Search

Item does not contain fulltext RATIONALE: 5-Hydroxytryptamine2C (5-HT2C) receptor agonists reduce the breakpoint in progressive ratio schedules of reinforcement, an effect that has been attributed to a decrease of the efficacy of positive reinforcers. However, a reduction of the breakpoint may also reflect motor impairment. Mathematical models can help to differentiate between these processes. OBJECTIVE: The effects of the 5-HT2C receptor agonist Ro-600175 ((alphaS)-6-chloro-5-fluoro-alpha-methyl-1H-indole-1-ethanamine) and the non-selective 5-HT receptor agonist 1-(m-chlorophenyl)piperazine (mCPP) on rats' performance on a progressive ratio schedule maintained by food pellet reinforcers were assessed using a model derived from Killeen's Behav Brain Sci 17:105-172, 1994 general theory of schedule-controlled behaviour, 'mathematical principles of reinforcement'. METHOD: Rats were trained under the progressive ratio schedule, and running and overall response rates in successive ratios were analysed using the model. The effects of the agonists on estimates of the model's parameters, and the sensitivity of these effects to selective antagonists, were examined. RESULTS: Ro-600175 and mCPP reduced the breakpoint. Neither agonist significantly affected a (the parameter expressing incentive value), but both agonists increased delta (the parameter expressing minimum response time). The effects of both agonists could be attenuated by the selective 5-HT2C receptor antagonist SB-242084 (6-chloro-5-methyl-N-{6-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}indoline-1-carbox amide). The effect of mCPP was not altered by isamoltane, a selective 5-HT1B receptor antagonist, or MDL-100907 ((+/-)2,3-dimethoxyphenyl-1-(2-(4-piperidine)methanol)), a selective 5-HT2A receptor antagonist. CONCLUSIONS: The results are consistent with the hypothesis that the effect of the 5-HT2C receptor agonists on progressive ratio schedule performance is mediated by an impairment of motor capacity rather than by a reduction of the incentive value of the food reinforcer.

Because of their potential therapeutic effects, N-methyl-D-aspartate (NMDA) receptor antagonists have been investigated for clinical use. Unfortunately, many channel-blocking antagonists have been associated with the production of side effects, including motor impairment and phencyclidine (PCP)-like subjective effects.This study investigated the relationship between NMDA receptor channel blockade and production of PCP-like side effects by evaluating a variety of NMDA channel blockers with different binding characteristics for the production of PCP-like discriminative stimulus effects.The NMDA channel blockers were tested in rats trained to discriminate 2 mg/kg PCP, i.p., from saline using a standard two-lever drug discrimination procedure with responding under a fixed ratio (FR) 32 schedule of food reinforcement.The high-affinity channel blockers PD 138289, PD 137889 and FR 115427, produced full, dose-dependent substitution for PCP. Of the moderate-affinity channel blockers, MRZ 2/579 fully substituted for PCP while 1-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline, 8-(2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline and alaproclate produced partial substitution. Drugs with the lowest affinity for the channel site and/or higher affinity for non-NMDA CNS sites, antazoline, idazoxan, 1-phenyl-1,2,3,4-tetrahydroisoquinoline, alpha-benzyl- N-methylphenethylamine and orphenadrine, failed to substitute for PCP.The results demonstrate that the cellular actions of the individual channel-blocking NMDA antagonists, in particular affinity for the channel site and NMDA receptor specificity, are important determinants of their discriminative stimulus effects. While higher affinity channel blockers show a correlation between affinity and PCP-like discriminative stimulus effects, behavioral disruption through action at non-NMDA receptors probably prevents achieving sufficient concentrations of the lower affinity compounds at NMDA receptors to produce PCP-like discriminative stimulus effects.

Human ethanol withdrawal manifests as multiple behavioral deficits with distinct time courses. Most studies with mice index ethanol withdrawal severity with the handling-induced convulsion (HIC). Using the accelerating rotarod (ARR), we recently showed that ethanol withdrawal produced motor impairment.This study aimed (a) to characterize further the ARR withdrawal trait, (b) to assess generalizability across additional behavioral assays, and (c) to test the genetic correlation between ethanol withdrawal ARR impairment and HICs.The severity of the ARR performance deficit depends on ethanol vapor dose and exposure duration, and lasts 1-4 days. Fatigue could not explain the deficits, which were also evident after intermittent exposure to ethanol vapor. Withdrawing mice were also impaired on a balance beam, but not on a static dowel or in foot slip errors per distance traveled in the parallel rod floor test, where they showed reduced locomotor activity. To assess genetic influences, we compared Withdrawal Seizure-Prone and -Resistant mice, genetically selected to express severe vs. mild withdrawal HICs, respectively. The ARR scores were approximately equivalent in all groups treated with ethanol vapor, though Withdrawal Seizure-Prone (WSP) mice may have displayed a slightly more severe deficit as control-treated WSP mice performed better than control-treated Withdrawal Seizure-Resistant mice.These studies show that ethanol withdrawal motor impairment is sensitive to a range of ethanol doses and lasts for several days. Multiple assays of behavioral impairment are affected, but the effects depend on the assay employed. Genetic contributions to withdrawal-induced ARR impairment appear largely distinct from those leading to severe or mild HICs.

