The protective effects of free wheel-running against cocaine psychomotor sensitization persist after exercise cessation in C57BL/6J mice.

Previous literature suggests that free access to a running wheel can attenuate the behavioral responsiveness to addictive drugs in rodents. In a few studies, wheel-running cessation accentuated drug responsiveness. Here, we tested whether free wheel-running cessation is followed by (1) an accentuation or (2) an attenuation of cocaine psychomotor sensitization, knowing that no cessation of (continuous) wheel-running is associated with an attenuation of cocaine responsiveness. Male C57BL/6J mice, aged 35 days, were housed singly either with (exercising mice) or without (non-exercising mice) a running wheel. At the end of a period of 36 days, half of the exercising mice were deprived of their wheel whereas the other half of exercising mice kept their wheel until the end of experimentation (which lasted 85 days). The non-exercising mice were housed without wheel throughout experimentation. Testing took place 3 days after exercise cessation. After 2 once-daily drug-free test sessions, mice were tested for initiation of psychomotor sensitization over 13 once-daily injections of 8 mg/kg cocaine. Post-sensitization conditioned activation (saline challenge) and long-term expression of sensitization were assessed 2 or 30 days after the last sensitizing injection (same treatments as for initiation of sensitization), respectively. Exercising mice and mice undergoing wheel-running cessation exhibited comparable degrees of attenuation of all cocaine effects in comparison with the continuously non-exercising mice, which showed the greatest effects. Thus, the efficaciousness of wheel-running at attenuating cocaine sensitization not only resisted to exercise cessation but was also unambiguously persistent (an important effect rarely reported in previous literature).

Differential effects of histamine H(3) receptor inverse agonist thioperamide, given alone or in combination with the N-methyl-d-aspartate receptor antagonist dizocilpine, on reconsolidation and consolidation of a contextual fear memory in mice.

Albeit there is no doubt that histamine and its H(3) receptors participate in several aspects of learning and memory, such as memory consolidation, nothing is known about their potential involvement in memory reconsolidation. On the basis of previous reports of pro-cognitive effects of histamine H(3) receptor inverse agonists (which augment histamine release), we investigated to what extent the most representative of them, thioperamide, is able to facilitate reconsolidation of a contextually-conditioned fear memory in C57BL/6J mice. We also examined the effects of thioperamide on the stark disruptive effect that the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801) typically exerts on both reconsolidation and consolidation. Post-training systemic injections (i.p.) of thioperamide facilitated consolidation at 10 and 20 mg/kg and reversed amnesia induced by an i.p. injection of 0.12 mg/kg dizocilpine at 5, 10 and 20 mg/kg. Importantly, none of the five thioperamide doses (2.5, 5, 10, 20 and 30 mg/kg) given right after reactivation (reexposure to the context in which training took place 48 h earlier) affected reconsolidation, whereas all similarly given doses of dizocilpine (0.03, 0.06 and 0.12 mg/kg) disrupted it more or less equally. By contrast, thioperamide was able to unambiguously reverse the deficit in reconsolidation induced by 0.12 mg/kg dizocilpine at 10 and 20, but not 5 mg/kg. This is the first demonstration of an involvement of the interactive articulation between histamine and NMDA receptors in the mechanisms of memory reconsolidation, which seems to be indifferent to an increase of brain histamine per se. The results suggest a qualitatively different participation of histaminergic signalling in the mechanisms of reconsolidation and consolidation. The precise circuits within which these interactions take place are yet to be identified.

Conditioned hyperkinesia induced by cocaine in mice is dose-dependent but not correlated with the unconditioned response or the contextually-sensitized response.

