMPH in a dose- dependent manner. (ii) At short intervals after treatment with 0.25 mg/kg and 0.50 mg/kg NIC, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16-24 h post-treatment, before returning to predrug levels. (iii) No evidence was observed for acute tolerance to NIC. CONCLUSIONS: The robust and long-lasting rebound cues associated with training level doses of NIC suggest that maximal tolerance would likely develop to the NIC cue during the acquisition phase of the conventional NIC-saline discrimination study.     

Time dependent pentylenetetrazol-like cues subsequent to diazepam administration

Seventy male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 schedule of reinforcement on the basis of whether they were injected subcutaneously with 0.75 mg/kg diazepam or 10.0 mg/kg pentylenetetrazol. Following discrimination acquisition, a dose-response function was generated for each drug during 5-min extinction periods. Subjects were then assigned to one of seven groups on the basis of their per cent responding during saline testing. Each group was injected with 5 mg/kg diazepam and then given a 5-min extinction test at intervals of 2, 4, 6, 8, 12, 16, 20, or 24 h subsequent to injection. The results indicated that at the shorter time intervals the animals responded on the diazepam lever. However, as the time interval between injection and testing lengthened, responding on the PTZ bar gradually increased until by 12 h following injection with diazepam the animals were responding as though they had received an injection of 5 mg/kg PTZ. Following this period of rebound, choice behavior returned to baseline by 24 h post-injection.     

Discriminative stimulus properties of the atypical antipsychotic clozapine and the typical antipsychotic chlorpromazine in a three-choice drug discrimination procedure in rats

Rationale The atypical antipsychotic drug (APD) clozapine elicits a robust discriminative cue that is generally selective for other atypical APDS in two-choice drug discrimination (DD) procedures.Objectives The present study determined whether a three-choice DD procedure with the atypical APD clozapine (CLZ) versus the typical APD chlorpromazine (CPZ) versus vehicle (VEH) could provide greater selectivity between atypical and typical APDs.Methods Sprague-Dawley rats were trained to discriminate 5.0 mg/kg CLZ from 1.0 mg/kg CPZ from VEH in a three-lever DD task with an FR30 food reinforcement schedule.Results Generalization testing with CLZ produced CPZ-appropriate responding at lower doses (ED₅₀=0.103 mg/kg) and CLZ-appropriate responding at higher doses (ED₅₀=1.69 mg/kg). Generalization testing with the atypical APD olanzapine produced similar results. In contrast, the atypical APD risperidone and the typical APDs CPZ and haloperidol produced only CPZ-appropriate responding. The muscarinic antagonist scopolamine produced CPZ-appropriate responding at lower doses and CLZ-appropriate responding at higher doses in a manner similar to CLZ and olanzapine. The co-administration of haloperidol (0.00625 mg/kg) with scopolamine shifted the dose–response curve for CLZ-appropriate responding to the left. The 5-HT_2A/2C antagonist ritanserin and the H₁ histamine antagonist pyrilamine did not substitute for either CLZ or CPZ. The ₁ adrenergic antagonist prazosin did not substitute for CLZ, but produced full substitution for CPZ.Conclusions The three-choice DD procedure clearly distinguished the atypical APDs CLZ and olanzapine from the typical APDs CPZ and haloperidol; however, the stimulus properties of the atypical APD risperidone were similar to CPZ, but not to CLZ. These findings further suggest that CLZ, as well as CPZ, elicits a compound cue.     

3H]nitrendipine labelling of the Ca2+ channel in skeletal muscle

Rats were trained to respond on one of two levers for food (drug lever) after injections of either 0.04 mg/kg fentanyl or 10 mg/kg cocaine HCI, and to respond on the saline lever after saline injections. The acquisition data indicate that this OR discrimination is feasable in the rat, though it developed slowly due to a bias of responding on the drug lever. The generalization data obtained here suggest that the OR discrimination method may establish relations between the cuing properties of drugs which are not apparent with the commonly used drug-saline method of drug discrimination.     