The development of acute tolerance to the motor impairment and anticonvulsant effects of ethanol was examined. Acute tolerance to the motor impairment effect of ethanol was shown by a decrease in the degree of intoxication, as measured on the moving belt task, at higher blood ethanol levels ranging from 206 to 256 mg/dl. There was no evidence of acute tolerance to the anticonvulsant effect of ethanol in rats tested over the same time period. These results indicate that, like chronic tolerance, acute tolerance to ethanol develops at different rates for different effects of the drug. The fact that chronic tolerance to the anticonvulsant effect of ethanol has been well documented raises doubts about the assumption that similar physiological changes underlie acute and chronic tolerance to a drug effect, and support the idea that the relationship between acute and chronic tolerance is more complex than previously thought.

The influence of practice while under intoxication was tested on the development of acute tolerance to the motor impairment effect of ethanol. In experiment 1, the motor impairment effect induced by an IP injection of 1.8 g/kg ethanol was quantified after various intervals in separate groups of animals. Lower impairment scores were observed in rats tested at 30 and 45 min after ethanol administration than in those tested at 15 min. In group that was tested repeatedly after ethanol administration, intoxication decreased more rapidly and to a greater extent. The same phenomenon was observed in experiment 2 when a higher dose of ethanol (2.2 g/kg) and later testing (60-180 min after ethanol administration) were employed. To maintain constant blood ethanol levels, those tested at later times received a supplementary dose of ethanol. Impairment scores were lower in rats tested at later times than in those tested earlier. Again, the impairment scores for the practice group decreased more rapidly and to a greater extent. Blood ethanol levels among various groups were essentially the same. Acute tolerance to ethanol can develop without opportunity for practice while under intoxication. Intoxicated practice, however, can facilitate acute tolerance development.

The role of initial sensitivity and genetic factors in the development of tolerance to ethanol were examined in rats selected for low (AT) and high (ANT) sensitivity to the motor impairment effect of ethanol. Following chronic ethanol treatment (5 g/kg PO, daily for 20 days), the AT and ANT rats acquired tolerance to the motor impairment effect of ethanol at a similar rate. The AT rats, however, acquired tolerance to the hypothermic effect of ethanol at a higher rate than the ANT rats. Such ethanol treatment did not produce any metabolic tolerance to ethanol in these animals. Since there is no difference in the initial response to the hypothermic effect of ethanol between the AT and ANT rats, the observed differences in the rate of tolerance development might be related to a direct genetic factor. The similar rate of tolerance development to the motor impairment effect of ethanol between the two lines was attributed to an interaction between an indirect (initial sensitivity) and a genetic factor in tolerance development.

Anxiolytic benzodiazepines have been shown to impair place learning in the Morris water maze. However, a clear-cut demonstration of a direct and specific effect on mnemonic processes has not yet been offered. In the present study, the effects of diazepam on place navigation in the Morris water maze were studied in rats. Three conditions were examined: learning, reversal learning and learning after familiarisation of animals with the maze. In view of the anxiolytic and sedative properties of diazepam, appropriate doses of the drug, i.e. those that produced an anxiolytic effect but no major motor impairment, were initially selected in the water-lick conflict and rotarod tests, respectively. Doses of 2.5 and 5 mg/kg PO increased punished drinking in the water-lick conflict test without significantly decreasing rotarod performance. These doses were then used to assess the effects of diazepam on spatial behaviour. Diazepam, at both doses, impaired place learning in behaviourally naive rats. Such an effect appeared to be transient: diazepam-treated rats eventually reached control performance. Moreover, analysis of the probe trial at the end of training revealed adoption of a spatial strategy to locate the submerged platform. Neither reversal learning nor learning after familiarisation was affected. These results do not replicate previous findings in the Morris water maze and provide some evidence that the diazepam-induced place learning deficit may be primarily anxiolytic in nature.

The duration of retention of tolerance to ethanol was tested in the alcohol-preferring (P) and alcohol-nonpreferring (NP) rats lines, using ethanol-induced hypothermia as a measure of tolerance. Rats received two injections of ethanol (3.5 g/kg) body wt, IP) and the time between the injections was 1, 2, or 3 days. When one day separated the two injections, tolerance to the hypothermic effect of a second “test” injection was found in both lines. When 2 or 3 days separated the two injections, the P line showed a loss of tolerance and the NP line showed sensitization to ethanol. Sensitization in the NP line grew stronger when the interval between injections was increased from 2 to 3 days. The duration of retention of tolerance to ethanol-induced hypothermia in the P line was shorter than has previously been reported for motor impairment in this line. It appears that the duration of tolerance retention in the P line depends on the test used to measure tolerance. Sensitization to ethanol in the NP line may be associated with low oral ethanol intake.

