Factors which affect the relative contributions of ovarian and uterine arteries to the blood supply of reproductive organs in guinea pigs

The establishment and stability of the behavioral baseline for rats in relation to the schedule of differential reinforcement of low rate under water reinforcer (DRL 20 sec for water) were studied, with the following results: When the DRL value was gradually stepped up from 1 sec to 20 sec with the advance of the sessions from 1to 16, the establishment of the behavioral baseline was slower than when DRL 20 sec was applied from the start. The establishment of the baseline was clearly accelerated by the prolongation of the length of time for training in one session from 60 min to 120 min. The baseline remained highly stable without being affected by the intermittent administration (2-3 times a week) of methamphetamine and diazepam, each in doses from 0.06 to 1.0 mg/kg, and of caffeine and pentobarbital, each in doses from 1.2 to 20 mg/kg, or by the discontinuation of the test from 1 to 15 days. However, during the retraining period following the test discontinuation it was found that the baseline fluctuated for a long time due to the elimination of water deprivation. The baseline stability, once established, could be maintained through about 300 daily sessions, with only a slight dependence on the change in environmental conditions such as humidity, temperature, and the season.     

Developmental analysis of behavioral dysfunction in rats with septal lesions.

At 7 days of age, 48 male Long-Evans hooded rats received lesions of the septal nuclei or control operations. Ss then received 30 hrs of training on a DRL 20-sec schedule for 1 hr/day beginning at either 27 or 96 days of age. At 126 days of age, all Ss received 10 additional training sessions. After operant testing, all Ss received 10 additional training sessions. After operant testing, all Ss were tested on spontaneous alternation, spatial reversal, and passive avoidance. Results indicate that on a DRL 20-sec schedule Ss that received lesions of the septum neonatally and were tested at different ages performed in a similar manner. Approximately 50% of the Ss with lesions of the septal nuclei reached efficiency levels comparable with those of normal controls. When tested for retention, these efficient Ss still performed similarly to normal Ss. Ss with septal lesions were facilitated in the acquisition of a spatial habit, were deficient in spatial habit reversal, were less likely to demonstrate spontaneous alternation, and were deficient in passive avoidance. It is concluded that neonatal lesions of the septal nuclei produce permanent behavioral impairments on a diversity of measures and that, although juvenile animals with limbic system damage often manifest behaviors different from adult Ss, the difference is not evident during operant testing (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Delta9-tetrahydrocannabinol, but not the endogenous cannabinoid receptor ligand anandamide, produces conditioned place avoidance

Although exogenous cannabinoid ligands such as delta9-tetrahydrocannabinol (THC) have been implicated in reward-related learning and aversion, the hedonic effects of the endogenous cannabinoid agonist anandamide (arachidonylethanolamide) have never been assessed. Thus, the effects of anandamide were tested in a place conditioning task. Male Wistar rats received THC (0.0-8.0 mg/kg) or anandamide (0.0-16.0 mg/kg) during conditioning sessions. The half-life of anandamide was increased by pretreatment with the protease inhibitor phenylmethylsulfonyl fluoride (2.0 mg/kg). A significant place aversion was found at the 1.0 and 1.5 mg/kg doses of THC. No significant place conditioning effects were found with anandamide. Locomotor activity during conditioning was significantly decreased by the 1.0, 1.5, 2.0 and 4.0 mg/kg doses of THC as well as the 8.0 and 16.0 mg/kg doses of anandamide. These results fail to implicate the endogenous cannabinoid anandamide in reward-related learning or aversion.     

Prostate cancer

In previous research, we found an independent interaction of alprazolam and caffeine in rats under acute dose regimens using two measures (reinforcement rate and shorter-response rate) of a differential reinforcement of low rate performance (DRL 45-s) in 3-h sessions. Applying the same behavioral endpoints, the present study investigated the alprazolam-caffeine interaction under chronic dose regimens. Both drugs were administered by the oral route. Acute alprazolam and caffeine dose-response curves (DRCs) were characterized and were then used to determine the maintenance dose for the respective chronic dose regimens. Both drugs decreased the reinforcement rate and increased the shorter-response rate in a dose-related fashion. An alprazolam DRC also was determined during chronic-caffeine, chronic-alprazolam, and concurrent chronic-caffeine-alprazolam dose regimens. Complete tolerance to caffeine-induced rate changes was observed on the second day. Incomplete tolerance occurred only at higher alprazolam doses (7-12.5 mg/kg). Cross tolerance was not found between alprazolam and caffeine. Upon discontinuation of both drugs, performance progressively returned to baseline. The four alprazolam DRCs as well as the effect-time profiles demonstrated that caffeine altered neither the magnitudes nor the patterns of alprazolam effects on the two rates under chronic dose regimens. The P?ch DRC method further confirmed the independent interaction of alprazolam and caffeine. Thus, the independence of the interaction held for both the acute and chronic dose regimens despite the development of tolerance in the latter regimens.     