Effects of training dose and two- versus three-choice testing procedure on nicotine discrimination responding in humans

Rationale: Discrimination of a drug’s interoceptive stimulus effects often depends substantially on training and testing conditions. Objectives: We examined changes in nicotine discrimination behavior in humans as a function of lowering the training dose and of varying the discrimination testing procedure. Methods: Smokers and never-smokers (n=10 each) were initially trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) and tested on generalization of discrimination responding across a range of doses from 0 to 20 μg/kg. Each subsequently learned to reliably discriminate progressively smaller doses of nicotine from placebo until his or her threshold dose for discrimination was identified (mean=2.7 μg/kg). A repeat testing of generalization responding across 0–20 μg/kg was then conducted, using placebo and the subject’s threshold dose as training doses. Generalization testing involved both two-choice and three-choice (novel response option) quantitative procedures. Results: A significant shift to the left was seen in nicotine-appropriate responding in the two-choice procedure when the nicotine training dose was lowered (i.e. from the first to the second test of generalization). In the three-choice procedure, however, there was no such leftward shift. Instead, in never-smokers, a flattening of nicotine-appropriate responding occurred with a lowering of the training dose, while novel-appropriate responding significantly increased. The subjective effects of ”head rush” and, in never-smokers only, ”jittery” also showed a shift to the left in their relationship with nicotine generalization dose when the training dose was lowered. Conclusions: These results confirm the importance of training and testing conditions on discrimination behavior and subjective drug responses within subjects and demonstrate the utility of the novel-response, three-choice procedure for assessing qualitatively different stimulus effects of novel drug doses. Received: 21 December 1998 / Final version: 11 March 1999     

Generalization testing with atypical and typical antipsychotic drugs in rats trained to discriminate 5.0 mg/kg clozapine from vehicle in a two‐choice drug discrimination task

Clozapine (CLZ) drug discrimination is used as a preclinical model to evaluate compounds for putative atypical antipsychotic properties. In rats, a 1.25 mg/kg CLZ training dose appears to have greater pharmacological specificity for atypical antipsychotic drugs than the traditional 5.0 mg/kg CLZ training dose; however, methodological differences among studies have precluded a direct comparison between these training doses. In the present study, rats were trained to discriminate a 5.0 mg/kg CLZ dose from vehicle in a two‐choice drug discrimination task using methods similar to those in a previous study from our laboratory that used a 1.25 mg/kg CLZ training dose. Clozapine produced full substitution (≥80% CLZ‐lever responding) for itself at the training dose (5.0 mg/kg). The atypical antipsychotics olanzapine, quetiapine, and ziprasidone also produced full substitution for 5.0 mg/kg CLZ, whereas the atypical antipsychotics risperidone and sertindole produced partial substitution (≥60% CLZ‐lever responding). The typical antipsychotic, thioridazine, produced full substitution for the 5.0 mg/kg CLZ training dose, but the typical antipsychotics chlorpromazine, fluphenazine, and haloperidol failed to substitute for clozapine. In a subgroup of 1.25 mg/kg CLZ‐trained rats, ziprasidone produced strong partial substitution (73.0 % CLZ‐lever responding) for the 1.25 mg/kg CLZ training dose. Based on these findings, some atypical antipsychotic drugs (i.e., quetiapine and ziprasidone) produce full substitution only for the 5.0 mg/kg CLZ training dose, whereas other atypical antipsychotic drugs (i.e., sertindole and risperidone) produce full substitution only for the 1.25 mg/kg CLZ training dose. Thus, both of these training doses are important for the screening of putative atypical antipsychotic drugs with the clozapine drug discrimination assay. Drug Dev. Res. 64:55–65, 2005. © 2005 Wiley‐Liss, Inc.     

