4-OH amphetamine enhances retention of an active avoidance response in rats and decreases regional brain concentrations of norepinephrine and dopamine.

In Exp I, an .82 mg/kg dose of 4-OH amphetamine hydrobromide (AMP) administered ip immediately following training in a 1-way active avoidance task enhanced retention performance of male ARS Sprague-Dawley rats measured 24 hrs later. In contrast, AMP in a dose range of .41–2.64 mg/kg, ip, did not affect retention of a swim escape task (Exp II). The behaviorally active dose of .82 mg/kg decreased dopamine concentrations in the amygdala and hippocampus. A dose of 8.2 mg/kg administered ip to naive untrained Ss (Exp III) decreased concentrations of norepinephrine measured in the amygdala, cortex, hippocampus, hypothalamus, and midbrain; decreased concentrations of dopamine in the amygdala, cortex, hippocampus, and striatum; and significantly reduced concentrations of norepinephrine and epinephrine in the adrenal medulla. In addition, because the integrity of the adrenal medulla is necessary for the enhancing action of AMP and because AMP reduces concentrations of catecholamines in the brain and adrenal medulla, it is possible that this drug affects retention performance by a dual action on the brain and the adrenal medulla. (20 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective hippocampal lesions and behavior: Effects of kainic acid lesions on performance of place and cue tasks.

Used kainic acid (KA; 1 and 2 μg/μl) lesions to study the effects of damage to the CA3 cell field and subiculum on performance of complex place and cue tasks by 54 male albino rats. In Exp I, neuroanatomical techniques determined the selectivity of the lesions. In a within-Ss design, Ss in Exp II were trained before the operations to run on an 8-arm radial maze with procedures that involved 2 kinds of learning (place and cue) and 2 memory functions (reference memory and working memory). Interrupting the intrahippocampal circuit by damaging the CA3 cell field with KA had minimal effects on performance; injections into subiculum and complete aspiration lesions of hippocampus resulted in impairments on the place but not the cue task. Only intraventricular injections of KA affected performance on both tasks. Results fail to support either the cognitive map or the working memory theory of hippocampal function. It is suggested that distant damage beyond the immediate area of injection complicates interpretation of the results and may limit the usefulness of KA as a neurotoxin in behavioral investigations. (57 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Estrogen and estrogen-progesterone treatments counteract the effect of scopolamine on reinforced T-maze alternation in female rats.

Determined if steroid hormone treatments would attenuate the effect of the muscarinic receptor blocker scopolamine on a memory task. Ovariectomized rats were trained first to alternate for food reward between the arms of a T maze. Following training, Ss treated with scopolamine hydrobromide (0.2 mg/kg, ip) did not alternate correctly between the arms of the T maze and responded at chance levels. However, when estradiol benzoate (25 μg) was administered 72, 48, and 24 hrs before testing alone or in combination with progesterone (500 μg) administered 48 hrs before testing, Ss alternated successfully between the arms of the T maze following scopolamine administration. Results indicate that gonadal steroids can completely counteract the impairment of T maze performance induced by scopolamine in female rats. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

CL 218-872 pretreatment and intervention block kainate-induced convulsions and neuropathology.

Two experiments were conducted to test the antiepileptic properties of CL 218-872, a triazolopyridizine reported to have anxiolytic and anticonvulsant effects without accompanying sedative and ataxic effects. In Exp 1 pretreatment with CL 218-872, a recently synthesized and potent triazolopyridizine, reduced kainic acid-induced convulsions and subsequent neuropathology in rats given ip doses of 25 mg/kg or greater. CL 218-872 at doses of 50 mg/kg or greater was more effective than a high dose of diazepam (20 mg/kg) in blocking status epilepticus-like convulsions and the associated widespread neuropathological sequelae. Moreover, diazepam pretreatment was associated with a higher mortality rate than CL 218-872. In Exp 2 the efficacy of intervention with 20 mg/kg diazepam was compared with that of 50 mg/kg CL 218-872 in suppressing ongoing convulsions and reducing subsequent brain damage following a convulsant dose of kainic acid. Although CL 218-872 and diazepam were equally effective behaviorally (i.e., in suppressing kainic acid-induced convulsions), CL 218-872 was superior in its ability to reduce subsequent neuropathology, especially in the hippocampus and neocortex. Because kainic acid has been suggested as a model for human status epilepticus, CL 218-872 may be a potentially therapeutic treatment for this disorder. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Differential effects of cholinergic blockade on performance of rats in the water tank navigation task and in a radial water maze.