Midazolam's dose effects on fixed-ratio response rate in rats depend on amount of prior training experience.

To investigate the effects of amount of prior training on the operant response rate-decreasing effects of midazolam, the authors examined 6 oral (PO) doses of this drug (0.3, 1.0, 3.0, 10.0, 17.3, 30.0 mg/kg, 30 min before sessions) in 3 separate groups of rats (Rattus narvegicus). The rats received 29, 85, or 106 daily sessions (low, medium, and high groups, respectively) of fixed-ratio 30 water-reinforced training before the dose-effect determinations. Despite all 3 groups having had similar baseline response rates, the medium- and high-experience groups were significantly more sensitive to the rate-decreasing effects of the 3 highest doses of midazolam. All 3 groups were equally unresponsive (neither increasing nor decreasing response rate) to PO midazolam treatment at the 3 lowest doses. The experience-related sensitization to midazolam's behavior-disrupting effects suggests a role for amount as well as type of behavioral history as a determinant of behavioral drug effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Skilled motor deficits in rats induced by ventrolateral striatal dopamine depletions: behavioral and pharmacological characterization

Rats were tested in an instrumental lever pressing procedure, in which a computer program recorded detailed parameters of responding such as response initiation and duration. Initially, rats with ventrolateral striatal dopamine depletions and control rats were tested on days 3-5 after surgery. Dopamine depletions produced by local injections of 6-hydroxydopamine substantially reduced the number of lever presses emitted. Dopamine depleted animals showed significant increases in average response initiation times, average length of fast initiation times, average length of pauses and total pause time. The distribution of initiation times was altered so that DA depleted rats showed significant reductions in the relative number of very high rate responses and also showed increases in the relative number of pauses. On day 7 after surgery, dopamine-depleted rats received one of three drug treatments: injections of ascorbate vehicle, injections of 20.0 mg/kg L-DOPA, and injections of 40.0 mg/kg L-DOPA. Injections of 40.0 mg/kg L-DOPA led to some improvement in several parameters of instrumental responding. Compared to the previous baseline day, the group that received 40.0 mg/kg L-DOPA showed a significant increase in number of responses on the drug treatment day, and also showed significant decreases in average response initiation time and total pause time. The group that received 40.0 mg/kg L-DOPA also showed significant increases in number of responses (expressed as a percent of the previous day) when compared to the control group that received injections of ascorbate vehicle. These results indicate that L-DOPA can partially reverse the skilled motor deficits produced by ventrolateral striatal dopamine depletions, and suggest that this test may be useful for the assessment of antiparkinsonian drugs.     

A simple slide-rule method for the assessment of renal tubular reaborption of phosphate in man

Twenty-five male Sprague-Dawley rats were trained in five two-lever operant chambers on a DRL-15 sec schedule of positive food reinforcement to discriminate 10 mg/kg cocaine from 1 ml/kg saline. Following acquistions of discrimination a counterbalanced design of extinction tests was performed before and after repeated administration of 20 mg/kg cocaine or saline (three times a day at five hr intervals for seven days). The extinction tests consisted of testing responses of animals following 1 ml/kg saline, 2.5 mg/kg cocaine, or 5 mg/kg cocaine. The results showed no significant difference in animals' level choice before and after repeated injection with saline. However, the percent cocaine lever choice with the two doses of cocaine was lower after repeated administration of cocaine than before the repeated injections. This indicates tolerance developed to the discriminative stimulus properties of cocaine.     

Chronic cadmium exposure alters cocaine self-administration in adult male rats.

Adult male rats (Rattus norvegicus) were exposed to a water supply in the home cage containing 100 ppm cadmium chloride and sodium saccharin (.65% wt/vol; cadmium group) or water containing only the saccharin amendment (group control). On Day 65 of exposure, animals from each group received jugular catheter implants and were subsequently trained over the course of 15 daily 2-hr sessions to self-administer a .25 mg/kg/infusion of cocaine HCl under a fixed ratio 1 schedule. Immediately following acquisition training, the full dose-effect function was determined for all animals by using cocaine doses of .03, .06, .125, .25, .50, and 1.0 mg/kg. Cadmium-exposed animals executed more active (cocaine) lever responses during acquisition training but were not different from controls in depressing a pharmacologically inactive lever. For dose-effect testing, cadmium exposed animals exhibited greater self-administration than controls at the higher doses of cocaine, and there was evidence that the cocaine dose that produced maximum responding was higher in cadmium-exposed than control animals. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Latent sensitization to apomorphine following repeated low doses.