The aims of the study were to test whether drug dose is positively related to the magnitude of the conditioned response following sensitization to the behavioural effects of cocaine and to investigate the relationship between the conditioned response and cocaine-induced sensitization. Male mice (C57BL/6J) were first injected over seven successive days with either saline or cocaine at 2.5, 5, 10 or 20 mg/kg s.c., in the testing room. On the test day, 24 h after the last injection, mice from all conditions were challenged with saline in the testing room to test for conditioned cocaine effects. Mice were video-recorded and various behaviours were later scored using a time-sampling technique. Cocaine-elicited orofacial stereotypy was significantly sensitized at the two highest doses and dose-dependently conditioned at the three highest doses. Cocaine-increased locomotion was sensitized at the three highest doses and significantly conditioned at 10 and 20mg/kg. Cocaine-increased sniffing did not change over pretreatment at any dose, and was conditioned only at 10 mg/kg. Cocaine-decreased immobility also did not change over pretreatment at any dose, but was conditioned at 10 and 20mg/kg. Concomitantly, rearing was reduced by cocaine at 10 and 20mg/kg, without sensitization being induced, and it was reduced under saline challenge after 5 mg/kg cocaine, while cocaine-decreased grooming was sensitized at the three highest doses and conditioned at 10 and 20 mg/kg cocaine. There was a positive relation between the size of the conditioned response for orofacial stereotypy and the magnitude of the unconditioned stimulus (the doses), a result conforming to the Pavlovian account of the placebo effect. This could also be concluded from considering the behaviour patterns as components of a unique placebo effect (hyperkinetic syndrome), since orofacial stereotypy, very apparent at 20 mg/kg cocaine, interfered at that dose with the full-blown expression of locomotion and sniffing, both yielding (approximately) inverted U-shaped dose-effect curves. However, no correlation was found between the magnitude of the conditioned response and the amplitude of sensitization (the difference between the initial unconditioned non-sensitized response and the last unconditioned sensitized response), a finding which indicates that conditioned responding does not participate in the generation of the sensitized effects, contrary to the 'excitatory conditioning model of contextual sensitization'.

Day-by-day maturation of the long-term expression of cocaine sensitization acquired before weaning in the rat.

This study aimed to identify the ontogenetic period during which long-term expression of behavioral sensitization to cocaine begins to emerge. Rat pups aged 4, 8, 12, or 16 days received a pretreatment of 4 daily injections of 15 mg/kg sc cocaine paired with the test chamber for 45 min. Pups were then tested for sensitization in that context after abstinence intervals ranging from 2 to 10 days. On test days, pups were videotaped, and their behavior was scored later. Sensitization was detected after intervals of 2, 4, 5, or 9 days in pups aged 4-7, 8-11, 12-15, or 16-19 days during pretreatment, respectively. These results suggest that the mechanisms for long-term retention of sensitization mature incrementally in the rat, starting to emerge gradually after the 1st week of age, whereas those relevant to short-term retention and initiation of sensitization are present earlier.

Short-term contextual sensitisation and conditioned hyperkinesia produced by cocaine in suckling rats aged 4-10 days and 14-20 days.

RATIONALE: It was hypothesised that the failure to generate sensitisation to the behavioural effects of a motor stimulant in suckling rats was mainly due to not pairing the drug with the test context during chronic pretreatment. OBJECTIVE: This study probed the capabilities of neonatal and infant rat pups to show short-term context-specific sensitisation and conditioned drug activity produced by cocaine. METHODS: Two similar experiments were conducted on rat pups aged 4-10 days or 14-20 days, each experiment comprising three phases: a sensitisation phase (days 4-8 and days 14-18 of age), a test session under cocaine for context specificity of sensitisation (day 9 and day 19 of age) and a test session under saline for conditioned drug effects (day 10 and day 20 of age). Over five daily sessions, pups first received an injection of either 16 mg/kg cocaine (paired group) or saline (unpaired group) in test chambers, and 110 min later the converse injections in the vivarium (in a cage that was different from the home cage). A third group received saline in both contexts. Behaviour was scored using videotapes. RESULTS: Sensitisation developed in the paired groups at both ages. In 4- to 10-day-old pups, sensitisation was expressed via locomotion (matrix crosses) and also horizontal and vertical activities (categories comprising several age-specific movements). In 14- to 18-day-old pups, it was displayed by increases in head movements and vertical activity, and by a decline in stationary position. These effects were confirmed to be context specific on the test sessions (day 9 or day 19), the paired groups producing by far the greatest values. On the conditioning test, the paired groups also produced the greatest amounts of the above-mentioned behaviours, revealing a conditioned drug effect. Additionally, the conditioned effect scores were higher than those of two additional groups that had been treated similarly to the others but outside the chamber until the two tests (controlling for a withdrawal effect and possible novelty-induced activity in the test context). There were no differences between these unexposed groups, indicating that no abstinence effect occurred. CONCLUSIONS: The results demonstrate that neonatal rats are capable of showing physiological/non-contextual cocaine-induced behavioural sensitisation as well as its context-specific expression and the conditioned activity following its establishment.

Selective effects of nicotine on attentional processes.