Rats can learn simultaneous four-drug discriminations in four-lever boxes

Rats were required to learn a four-drug discrimination in compartments containing four levers. The training drugs were phenobarbital 35 mg/kg, nicotine 0.8 mg/kg, fentanyl 0.04 mg/kg, and methylphenidate 5 mg/kg. Responding on a different lever was reinforced with 0.1 ml sweetened water under each drug condition. The experiment tested whether such four-drug discriminations could be learned, and whether the rate of acquisition and/or asymptotic accuracy of the discriminations would be increased in boxes where each lever was surrounded by a unique sensory environment created by special materials on the floors, walls, and ceiling in the vicinity of the lever (e.g., plastics, wire screens). Four different training compartments were employed. The required discriminations were learned by most rats. The use of unique decorations around each lever decreased the mean number of sessions before the appearance of discriminative control from 90 to 67. It also made asymptotic accuracy significantly higher in some sensory environments than in others. suggesting that animals “preferred” some environments. The training drugs were apparently not equally discriminable at the doses employed, as both sessions to criterion and asymptotic accuracy differed for the various drugs employed.     

Generalization to atypical antipsychotic drugs depends on training dose in rats trained to discriminate 1.25 mg/kg clozapine versus 5.0 mg/kg clozapine versus vehicle in a three-choice drug discrimination task

The prototypical atypical antipsychotic drug (APD) clozapine (CLZ) elicits a discriminative cue that appears to be similar to the stimulus properties elicited by atypical, but not typical, antipsychotic drugs in two-choice drug discrimination procedures. However, the ability of CLZ to generalize to atypical APDs depends on the training dose, since several atypical APDs (e.g. sertindole, risperidone) do not substitute for a 5.0 mg/kg CLZ training dose in rats, but do so for a 1.25 mg/kg CLZ training dose. Yet, a 1.25 mg/kg CLZ discriminative stimulus has not generalized to all atypical APDs either (e.g. quetiapine); thus, both 1.25 mg/kg and 5.0 mg/kg CLZ discriminative stimuli may be necessary to provide a better screen for atypical APDs. The present study sought to determine whether a three-choice 1.25 mg/kg CLZ versus 5.0 mg/kg CLZ versus vehicle drug discrimination task in rats might better distinguish atypical from typical APDs. Adult male Sprague-Dawley rats were trained in this three-choice drug discrimination task with a fixed ratio 30 reinforcement schedule for food. Clozapine produced full substitution (>or=80% condition-appropriate responding) for both the 1.25 mg/kg CLZ dose (ED50=0.09 mg/kg) and the 5.0 mg/kg CLZ dose (ED50=2.71 mg/kg). The atypical APD olanzapine produced full substitution for the 5.0 mg/kg CLZ dose, but not for the 1.25 mg/kg CLZ dose (ED50=1.55 mg/kg). In contrast, the atypical APD quetiapine produced full substitution for the 1.25 mg/kg CLZ dose (ED50=0.13 mg/kg), but not for the 5.0 mg/kg CLZ dose. Similarly, the atypical APD sertindole produced full substitution for only the 1.25 mg/kg CLZ dose (ED50=0.94 mg/kg). Risperidone, another atypical APD, produced partial substitution (>or=60% and 相似文献   

Schedule-dependent effects of haloperidol and amphetamine: multiple-schedule task shows within-subject effects

A two-lever, multiple-schedule task was used to evaluate the effects of haloperidol (HA) and amphetamine (AM) on responding controlled by continuous reinforcement (CRF) and progressive ratio (PR) schedules of reinforcement. Rats were trained to press one lever for food delivered on a CRF schedule and the other lever for food delivered on a PR schedule. The operative schedule was signaled by the illumination of a cuelight mounted above the appropriate lever. Following 30 sessions of training, dose-response functions were determined for HA (0.0075, 0.015, 0.03, and 0.06 mg/kg) and AM (0.0625, 0.125, 0.25, 0.50, 0.75, and 1.00 mg/kg). Both drugs produced dose- and schedule-dependent effects. For example, administration of 0.03 mg/kg HA did not affect responding under the CRF schedule but did reduce responding during PR components, whereas administration of 0.06 mg/kg reduced responding under both schedules of reinforcement. Some doses of AM produced increased responding under the CRF schedule and, within the same session, decreased responding under the PR schedule. The results with HA are consistent with the view that interfering with dopaminergic function affects the allocation and maintenance of responding and that this effect depends on properties of the schedule of reinforcement. The results with AM emphasize that statements about the effects of the drug on positively reinforced behavior cannot be made without reference to specific schedules of reinforcement.     