In 2 experiments, the effect of repeated injections of apomorphine on locomotor activity of rats was determined. In each experiment, different groups of rats were injected with either apomorphine (0.2, 1.0, or 5.0 mg/kg) or vehicle at either 24 or 72 hr intervals and tested for locomotor activity in photocell arenas. In Exp II, following 13 treatment sessions with various doses, all groups were first tested for activity following a 5.0 mg/kg dose of apomorphine and then given vehicle only prior to the final activity test session. Major findings were as follows: (a) repeated injections of 1.0 and 5.0 mg/kg apomorphine produced a progressively greater increase in activity with each injection (i.e., sensitization); (b) injections of 0.2 mg/kg of apomorphine produced a slight inhibition of activity, which did not change with repeated injections; (c) prior treatment with 0.2 mg/kg of apomorphine resulted in a significantly greater activity increase following a 5.0 mg/kg dose of apomorphine than did prior vehicle treatments; and (d) chronic pretreatment of rats with apomorphine did not affect their activity level following a vehicle injection. Findings suggest that sensitization to apomorphine is a graded, rather than an all or none, phenomenon dependent on the dose of apomorphine repeatedly administered. In addition, results are inconsistent with autoreceptor tolerance and conditioning explanations of dopamine agonist-induced sensitization effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cannabinoid-induced alterations in regional cerebral blood flow in the rat

A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, and neuroanatomical level. However, less is known of the functional localization in the brain for the behavioral and physiological actions of these drugs. We have examined the effects of delta 9-tetrahydrocannabinol (THC) and its active metabolite 11-OH-THC on regional cerebral blood flow in the rat in order to determine functional CNS sites of action for the cannabinoids. Conscious rats were injected i.v. with one of four doses of THC (0.5, 1, 4, 16 mg/kg). 11-OH-THC (4 mg/kg), or vehicle 30 min prior to sacrifice. Regional cerebral blood flow was determined autoradiographically using the freely diffusible tracer method of Sakaruda et al. Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured. Decreases in regional cerebral blood flow following THC were seen in such areas as the CA1 region of the hippocampus, frontal and medial prefrontal cortex, the nucleus accumbens, and the claustrum. Thresholds for these effects ranged from 0.5 to 16 mg/kg. Areas unaffected by THC include the medial septum, ventral tegmental area, caudate, temporal, parietal and occipital cortex, and cerebellum. These data indicate that THC and its active metabolite, 11-OH-THC, cause a heterogeneous alteration in the activity of specific CNS sites, many of which are involved in the characteristic behavioral actions of THC.     

The effects of chlordiazepoxide on low-rate behavior are gender dependent

Gender differences in anxiety have long been assumed to exist, but the experimental evidence is contradictory. It has also been suggested that antianxiety agents may have gender-dependent behavioral effects. The present experiment was designed to establish whether or not intact male and female rats behave differently when exposed to a Differential-Reinforcement of Low-Rate 72-s schedule of reinforcement (assumed to assess some of the inhibitory behavioral tendencies associated with anxiety), and whether or not the behavioral effects of acute chlordiazepoxide administration would differ between the sexes. There were no differences between male and female rats in the total number of responses, the total number of obtained reinforcers, or response efficiency in the absence of drug administration. Male and female Wistar rats were then challenged with different doses of chlordiazepoxide (vehicle, 1, 3, 10, 17, and 30 mg/kg). Low doses of chlordiazepoxide (1 and 3 mg/kg) decreased response efficiency, and medium doses (10 and 17 mg/kg) increased response efficiency in male and female rats. The highest dose of CDP (30 mg/kg) further increased response efficiency in male rats, but decreased response efficiency in female rats. These results suggest that the behavioral effects of chlordiazepoxide are dose dependent and that the effects of a large dose of chlordiazepoxide differ between male and female rats. Whether or not gender differences in drug metabolism or whether schedule contingencies played an important role in these observations remains to be determined in future experiments.     

Drug-induced reinstatement to heroin and cocaine seeking: A rodent model of relapse in polydrug use.