Tested the disruptive effect of cholinergic blockade under conditions in which either the working memory or the spatial mapping requirements of the behavioral task were emphasized. In Exp I, 13 male hooded rats were trained in an 8-arm radial water maze to asymptotic performance. When delays of 5, 10, 20, and 40 min were inserted between Choice 4 and Choice 5, incidence of errors in Choices 5–8 increased after pretrial (20 min) intraperitoneal scopolamine (0.2 mg/kg) faster than under control conditions and approached chance level with the 40-min delay. Scopolamine after Choice 4 or pretrial methylscopolamine was ineffective. In Exp II, 30 Ss were trained in a Morris water tank. Acquisition was impaired by pretrial injection (20 min) of 0.1 and 0.2 mg/kg scopolamine, but a higher dose (1.0 mg/kg) was required to impair overtrained performance. In a working memory version of the navigation task, scopolamine administered 20 min before the 1st trial deteriorated retention tested 40 min later at a dose of 1.0 but not at 0.4 and 0.2 mg/kg. It is concluded that the disruptive effect of scopolamine is proportional to the demands on the working memory component of the task, whereas the use of an overtrained mapping strategy is relatively resistant to cholinergic blockade. (35 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Angiotensin and salt appetite: Physiological amounts of angiotensin given peripherally increase salt appetite in the rat.

In 2 experiments, adrenalectomized male Sprague-Dawley rats were maintained ad lib on distilled water, 3% saline, and sodium-free food. In Exp I, 45 Ss were given desoxycorticosterone acetate (DOCA [.1–2 mg/kg/day, intramuscularly]) for 5 days to determine the dose of DOCA that would produce the lowest voluntary saline intake, and 800 μg/kg/day was found to produce the nadir in saline intake. In Exp II, 40 Ss were placed ad lib on distilled water, saline, and sodium-free food as described above, maintained on 800 μg/kg/day DOCA, and infused with 4, 25, or 100 μg/kg/day angiotensin II (AII) or 0.9% saline. The 3 AII groups showed significant percentage changes in their saline intake above pre-AII levels; the saline control group showed no change in saline intake from pre-AII level. Results demonstrate the production of salt appetite in rats by peripheral administration of physiological doses of AII. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Memory facilitation by posttraining and pretest ACTH, epinephrine, and vasopressin administration: Two separate effects.

Rats were trained in a step-down inhibitory avoidance task using a 0.3-mA, 2-s, 60 Hz footshock and tested 24 hr later. The animals received, 1 min after training and/or 5 min before testing, an ip injection of saline, ACTH1–24 (0.2 μg/kg), lysine-vasopressin (10 μg/kg), epinephrine (5 μg/kg), naloxone (0.4 mg/kg), or a combination of naloxone with one of the hormones. Both the posttraining and the pretest injection of the hormones enhanced retention test performance; the enhancement was larger in animals that received the two treatments. Posttraining, but not pretest, naloxone administration also caused an enhancement. However, posttraining naloxone potentiated, and pretest naloxone antagonized, the effect of the concomitantly injected hormones. These data show that the posttraining and the pretest effect of the hormones are independent, are due to different mechanisms, and can be additive. In addition, it does not seem possible to explain posttraining memory facilitation by the hormones as owing to an addition to the reinforcement. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discrimination learning requiring different memory components in rats: Age and neurochemical comparisons.