Differentiation between the stimulus effects of (+)-lysergic acid diethylamide and lisuride using a three-choice,drug discrimination procedure

The discriminative stimulus properties of (+)-lysergic acid diethylamide (LSD) and lisuride hydrogen maleate (LHM), were compared in a three-choice, water reinforced (FR 20) situation in which rats were required to press one lever following LSD (0.08 mg/kg), a second lever following LHM (0.04 mg/kg), and a third lever following saline. Reliable drug-appropriate responding was established in 72 sessions. Dose-response tests with LSD and LHM indicated that, as dose increased, the per cent of responding on the lever associated with the particular training drug also increased; little or no cross-transfer occurred between LSD and LHM. In generalization tests, the serotonin (5-HT) agonist quipazine substituted for LSD but not LHM while the dopamine (DA) agonist apomorphine mimicked LHM but not LSD; an unrelated compound, pentylenetetrazol (PTZ), produced responding on the saline-appropriate lever. In combination tests, 5-HT antagonists (e.g., BC-105 and low doses of pirenperone) blocked responding on the LSD lever while DA antagonists (e.g., haloperidol and much higher doses of pirenperone) blocked LHM-appropriate responding. These data suggest that the three-lever (D-D-N) procedure is similar to, but can be more sensitive than the two-lever (D-N) procedure (because it can differentiate between LSD and LHM); they therefore at least partially support the hypothesis that three-choice discriminations can be conceptualized as two separate, two-choice (D-N) discriminations (Jarbe and Swedberg 1982). The results also confirm suggestion that the stimulus effects of LSD and LHM are mediated by different mechanisms; the primary action of LSD is serotonergic (5-HT₂), while that of LHM is dopaminergic (White 1986).Some of these data were presented at the meeting of the Society of Neuroscience, Toronto, 1988 (Satellite Session of the Society for the Stimulus Properties of Drugs). They were also submitted (in somewhat different form) to the Graduate School of the University of South Carolina in partial fulfillment of the requirements for an MA degree (in Experimental Psychology)     

Preliminary analysis of the discriminative stimuli induced by the calcium channel “agonist” BAY K 8644

Rats were trained in a drug discrimination paradigm to press one of two levers for food reward after injection of the racemic dihydropyridine (DHP) Ca²⁺ -channel activator BAY K 8644 (2.5 mg/kg) and to press the other after vehicle injection. The discrimination was reliably attained in an average of 48 sessions. Thereafter, tests with various doses of BAY K 8544 yielded a dose-dependent selection of the BAY K 8644 lever, with an ED₅₀ of 0.74 mg/kg. The (?)-enantiomer of BAY K 8644 generalized dose-dependently (ED₅₀ = 1.04 mg/kg), while the (+)-enantiomer showed no generalization up to 10 mg/kg. Furthermore, nifedipine pretreatment fully antagonized the BAY K 8644 stimulus. These data indicate that BAY K 8644 produces physiological effects that can readily serve as discriminative stimuli in rats. The results also support the mediation of the BAY K 8644 stimulus through agonistic interaction with the calcium channel DHP receptor.     