RATIONALE: It is now well established from electrophysiological and behavioural evidence that nicotine has effects on information processing. The results are usually explained either by a primary effect of nicotine or by a reversal effect of a nicotine-induced, abstinence deficit. In addition, there is dispute about the cognitive processes underlying the changes in performance. METHODS: This study has approached the first question by using the nicotine patch, in order to administer nicotine chronically. In addition, we examined the effects of nicotine on attention with a selection of tests which assessed the intensity and selectivity features of attention, using the Random Letter Generation test, the Flexibility of Attention test and the Stroop test. RESULTS: Nicotine enhanced the speed of number generation and the speed of processing in both the control and interference conditions of the Stroop test. There were no effects on attentional switching of the Flexibility of Attention test. CONCLUSION: The results are consistent with the hypothesis that nicotine mainly improves the intensity feature of attention, rather than the selectivity feature.

Conditioning of and contextual sensitization to apomorphine-induced climbing in mice: evidence against the habituation hypothesis.

Several predictions of the habituation hypothesis of conditioned drug effects were tested by looking at contextual sensitization to apomorphine-induced climbing in mice (Mus musculus). Mice were first sensitized to that effect after 9 daily injections of 0.4 mg/kg apomorphine in the test context. Other mice received the same treatment outside the test context. On Day 10, all mice were challenged with either saline (conditioned drug effects test) or apomorphine (contextual sensitization test). On both tests, the levels of climbing of mice that received apomorphine paired with the test context during the intermittent treatment were significantly higher than those of mice that were experiencing the test context for the first time (unexposed mice). Also, the rate of extinction in conditioned mice did not parallel the rate of habituation in the unexposed mice. Results contradict the habituation hypothesis of conditioned drug effects and contextual sensitization.

Anticipatory responding, exclusive drug-context pairing and conditioned effects in sensitization to apomorphine-induced climbing in mice.

1. The conditioning aspects of contextual sensitization were examined in the case of apomorphine-induced wall-climbing in mice, measuring onset latencies of the pharmacological response and controlling differential habituation to the test context during drug treatment. 2. Sensitization was generated in male out-bred mice which received intermittent i.p. injections of 0.4 mg/kg apomorphine over 9 daily sessions. On day 10, they were tested for contextual sensitization (all mice under apomorphine). On day 14, after 3 sessions of reinstatement, mice were tested for conditioned climbing (all mice under saline). 3. It was found that simultaneous exposure to both apomorphine and the test context facilitated the expression of a full-blown contextual sensitization (some non-contextual sensitization emerging too); importantly, sensitization was accompanied by a progressive shortening of the latencies to climb (before injections); conditioned climbing appeared only in mice pairing the drug with the test context, that response being absent in mice treated outside the context or never exposed to the context. 4. It is likely that contextual sensitization to apomorphine-induced climbing relies on Pavlovian conditioning processes rather than on habituation-related processes.

Effects of nicotine administered via a transdermal delivery system on vigilance: a repeated measure study.

Fifteen 18- to 25-year-old male smokers were tested in a within-subjects design to determine the influence of a transdermal patch of 21 mg nicotine on vigilance. Subjects were tested on the RVIP test (Rapid Visual Information Processing test) 1.30, 3.00 and 6.30 h after patch application, to verify the involvement of the dose of nicotine on the performance. This study confirms and extends the increasing effects of nicotine on vigilance previously found with orally and transdermally given nicotine. Moreover, it showed that such performance was independent of the time of nicotine absorption (1.30, 3.00 and 6.30 h after patch application), which suggests that a relatively low dose of nicotine suffices to activate vigilance processing. Regarding motor performance, no convincing effect of nicotine was observed on reaction time.

Amphetamine-induced conditioned activity and sensitization: the role of habituation to the test context and the involvement of Pavlovian processes.

Behaviours associated with drug action can sometimes be elicited, in the absence of drug, by exposure to stimuli that were present during drug administration. Such a finding is usually interpreted as a conditioned drug effect. Often, however, the outcome could arise if drug administration in a particular environment retarded behavioural habituation to that environment. To test the 'habituation hypothesis' of conditioned drug effects, mice received 10 daily injections of d-amphetamine ('paired' group) or saline ('unpaired') in test boxes, and the converse injections in the colony room. Another group received saline in both environments. The apparatus and procedures yielded minimal habituation of behaviours (ambulation and rearing) over sessions. Only the paired group demonstrated behavioural sensitization, indicating environment-specific sensitization. The paired group also showed more ambulation and rearing than the others on the critical test of conditioning (saline injection in test box); moreover, their conditioning test scores were higher than those of the other groups on their first exposure to the test boxes, contradicting the habituation hypothesis. Further supporting the involvement of Pavlovian conditioning, levels of ambulation and rearing measured for 10 min before each injection increased in the paired group, relative to the unpaired groups, over successive pairing sessions. Tests controlling for differential handling/injection experience produced results consistent with those previously obtained. Together, the findings are incompatible with the habituation hypothesis, and further support the role of Pavlovian conditioning.