The motor impairing effects and plasma concentrations of barbital and lorazepam were studied in the alcohol tolerant (AT) and alcohol non-tolerant (ANT) rat lines developed for low and high sensitivity to motor impairment from ethanol. The mixed (M) line, from which the AT and ANT rats were derived, was also included in the study. Like ethanol, barbital and lorazepam impaired the performance of the ANT rats more than that of the AT rats. The motor performance of the M rats was relatively more impaired after barbital than after lorazepam administration at the same dose used in the AT and ANT rats. At the two latter time points (2.5 and 3.5 h) the sensitive ANT rats had significantly higher serum barbital concentrations than the AT rats. The serum barbital concentrations of the AT and ANT rats did not differ, however, at the two first time points (0.5 and 1.5 h) of the tilting plane tests, although the ANT rats were significantly more intoxicated. The concentrations of lorazepam in plasma do not explain the differential motor impairment either, since the sensitive ANT rats had lower plasma concentrations than the insensitive AT rats. The results, thus, suggest that the selection involved in the development of the AT and ANT lines has not been specific for ethanol. The results also support the idea that ethanol, barbiturates and benzodiazepines have some modes of action in common.

The actions of indomethacin on the effects produced by ethanol were determined in rats and mice by measuring motor coordination (Rotorod test), sleep times, and body temperatures. Mice receiving indomethacin in combination with ethanol slept shorter times than those receiving ethanol alone. The blood and brain ethanol concentrations at time of awakening were significantly higher in the mice receiving the combination of drugs. Ethanol actions on motor impairment in rats and mice and on hypothermia in mice were not altered by pharmacologically relevant doses of indomethacin. The data show that indomethacin antagonizes only some of the observed effects of ethanol. It is suggested that a common mechanism, such as prostaglandin synthesis, is not involved in the interactions of both drugs.

Chronic tolerance to ethanol-induced sleep, motor impairment (moving belt test), and hypothermia were examined in two lines of rats that had been selectively bred for their different initial sensitivities to ethanol. In agreement with previous work (Mayer et al. 1982, 1983), the least-affected (LA) rats were found to be less sensitive than their most-affected (MA) counterparts in all three tests. Chronic treatment with ethanol resulted in a more rapid and more marked tolerance development in MA animals than in LA ones. The two lines did not differ in final level of tolerance achieved for either sleep time or hypothermia. However, significant differences were observed with respect to the moving belt test, in that at the end of chronic ethanol treatment the MA animals were more resistant to ethanol than the LA ones. These studies support the existence of a relationship, but not necessarily a direct genetic linkage, between initial sensitivity and acquired tolerance.

The development of tolerance to the motor impairment effect of ethanol was examined in separate groups of rats receiving and not receiving intoxicated practice. Tolerance to the motor impairment effect of ethanol developed whether or not rats received intoxicated practice during chronic ethanol treatment. Depending on the treatment dosage and test dose, intoxicated practice might enhance the level of tolerance attained. Tolerance to other effects of ethanol (hypothermia and narcosis) developed as a function of the treatment dosage. Intoxicated practice on the moving belt did not modify the development of tolerance to these effects of ethanol. Tolerance to the motor impairment effect of ethanol, however, was retained much longer in the intoxicated practice group following the termination of ethanol treatment.

"Most affected" (MA) and "least affected" (LA) rats, bred for extremes in motor impairment following an alcohol challenge, differed in their performance on two active avoidance tasks. In two-way shuttle avoidance, the MA line performed significantly better than the LA group, both in terms of response latencies and percent avoidances. The inferior performance of the LA line persisted across the 15 days of testing, and appeared to reflect an difference in asymptotic performance levels. In one-way avoidance, the MA line showed significantly better acquisition than the LA group; however, this difference dissipated across the 3 days of training. When tested following alcohol administration in either the one- or two-way avoidance paradigm, the MA rats showed a greater performance deficit than LA animals. These data were interpreted as indicating the generality of alcohol-related line differences to a situation motivated by aversive consequences. Moreover, the line difference in avoidance acquisition represents one of the few non-drug-related phenotypic differences that have been found in these lines. In previous generations, disparate base rates of wheel running have been reported, and the data presented here confirm and extend this finding.