Three experiments compared the performances of 19 young (8–9 mo old) and 23 aged (22–24 mo old) male ACI rats in a T-maze involving a spatial discrimination in the stem of the T-maze that required long-term reference memory, and discrete-trial, alternation discrimination in the arms of the T-maze that required working memory. Following acquisition training in 1 maze, Ss were trained in a 2nd maze in which the correct response in stem was opposite to that in the 1st maze. In Exps I and II, aged Ss made more errors in all phases of maze training than did young Ss, suggesting that all components of memory processing were affected equivalently. In Exp III, aged Ss were unimpaired in the ability to perform in a T-maze task involving a brightness discrimination with intramaze cues. This result suggests that the age-related impairment in the 2-component T-maze task was restricted to the cognitive demands of the task. Neurochemical analyses revealed a slight (8%) but significant age-related decline in the activity of glutamic acid decarboxylase but not of choline acetyltransferase. Although the correlation between maze performance and regional enzyme activities generally supported previous observations, the only significant correlation to emerge was between working memory performance and glutamic acid decarboxylase activity in the cingulate cortex. (45 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Long-term neuroprotection by benzodiazepine full versus partial agonists after transient cerebral ischemia in the gerbil [corrected

The ability of diazepam, a benzodiazepine full agonist, and imidazenil, a benzodiazepine partial agonist, to protect hippocampal area CA1 neurons from death for at least 35 days after cerebral ischemia was investigated. Diazepam (10 mg/kg) administered to gerbils 30 and 90 minutes after forebrain ischemia produced significant protection of hippocampal area CA1 pyramidal neurons 7 days later. In gerbils surviving for 35 days, diazepam produced the same degree of neuroprotection (70% +/- 30%) in the hippocampus compared with 7 days after ischemia. The therapeutic window for diazepam was short; there was no significant neuroprotection when the administration of diazepam was delayed to 4 hours after ischemia. The neuroprotective dose of diazepam also produced hypothermia (approximately 32 degrees C) for several hours after injection. To assess the role of hypothermia in neuroprotection by diazepam, hypothermia depth and duration was simulated using a cold-water spray in separate gerbils. Seven days after ischemia, neuroprotection by hypothermia was similar to that produced by diazepam. However, 35 days after ischemia, there was no significant protection by hypothermia, suggesting that hypothermia does not play a significant role in long-term diazepam neuroprotection. Imidazenil (3 mg/kg), which produced only minimal hypothermia, protected area CA1 of hippocampus to the same degree as that by diazepam 7 days after ischemia. At 35 days after ischemia, significant protection remained, but it was considerably reduced compared with 7 days. Like diazepam, the therapeutic window for imidazenil was short. Imidazenil neuroprotection was lost when the drug was administered as early as 2 hours after ischemia. The ability of ischemia to produce deficits in working memory and of benzodiazepines to prevent the deficits also was investigated. Gerbils trained on an eight-arm radial maze before ischemia demonstrated a significant increase in the number of working errors 1 month after ischemia. The ischemia-induced deficits in working memory were completely prevented by diazepam but not by imidazenil. There was a significant, but weak, negative correlation between the degree of CA1 pyramidal cell survival and the number of working errors in both the diazepam and imidazenil groups. Thus, if given early enough during reperfusion, both benzodiazepine full and partial agonists are neuroprotective for at least 35 days, but the lack of sedating side effects of imidazenil must be weighed against its reduced efficacy.     

Biotransformation of 17-alkylsteroids in the equine: gas chromatographic-mass spectral identification of ten intermediate metabolites of methyltestosterone

Parenterally administered domoic acid, a structural analog of the excitatory amino acids glutamic acid and kainic acid, has specific effects on brain histology in rats, as measured using different anatomic markers. Domoic acid-induced convulsions affects limbic structures such as hippocampus and entorhinal cortex, and different anatomic markers can detect these neurotoxic effects to varying degrees. Here we report effects of domoic acid administration on quantitative indicators of brain metabolism and gliosis. Domoic acid, 2.25 mg/kg i.p., caused stereotyped behavior and convulsions in approximately 60% of rats which received it. Six to eight days after domoic acid or vehicle administration, the animals were processed to measure regional brain incorporation of the long-chain fatty acids [1-(14)C]arachidonic acid ([14C]AA) and [9,10-(3)H]palmitic acid ([3H]PA), or regional cerebral glucose utilization (rCMRglc) using 2-[1-(14)C]deoxy-D-glucose, by quantitative autoradiography. Others rats were processed to measure brain glial fibrillary acidic protein (GFAP) by enzyme-linked immunosorbent assay. Domoic acid increased GFAP in the anterior portion of cerebral cortex, the caudate putamen and thalamus compared with vehicle. However, in rats that convulsed after domoic acid GFAP was significantly increased throughout the cerebral cortex, as well as in the hippocampus, septum, caudate putamen, and thalamus. Domoic acid, in the absence of convulsions, decreased relative [14C]AA incorporation in the claustrum and pyramidal cell layer of the hippocampus compared with vehicle-injected controls. In the presence of convulsions, relative [14C]AA incorporation was decreased in hippocampus regions CA1 and CA2. Uptake of [3H]PA into brain was unaffected. Relative rCMRglc decreased in entorhinal cortex following domoic acid administration with or without convulsions. These results suggest that acute domoic acid exposure affects discrete brain circuits by inducing convulsions, and that domoic acid-induced convulsions cause chronic effects on brain function that are reflected in altered fatty acid metabolism and gliosis.     