Evidence for behavioral sensitization to cocaine in preweanling rat pups.

While chronic intermittent administration of stimulants often induces behavioral sensitization in adulthood, stimulant sensitization has rarely been reported prior to weaning [around postnatal day (P) 21]. Consistent pairing of drug administration with the test context often facilitates sensitization in adults, yet young animals have been typically returned to the home cage immediately post-injection. To determine whether promoting context-dependent sensitization might facilitate expression of sensitization in preweanlings, Sprague-Dawley rats were injected daily from P14 to P20 with 0, 5, 15, or 30 mg/kg cocaine HCl and placed for 30 min in either the experimental chamber or home cage. On P21 (test day), subjects were challenged with either 15 mg/kg cocaine or saline prior to placement in the experimental chamber. Significant sensitization of cocaine-induced stereotyped head movements was evident in animals given 15 or 30 mg/kg chronically in the experimental chamber, but not when these same doses were given in the home cage. Less consistent evidence for cocaine-induced sensitization was seen when examining locomotion, although trends for sensitization of this behavior were seen in animals chronically injected in either the test chamber or home cage. Thus, preweanlings can exhibit cocaine sensitization, particularly in terms of stereotypy, when tested shortly after the chronic exposure period, with expression of this sensitization being facilitated by pairing the chronic injections with the test context.

gamma-Aminobutyric acidA agonists differentially augment gnawing induced by indirect-acting dopamine agonists in C57BL/6J mice.

Evidence from structure-activity, molecular biology, ligand binding and behavioral studies has suggested potential differences in the pharmacological effects of indirect dopamine agonists. Striatal dopaminergic neurotransmission is under the regulatory control of GABAergic inputs. The ability of agonists of gamma-aminobutyric acidA (GABAA) receptors to enhance stereotyped gnawing was used as a method for dissociating the pharmacological effects of indirect-acting dopamine agonists. Gnawing on corrugated cardboard was studied in C57BL/6J mice. The GABAA agonists, gaboxadol HCl (THIP) and muscimol, were not effective in augmenting gnawing in the presence of the direct-acting dopamine agonists, apomorphine, pergolide, RU 24213 or SKF 38393. In addition, THIP did not enhance the gnawing produced by cocaine, bupropion, GBR 12909 or WIN 35428. In contrast, THIP produced marked augmentation of the gnawing induced by methylphenidate, (+)-amphetamine, methamphetamine, amfonelic acid, indatraline, nomifensine, diclofensine, mazindol and GBR 12935. The qualitative differences in potentiation were not caused by differences in the maximal effect of the drugs alone, inadequate dose or routes of administration, or by differences in duration of action. Neither can the absence of potentiation be accounted for by unique effects of THIP; muscimol was only marginally effective in potentiating the effects of WIN 35428 and bupropion but completely inactive in augmenting the effects of cocaine and GBR 12909. Muscimol was efficacious in augmenting the effects of the drugs for which THIP was active. These results add to a small but growing literature that demonstrates differences in the in vitro and in vivo pharmacological effects of indirect dopamine agonists. The methods used here may help in defining the molecular and neural substrates of these differential effects.

Neonatal and preweanling rats are able to express short-term behavioral sensitization to cocaine.

The present study assessed the ability of suckling rats to express short-term behavioral sensitization to cocaine prior to weaning. Rat pups, aged either 3, 5, 10, 12, 17 or 19 days at the beginning of the experiment, were placed in a chamber after daily injection with cocaine (7.5 or 15 mg/kg. i.p.) for either 2 or 4 consecutive days, and were tested for behavioral responsiveness to cocaine in the same chamber 24 h later (at either 7, 14 or 21 days of age). Such a short post-treatment interval was adopted, along with a consistent pairing of the testing context with the drug effect and a sensitive technique of behavioral measurement (video recording), in order to maximize the possibility of detecting any cocaine sensitization. Locomotion was sensitized at all ages, after both regimens in 14-day-old pups, but solely after 2 injections in 21- and 4 injections in 7-day-old pups. Sensitization was also expressed via behaviors specific to each age. Four cocaine injections augmented cocaine-induced uncoordinated movements of head, paws and body (horizontal activity) in 7-day-old pups, and mouth movements in 14-day-old pups. In 21-day-old pups, sensitization was dose- and regimen-dependently expressed via adult-like stereotyped head movements. In neonatal 7-day-old pups, cocaine sensitization was also visible as reductions in immobility (both injection regimens). Contrary to previous studies, these results indicate that, given the use of an appropriate methodology, short-term sensitization to the motoric effects of cocaine can be expressed by suckling rats prior to weaning, even after relatively short regimens of daily injections.