A modified before-after design was used to assess the influence of behavioral contingencies on the development of tolerance to ethanol, monitored with both a behavioral (moving belt, shock avoidance) task and a physiological (body temperature) response measure. Male Long-Evans rats received ethanol (2.0 g/kg IP) and daily moving belt training under one of four conditions: (1) daily injection of ethanol before moving belt sessions; (2) daily injection of ethanol after belt sessions, with intermittent intoxicated practice; (3) daily injection of ethanol after belt sessions, with no intoxicated practice; (4) daily injections of saline, with intermittent intoxicated practice. After a 28-day tolerance acquisition phase, all groups received a final moving belt test and temperature assessment after injection of ethanol. Development of tolerance to the motor effects of ethanol was seen only in animals receiving daily injections before behavioral training. By contrast, tolerance to the hypothermic effect of ethanol developed equally in all groups. The augmented development of tolerance to the motor effects of ethanol may not, therefore, indicate a generalized state of neuronal adaptation; rather, it appears to reflect a fairly specific response acquired by the organism.

Alcohol-accepting (AA) and alcohol-nonaccepting (ANA) rats (Alko, Finland) were tested for their ability to master a shock-motivated (0.6 mA scrambled AC current) T-maze discrimination in which IP injections of ethanol (1.0 g/kg, 10% w/v in saline, 20-min latency) and, on alternate days, equivolume saline were employed as a discriminative stimuli signalling the safety of right or left goal compartments. ANA rats reached the criterion level of performance (eight of ten correct first-trial responses) more quickly than did AA rats (12.3 +/- 2.3 versus 31.4 +/- 7.7 sessions, P less than 0.01) and also maintained a superior level of performance through-out the course of the experiment, suggesting that ethanol may have been a more salient cue for ANA rats than for AA rats. Injections of acetaldehyde (0.1-0.25 g/kg, 1.0-2.5% w/v in saline) produced ethanol-appropriate responding to a greater extent in ANA rats than in AA rats, indicating that the actions of acetaldehyde may contribute importantly to the stimulus condition produced by the injection of ethanol in ANA rats. Sodium pentobarbital (10.0 g/kg) was equally effective in mimicking the action of ethanol in both AA and ANA rats. AA and ANA rats did not differ significantly in the impairment of motor performance produced by a range of ethanol doses, suggesting that differences in stimuli related to motor impairment do not contribute to the differences observed in the cue value of ethanol for AA and ANA rats.

Rats selectively bred for disparate degrees of ethanol-induced depression of spontaneous locomotor activity (‘most affected’ = MA; ‘least affected’ = LA) were trained on a swim task. Undrugged rats of the MA line swam significantly faster than rats of the LA line. Ethanol, 0.0–2.25 g/kg i.p., produced dose-dependent increases in swim time in rats of the 13th generation (F13). Averaged over trials, these increases were greater in LA than in MA rats and greater in males than in females, but there was no sex difference in peak impairment. Increases in swim time were uncorrelated with predrug performance. These findings were confirmed in younger F17 rats receiving 1.75 g EtOH/kg i.p. Although the lines differed in ethanol-induced impairment, F17 males of the two lines were not differentially impaired by pentobarbital (12.5–22.5 mg/kg, i.p.). The existence of task-dependent line differences in ethanol sensitivity emphasizes the nonunitary nature of ethanol-induced ‘behavioral depression.’

The effects of pretreatment with chloropromazine, promethazine or SKF 7265 on the severity of reserpine-induced rigidity were evaluated using a series of behavioral responses. Chlorpromazine (10 mg/kg) reduced the severity of the syndrome, particularly the tremor, but only at doses that also produced marked sedation. SKF 7265 was more effective than chlorpromazine and produced no detectable sedation or other motor impairment. Promethazine was ineffective in protecting against the effects of reserpine. These studies demonstrate that motor and behavioral abnormalities induced by high doses of reserpine can be blocked without inducing generalized sedation. This would suggest that it is possible to separate pharmacologically the motor pathways responsible for reserpine rigidity and those responsible for sedation.

Rats were rendered tolerant to ethanol by daily gavage of 4--5 g/kg. The degree of motor impairment on the moving belt test and of hypothermia after i.p. test doses of ethanol was measured prior to and at various times during the chronic treatment, to assess the rates of tolerance development. L-Tryptophan (75 mg/kg twice daily) was administered chronically to elevate brain serotonin level. This treatment did not alter the motor impairment or hypothermia produced by the initial test doses of ethanol (2.0 and 2.5 g/kg respectively). However, the development of tolerance to both the motor impairment and hypothermia effects of ethanol was accelerated in the tryptophan-treated rats. This finding complements our earlier observations that depletion of 5-HT with p-CPA slows down tolerance. Blood ethanol measurements at 20 min (motor impairment) or 90 min (hypothermia) after the administration of the test dose reveal no significant difference between the control and tryptophan-treated rats, suggesting that tryptophan did not influence the metabolism of ethanol. This finding supports the hypothesis that brain serotonin modulates the development of tolerance to ethanol.