Role of D1 and D2 dopamine receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine in rats

The purpose of the present study was to assess the role of dopamine D₁ and D₂ receptors in the discriminative stimulus properties of the atypical antipsychotic clozapine (CLZ). Two groups of rats were trained to discriminate either a moderate dose of clozapine (5.0 mg/kg) from vehicle or a high dose of clozapine (10.0 mg/kg) from vehicle in a two‐lever drug discrimination paradigm. Generalization testing with clozapine yielded an ED₅₀ of 0.9 mg/kg (95% confidence limits = 0.5–2.0 mg/kg) for the 5.0 CLZ group and 2.0 mg/kg (95% confidence limits = 1.4–2.8 mg/kg) for the 10.0 CLZ group. Substitution testing with the D₁ antagonist SCH 23390 and the D₂ dopamine antagonist haloperidol failed to produce clozapine‐appropriate responding for either of the clozapine training doses. The antipsychotic drug thioridazine (which binds to a number of neurotransmitters in addition to dopamine) produced partial substitution (64.5% drug lever responding) in the 5.0 CLZ group at the 5.0 mg/kg dose. These results suggest that antagonism of D₁ and D₂ dopamine receptors alone is not sufficient to produce clozapine‐appropriate responding, even with the higher training dose of 10.0 mg/kg. Drug Dev. Res. 46:139–147, 1999. © 1999 Wiley‐Liss, Inc.     

Rats that acquire a THC discrimination more rapidly are more sensitive to THC and faster in reaching operant criteria

Male Sprague-Dawley rats were trained to discriminate delta-9-tetrahydrocannabinol (THC) from saline in a two-lever operant task using successive training criteria. Untreated animals were first shaped to barpress for a milk reward with one lever available. As each animal reached criterion the second lever was installed, the first lever was removed, and the animal was treated with 3.0 mg/kg THC 30 min prior to barpress training. When criterion on the second lever was reached the rats were trained to discriminate THC from vehicle injections with both levers available. Following acquisition of the discrimination, test doses of THC at 0.00, 0.375, 0.75, 1.5 and 3.0 mg/kg revealed that the half of the 24 rats who reached criterion (STC) more rapidly exhibited significantly greater sensitivity to THC at the 0.75 mg/kg test dose than did the 12 slow-learner rats; the former group generated an ED50 of 0.77 mg/kg, whereas the ED50 for the later group was 1.63 mg/kg. The fast learners acquired both the initial barpress response and the discrimination more rapidly than did slow-learners. Results suggest that some animals are inherently more sensitive to THC and faster in meeting learning criteria.     

Drug discrimination in rats: evidence for amphetamine-like cue state following chronic haloperidol

Two groups of male Sprague-Dawley rats were trained to discriminate which of two levers to press for milk reinforcement on a VI-20 sec schedule of reinforcement on the basis of whether they were injected intraperitoneally with d-amphetamine (0.50 mg/kg or 1.50 mg/kg) or saline 15 min prior to daily 30 min training sessions. Following acquisition of the discrimination, dose-response functions were generated for both training-dose groups during 5 min test sessions. All subjects were then injected with 1.0 mg/kg of haloperidol for ten consecutive days and retested on either saline or intermediate doses of amphetamine on days 1, 2, 4 and 7 following the final haloperidol injection. The results indicated that chronic haloperidol enhanced the discriminative stimulus properties of amphetamine in both training groups. More importantly, when tested on saline, subjects in both training groups made significantly more responses on the d-amphetamine lever than observed prior to chronic haloperidol. On the basis of linear regression analysis of the dose-response curves it was shown that rats in both groups responded as though they had been injected with 0.18 mg/kg of d-amphetamine. In a second experiment this increase in amphetamine-lever responding when animals were tested with saline following chronic haloperidol was replicated and in addition it was observed that chronic amphetamine had the opposite effect on this measure.     