Leu-enkephalin impairs memory of an appetitive maze response in mice.

Result of 3 studies show that subcutaneous injection of leu-enkephalin (LE [300 μg/kg]) impaired memory of a Y-maze response in male Swiss-Webster mice when Ss were trained to obtain food in 1 arm of the maze. The dose-response function was U-shaped, with neither 100 nor 600 μg/kg having any effect. Des-tyr-leu-enkephalin, a nonopioid peptide, had no effect at doses equimolar to the LE. LE (300 μg/kg) was without effect if the drug injection was delayed 90 min. Findings show that LE affects appetitive conditioning in much the same way as avoidance conditioning, a finding that suggests that LE may generally influence learning and memory. (23 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Response–reinforcer associations after caudate-putamen lesions in the rat: Spatial discrimination and overshadowing–potentiation effects in instrumental learning.

Exp I, with 12 male hooded rats, demonstrated that Ss with caudate-putamen lesions exhibited an impairment in the acquisition and reversal of a spatial maze task when compared with unoperated control Ss. Exp II, with 24 Ss, investigated leverpress responding supported by a VI schedule in 3 groups of Ss: a group with caudate-putamen lesions, a group with lesions of the posterior cortex, and an unoperated control group. The presentation of a 0.5-sec, response-contingent light correlated with reinforcement generated an elevated response rate in the 2 operated groups but tended to suppress responding in the control group, perhaps by overshadowing the response–reinforcer relation. Only the group with cortical lesions maintained the elevated rate when the light was uncorrelated with food delivery. Exp III confirmed for these same Ss that caudate-putamen lesions produced a spatial learning deficit. No deficit was observed in the posterior cortex group. It is suggested that caudate-putamen lesions disrupt the mechanism underlying the response–reinforcer association on which spatial maze learning and free operant responding in part depend. (48 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Opiates and medial hypothalamic knife cuts cause hyperphagia through different mechanisms.

In Exp I, male Sprague-Dawley rats were given bilateral parasagittal medial hypothalamic knife cuts (KCs) or a sham procedure and fed a high-fat diet. KC and sham-operated Ss were approximately equally sensitive to the suppressive effects of naloxone (0.1–20 mg/kg, subcutaneously [sc]) on food intake. Ketocyclazocine (0.1–20 mg/kg, sc) generally increased daytime food intake in sham-operated Ss; in contrast, the normal hyperphagia of KC Ss was in most cases either unchanged or decreased by ketocyclazocine. In Exp II, neither diet composition nor hypothalamic KCs significantly affected the feeding responses to naloxone or the stimulatory effects of butorphanol tartrate (0.1–20 mg/kg, sc). It was hypothesized that the differential effects of ketocyclazocine in KC and sham-operated Ss were a consequence of the sedative effects of the drug combined with the elevated baseline of the KC Ss. This hypothesis was supported by Exp III, which showed that ketocyclazocine also reduced nocturnal intake in unoperated Ss and that butorphanol increased intake. That feeding responses to naloxone and butorphanol were essentially unchanged by hypothalamic KCs suggests that the opioid feeding system is independent of the longitudinal feeding inhibitory pathway believed to be involved in KC-induced hyperphagia. (36 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of physostigmine upon consolidation of memory in mice.