The authors investigated several features of polydrug use in rats. Heroin and cocaine were self-administered following responses on different levers, with only 1 drug and 1 lever available on alternate days of training. Four doses of each drug (heroin: 25, 50, 100, and 200 μg/kg/infusion; cocaine: 0.25, 0.5, 1, and 2 mg/kg/infusion) were tested, and each rat was exposed to a single dose combination. Rats readily developed drug-specific and dose-related responding. During extinction, rats displayed a significant bias for responding on the cocaine-associated lever. Priming injections of either cocaine (20 mg/kg) or heroin (0.25 mg/kg) reinstated responding that was selective for the lever previously associated with each drug These results suggest that in this type of polydrug use, drugs have the capacity to activate drug-seeking behavior selectively oriented toward stimuli previously associated with their administration. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contingent tolerance, compensatory responses, and physical dependence in diazepam-treated amygdala-kindled rats

Three groups of amygdala-kindled rats received 10 bidaily treatment trials: On each trial, the drug-before group received a diazepam (2.5 mg/kg i.p.) injection 1 hr before a convulsive stimulation, the drug-after group received a diazepam injection 1 hr after a stimulation, and the vehicle control group received a vehicle injection either 1 hr before or 1 hr after a stimulation. After treatment, only the drug-before group displayed significantly longer forelimb clonus under the influence of diazepam (that is, they displayed contingent tolerance to diazepam's anticonvulsant effect) and significantly longer forelimb clonus while drug free. Following a 14-day retention period, the rats in the drug-before group retained significant levels of contingent tolerance but did not display significant increases when tested drug free. These data suggest that compensatory responses do not play a causal role in the expression of contingent tolerance.     

Immediate effect of septal area damage on DRL performance in the rat.

Investigated the immediate and long-term effects of septal area lesions on performance on a differential reinforcement of low rates (DRL) 10-sec schedule. Ss were 43 male albino rats. Septal area lesions produced immediate disruption of DRL responding in unanesthetized Ss, but cingulate area lesions or sham treatments did not. The induction of septal seizures without lesions produced only minimal disruption. For the first few testing sessions, Ss tested 7 days after receiving septal area lesions were indistinguishable in DRL performance from those tested immediately; the former, however, showed poorer recovery. It is concluded that neural or other changes requiring time to develop postoperatively are not essential to the disruption of DRL performance, but they may impede behavioral recovery. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Cesium chloride gradients of chromatin after treatment with micrococcal nuclease

Chronic administration of delta9-tetrahydrocannabinol (THC) for 5--8 weeks at 4 dose levels (2, 10, 20, 50mg/kg/day) or of pilocarpine (12.5, 25 mg/kg/day) for 3 weeks induced mouse-killing in 25--70% of previously "non-killer" rats of the Sprague-Dawley strain. The maximum percent of drug-induced mouse-killing depended on the daily dose and housing conditions, 20mg/kg/day THC and 25 mg/kg/day pilocarpine in single-housed rats being the most effective treatments. Drug-induced mouse-killing appeared to be a form of behavioral pathology, differing from the species-specific predatory response, when it first appeared. Concurrent assessment of locomotor and rearing activities showed dose-dependent depressant effects of THC and pilocarpine without evidence for tolerance. Different dose-dependencies and time courses suggest that changes in motor activities are not directly linked to the appearance of the killing behavior.     

Contingent suppression of tolerance to the "anorexigenic" effect of haloperidol.

Whether tolerance develops to the "anorexia" induced by haloperidol (HAL) was determined. Rats were given HAL (2.5 or 5 mg/kg) either before or after access to milk for 53 days. Controls were given injections of saline. On Day 54, when all groups received pretest injections of the drug, only rats previously given posttest injections of HAL were tolerant. The absence of tolerance in rats previously given pretest injections suggests that tolerance is suppressed when rats are given access to food in the drugged state. It is concluded that tolerance develops to HAL as a result of pharmacological exposure but is suppressed by the "anhedonic" effect of the drug. The relevance of these findings to the role of reinforcement in behavioral tolerance is briefly discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Chronic exposure to morphine does not alter the neural tissues subserving its acute rewarding properties: Apparent tolerance is overshadowing.