Amphetamine-haloperidol discrimination: effects of chronic drug treatment

Rats responding for food reinforcement were trained in a 2-lever drug discrimination task. Groups of rats were trained to discriminate one of four doses of amphetamine (0.0, 0.1, 0.3, or 0.5 mg/kg) from haloperidol (0.02 mg/kg). Both the rate of acquisition and level of discrimination at asymptote were a function of amphetamine training dose. Following acquisition of this discrimination, choice behavior was assessed in the absence of drug during two test sessions. Twenty-four hours following the second drug-free test session, chronic drug treatment commenced. Half of the animals received 10 mg/kg amphetamine for 10 consecutive days while the other half received 1 mg/kg haloperidol during the same period. Choice behavior was assessed during three 2.5-minute unreinforced drug-free test sessions 24, 48, and 72 hours following the chronic drug regimen. Following chronic haloperidol, animals responded as though a small dose of amphetamine had been administered, while following chronic amphetamine, they responded as though a small dose of haloperidol had been administered. Collectively, these results suggest that animals trained to discriminate amphetamine from haloperidol respond on the basis of a continuum of dopaminergic function. Further, this continuum can be used to elucidate the net effect of pharmacologically-induced alterations in dopaminergic function, as well as the effect of nonpharmacological manipulations that may result in dopaminergic changes.     

Discriminative stimulus properties of a small dose of cocaine

This study characterized the interoceptive discriminative stimulus (IDS) produced by a small dose of cocaine. Rats were trained to use a dose of cocaine of 1.25 mg/kg vs saline as the basis for choosing one of two levers for food reinforcement on a fixed ratio 10 schedule. The discrimination was acquired over approx. 60 training sessions. d-Amphetamine generalized to cocaine with approximately equal potency (ED₅₀'s for cocaine and d-amphetamine were 0.07 and 0.06 mg/kg, respectively); 20 mg/kg cocaine and 10 mg/kg methylphenidate also generalized to the cocaine lever. Pentylenetetrazol, 20 mg/kg, did not generalize to the cocaine lever, and diazepam, 10 mg/kg, did not block the 1.25 mg/kg cocaine discrimination. These data indicate that when a small dose of cocaine is used as the basis of discrimination training, the discriminative stimulus that it produces is qualitatively and quantitatively similar to that produced by small doses of amphetamine, is still discriminated with a large dose of cocaine, and is dissimilar to the discriminative stimulus produced by pentylenetetrazol.     

Qualitative discrimination between cocaine and amphetamine in rats

After extensive training, rats discriminated amphetamine (1 mg/kg) from cocaine (either 5, 10 or 12.5 mg/kg) in a two lever drug versus drug discrimination task. In tests with saline, selection of the cocaine lever occurred in animals trained with 5 mg/kg cocaine. At higher training doses of cocaine, a (dose-related) tendency for lever selection to be equally distributed between the two levers was seen after saline injections. These data show that, at specific pairs of doses of cocaine and amphetamine, a qualitative discrimination between the drugs develops.     

The discriminative stimulus properties of ethanol and acute ethanol withdrawal states in rats

Twelve male Sprague-Dawley rats were trained in a standard two-choice Drug 1-Drug 2 discrimination task utilizing 3.0 mg/kg chlordiazepoxide (CDP, an anxiolytic drug) and 20 mg/kg pentylenetetrazol (PTZ, an anxiogenic drug) as discriminative stimuli under a VR 5-15 schedule of food reinforcement. Saline tests conducted at specific time points after acute high doses of ethanol (3.0 and 4.0 g/kg) indicated a delayed rebound effect, evidenced by a shift to PTZ-appropriate responding. Insofar as such a shift in lever selection indexes a delayed anxiety-like state, this acute 'withdrawal' reaction can be said to induce an affective state similar to that seen with chronic ethanol withdrawal states. Ethanol generalization tests: (1) resulted in a dose- and time-dependent biphasic generalization to CDP, (2) failed to block the PTZ stimulus and (3) failed to block the time- and dose-dependent elicitation of an ethanol-rebound effect. These data suggest that ethanol's anxiolytic effects are tenuous.