Investigated the influence of physostigmine upon the consolidation process in 4 experiments with 162 male DBA/2J mice. Ss were trained to escape shock in a 'Y'-maze. In Exp I physostigmine (.4 mg/kg, ip) impaired a previously learned task 2 days after initial learning but improved performance 11 days after initial learning. In Exps II and III, it was determined that the impairment of memory found on Day 3 was transitory and no longer evident once the drug was no longer active in an S's system. The findings of Exp IV, in which the Day 12 facilitory effect was examined, were essentially the same as those of Exps II and III. Results tend to support an inhibitory or motivational hypothesis rather than a consolidation hypothesis. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Strychnine increases acoustic startle amplitude but does not alter short-term or long-term habituation.

Used the glycine antagonist strychnine (1.0 mg/kg, ip, 10 min before treatment) to investigate the involvement of glycinergic neurons in the development and/or expression of short-term (within-session) habituation (Exp I) and long-term (between-sessions) habituation (Exps II and III) of the acoustic startle response in 120 male albino Sprague-Dawley rats. Over a range of eliciting-stimulus intensities (95, 105, and 115 db) and interstimulus intervals (3, 7, 13, and 27 sec), strychnine markedly increased startle amplitude, relative to water injection, whereas it failed to attenuate the rate of within-session habituation (Exp I). In Exp II, Ss that were exposed to daily sessions of startle-eliciting stimuli for 4 days and then tested on Day 5 showed lower levels of startle amplitude than Ss with no prior habituation training. Strychnine injected prior to the test session again increased startle amplitude but did not block the expression of between-sessions habituation. In Exp III, Ss injected with either strychnine or water prior to each of 3 daily habituation training sessions and subsequently tested on Day 4 showed similar between-sessions habituation. In general, results show that strychnine increased startle amplitude without affecting either within-session or between-sessions habituation of acoustic startle. (12 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"Recovery of spatial alternation deficits following selective hippocampal destruction with kainic acid": Correction to Kesslak and Gage (1986).

Reports an error in "Recovery of spatial alternation deficits following selective hippocampal destruction with kainic acid" by J. Patrick Kesslak and Fred H. Gage (Behavioral Neuroscience, 1986[Apr], Vol 100[2], 280-283). In the aforementioned article, the degrees of freedom reported in the Results section are incorrect. In the sixth paragraph on page 281, the second sentence should read as follows: Results of the ANOVA indicated a significant effect for surgical treatments. F(2, 25)=25.44, p1986-21445-001.) Examined whether the sympathetic ingrowth of superior cervical ganglion (SCG) fibers sprouting into the hippocampus following kainic acid (KA) lesion of CA3 and CA4 pyramidal cells in male Sprague-Dawley rats would contribute to behavioral recovery. 31 Ss were trained on a forced-choice task. After reaching criterion performance levels, Ss received either KA (8 nM/0.4 μl) or saline injections into the hippocampus and were again tested on the forced-choice task. Half of the Ss had their SCG removed 35 days after injections, and all were again tested on the forced-choice task. Analysis of variance (ANOVA) showed Ss receiving KA took significantly longer to reach criterion following injections. Removal of the SCG after recovery reintroduced the performance deficit of KA-treated Ss on the alternation task; no other group showed any effect for SCG removal. Results indicate that the SCG may have a modulatory effect in behavioral recovery, although other mechanisms may also be operating. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

L-dopa repairs deficits in locomotor and investigatory exploration produced by denervation of catecholamine terminal fields in the forebrain of rats.

In a previous study by the authors (see record 1980-27512-001), rats were shown to have decreased locomotor and investigatory exploration after bilateral microinjections of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus. Theses deficits correlated with the loss of catecholamine (CA) terminals in neocortical, limbic, and anteromedioventral striatal brain sites. To test whether this correlation was causal, central CAs were increased in 2 experiments with male Sprague-Dawley rats by the ip injection of levodopa (10–40 mg/kg) after inhibition of extracerebral levo-amino-acid decarboxylase. Such treatment repaired the deficits in locomotor exploration and investigation in 6-OHDA Ss. Pretreatment with the CA antagonist chlorpromazine (1–2 mg/kg) blocked the increase in locomotor exploration and investigation produced by levodopa in 6-OHDA Ss. Results suggest, but do not prove, that levodopa produced these behavioral effects by increasing central CAs at the denervated CA receptor sites in the forebrain. Data are complementary evidence for the hypothesis that forebrain CA synaptic action is necessary for normal exploratory behavior. (22 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of intertrial reinstatement of training stimuli on complex maze learning in rats: Evidence that "acquisition" curves reflect more than acquisition.