Drug-naive, but not morphine-dependent, rats preferred places paired with morphine (2 mg/kg) over unfamiliar neutral places. Both drug-naive and morphine-dependent rats preferred places paired with higher doses of morphine (20 mg/kg) over unfamiliar places. Lesions of the tegmental pedunculopontine nucleus (TPP) blocked the conditioned place preferences produced by both 2 and 20 mg/kg morphine in drug-naive rats but not the preferences produced by 20 mg/kg morphine in dependent rats. When morphine-dependent animals received withdrawal-alleviating doses of morphine (20 mg/kg) 3.5 hrs before pairing one environment with 2 mg/kg morphine, they showed morphine-conditioned place preferences that were abolished by TPP lesions. The apparent behavioral tolerance to the TPP-mediated rewarding effects may have resulted from overshadowing by separate withdrawal-related motivational mechanisms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Within-subject variability in cocaine pharmacokinetics and pharmacodynamics after intraperitoneal compared with intravenous cocaine administration.

Performance in rats (Rattus norvegicus) was measured on a differential reinforcement of low-rate schedule (DRL 45-s) in 1.5-hr sessions after 2 mg/kg intravenous (IV) or 10–20 mg/kg intraperitoneal (IP) cocaine administration, with each dose given twice and separated by 3–5 days. For successive IV doses, cocaine effects were similar, with minimal within-subject variability. For IP cocaine, the effects were not always similar; performance was variable and sometimes remained at baseline level. These diminished effects occurred following either the 1st or 2nd IP injection. A parallel pharmacokinetic study of cocaine confirmed that within-subject variability existed in cocaine concentration-time profiles after IP cocaine, and that a low serum cocaine concentration-time profile could account for the diminished effects. The IP route for cocaine administration should be used with caution. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

BIMT 17: a putative antidepressant with a fast onset of action?

BIMT 17, the only compound reported to be a full 5-HT1A agonist and a 5-HT2A antagonist at the frontal cortex, was assessed in three animal paradigms sensitive to antidepressants in rats: olfactory bulbectomy (OB), differential-reinforcement-of-low rate 72-s (DRL 72-s) and learned helplessness (LH). In the OB rats, BIMT 17, given once daily for 14 consecutive days at an i.p. dose of 10 mg/kg, but not of 20 mg/kg, reduced the increase in ambulation of OB rats, 24 h after the last administration. In the DRL 72-s test, BIMT 17 had a different profile than imipramine. A single i.p. injection of 5, 10, 15 or 20 mg/kg BIMT 17, in contrast to the same doses of imipramine, did not affect response and reinforcement rate in DRL 72-s 1 h after the administration. On the other hand, BIMT 17 slightly shifted the peak of the interresponse time (IRT) distribution towards shorter IRT duration, while imipramine shifted the peak of the IRT distribution towards longer IRT duration. In the LH test, acute oral doses (36, 48 or 60 mg/kg) of BIMT 17, given 30 min before testing, reduced the number of escape failures in LH without altering the intertrial crossings. This effect was also induced by a repeated, but not single, administration with 8 or 16 mg/kg imipramine. The plasma levels following i.p. 10 or oral 48 mg/kg BIMT 17 were in the same range. These results indicate that BIMT 17 does not behave like imipramine in all the tests, and suggest that BIMT 17 acts through different mechanisms of action than imipramine. Only clinical trials will tell whether these mechanisms will be relevant, but if so, BIMT 17 might induce a faster onset of therapeutic activity.     

U-69593, a kappa opioid receptor agonist, decreases cocaine-induced behavioral sensitization in female rats.

This study was designed to investigate if the kappa opioid system regulates the locomotor response to cocaine in the female rat and to determine if the effect is dependent on estradiol treatment. Adult rats were ovariectomized (OVX) and half received an estradiol (OVX-EB) implant. After a week, rats were injected for 5 consecutive days with vehicle or with the kappa opioid receptor (KOPr) agonist U-69593 (0.16, 0.32, and 0.64 mg/kg) 15 min prior to cocaine injection (15 mg/kg). Following a 7-day drug-free period, rats were challenged with cocaine (Day 13). The locomotor response to cocaine was measured on Days 1, 5, and 13. U-69593 (0.32 mg/kg) decreased cocaine-induced locomotor activity in drug-na?ve OVX rats and in those that received the OVX-EB implant. These results indicate that the acute effects of U-69593 are independent of estradiol treatment. Repeated exposure to U-69593 (0.32 mg/kg) prior to cocaine decreased the development of behavioral sensitization in OVX-EB-implanted rats. This decrease in cocaine-induced hyperlocomotion persisted after 1 week of cocaine withdrawal. These data indicate that the KOPr system participates in estradiol modulation of cocaine-induced behavioral sensitization in the female rat. (PsycINFO Database Record (c) 2010 APA, all rights reserved)