In Exps I–III (224 male Sprague-Dawley rats), Ss were run in a complex maze to escape weak footshock or to approach an appetitive reinforcer. Extramaze intertrial reinstatement of the same reinforcer as that used in training was found to enhance subsequent maze performance. Exp IV (80 Ss) determined that appetitively and aversively motivated performance benefitted from brief intertrial exposures to the start box of the maze. In Exp V (64 Ss), a facilitatory effect indicated that memory trace activity need not be maintained between training and reinstatement or between reinstatement and subsequent training. Exp VI (80 Ss) examined the effects of reinstatement at the beginning, middle, or end of 5-min intertrial intervals and found enhanced performance in the last 2 conditions. Exp VII (24 Ss) established that 4 successive reinstatement treatments without interpolated training trials were no more beneficial than a single reinstatement. Exp VIII (16 Ss) determined that forgetting had occurred over the standard 5-min interval between training trials. Exp IX (32 Ss) found that reinstatement alleviated forgetting that had already transpired. (49 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of paced coital stimulation on estrus duration in intact cycling rats and ovariectomized and ovariectomized-adrenalectomized hormone-primed rats.

Two experiments, with 121 female Long-Evans rats, investigated sexual behavior in intact cycling Ss and ovariectomized and ovariectomized-adrenalectomized hormone-primed Ss. A partitioned test cage was used in which the female controlled the timing of sexual contacts with males. Females received 9 or 10 intromissions in the partitioned test cage (paced) or with the partition removed (nonpaced), or they received solitary exposure to the test cage or to mounts without intromission with the use of vaginal masks. Intact cycling (Exp I) and gonadectomized hormone-primed (Exp II) Ss displayed similar patterns of contact with males. Exits from and latencies to return to the male compartment increased as the intensity of the antecedent coital stimulation increased. Cycling Ss given experience with paced or nonpaced mating on the evening of proestrus did not exhibit differences in pacing behavior on a 2nd test 17–24 days later. Those receiving paced coital stimulation showed a shorter duration of estrus than did those receiving nonpaced stimulation. Gonadectomized Ss given 3 successive doses of estradiol benzoate (20, 40, and 8 μg/kg, sc) in combination with progesterone (2 mg/kg) did not show shorter periods of estrus than nonpaced or mounts-only Ss. Results suggest that ovarian output in response to paced cervical-vaginal stimulation may contribute to the termination of estrus in the rat. (39 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned increases in locomotor activity produced with morphine as an unconditioned stimulus, and the relation of conditioning to acute morphine effect and tolerance.

In 5 experiments with 164 male Wistar rats, Ss administered morphine (5 mg/kg, sc) during each of several daily sessions in an open field showed an increase in locomotor activity. Since increases were not observed in Ss given morphine in a different environment (home cage) and saline in the open field, it is concluded that they were due to conditioning. Increases in activity were retained over a 7-day rest period; they were also produced when a 2nd opiate (5 μg/kg etorphine) was substituted for morphine, were not seen when 2 mg/kg naloxone (ip) was administered during treatment, and were present in Ss showing tolerance to opiate-produced hypoactivity. Morphine's direct effect on activity is believed to have a biphasic dose–response curve; therefore, the relation of dose to conditioning was also studied. Increases in activity were the only conditioned behaviors observed; they were present only at the higher doses (16, 4, and 1 vs .25, .065, and 0 mg/kg), and they occurred whether or not the dose was associated with unconditioned hypoactivity. Discussion deals with the relation of conditioning and morphine tolerance, the question of whether the UCS of morphine conditioning is a compensatory or a direct effect of morphine, and the similarity of conditioned increases in activity produced by morphine and by other reinforcing stimuli. (40 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)