Dopamine 'D2-like' receptor agonists in combination with cocaine: absence of interactive effects on locomotor activity.

This study examined interactions between cocaine and drugs that act as direct agonists at subtypes of "D2-like" dopamine receptors. The drugs 7-OH-DPAT, quinpirole and RU24213 were studied alone and in combination with cocaine for their effects on locomotor activity in non-habituated mice. Locomotor activity was measured by photobeam crossings over 140 min. At the doses given (7-OH-DPAT: 0.006-6.4 mg/kg; quinpirole: 0.001-1 mg/kg; RU24213: 0.008-8 mg/kg) all three direct agonists dose-dependently reduced locomotor activity throughout the test, whereas cocaine (0.6-20 mg/kg) produced dose-related hyperactivity. Next, for each direct agonist, a series of doses was selected (up to threshold behaviourally-active doses) as pretreatments to a sub-maximally stimulant dose of cocaine (15 mg/kg). 7-OH-DPAT and quinpirole did not modulate the effects of cocaine; RU24213 produced, at best, a very modest attenuation of the effects of cocaine. Finally, a series of cocaine doses (below stimulant threshold) was given before a single dose of each direct agonist (the lowest dose to reduce activity significantly). Cocaine did not reliably alter the hypoactivity produced by any of the D2-like agonists. By demonstrating negligible interactions between cocaine and D2-like agonists, the results fail to demonstrate any necessary involvement of D2-like receptors in one of the behavioural effects of cocaine.

Pharmacological characterization of the enhancement of apomorphine-induced gnawing in mice by cocaine.

The present study was designed to provide additional information on the behavioral and pharmacological mechanisms associated with the augmentation of apomorphine-induced gnawing in C57BL/6J mice. (-)-Cocaine enhanced apomorphine-induced gnawing at doses devoid of effects on gnawing when given alone. The effect was stereoselective, with (+)-cocaine devoid of activity in this test. Peripheral synapses may also not be critical to the cocaine enhancement, as cocaine methiodide, a charged species, was also without effect. The local anesthetic actions of cocaine were evaluated with lidocaine, a local anesthetic without prominent dopaminergic actions. Like (-)-cocaine, lidocaine augmented the gnawing response to apomorphine without increasing climbing or gnawing when given alone. (+)-Amphetamine enhanced apomorphine-induced gnawing but only at a high dose that increased gnawing by itself. The selective dopamine uptake blocker. GBR 12909, augmented apomorphine-induced gnawing without increasing gnawing when given alone; however, unlike cocaine or lidocaine, GBR 12909 increased climbing at doses that augmented the gnawing response. These data indicate that the cocaine-augmented gnawing response to apomorphine does not appear to be the result of psychomotor stimulation per se. Rather, this effect may be due to blockade of dopamine uptake and/or the local anesthetic actions of cocaine.

Differential effects of direct and indirect dopamine agonists on the induction of gnawing in C57Bl/6J mice.

The ability of indirect dopamine agonists to induce gnawing in male C57Bl/6J mice was compared to that of direct dopamine agonists acting at dopamine D1 or D2 receptor subtypes. Holes left by the mice on the corrugations of packing cardboard were used as an objective index of gnawing. Indirect dopamine agonists, including dopamine releasers such as fencamfamine, (+)-amphetamine and amfenolic acid and dopamine uptake inhibitors such as cocaine, GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-[3- phenylpropyl]piperazine diHCl) and nomifensine produced dose-dependent increases in gnawing. None of the direct agonists (e.g., apomorphine, quinpirole or SKF 82958 [(+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine]) increased gnawing. Although these compounds varied in potency and efficacy, 18 structurally diverse compounds induced gnawing in 100% of the mice tested. Four weak indirect agonists (3,4-methyl-enedioxymethamphetamine, amantadine, 2-phenylethylamine and benztropine) failed to induce gnawing. The lack of efficacy of postsynaptic dopamine agonists was not changed by various combinations of postsynaptic agonists (e.g., dopamine D1 and D2 agonists in combination). Nonetheless, the dopaminergic nature of the gnawing response was confirmed in experiments in which a host of compounds with primary actions at nondopaminergic sites did not induce gnawing; compounds included nicotine, caffeine, dizocilpine, lidocaine, fluoxetine and nisoxetine. In addition, both the dopamine D1 antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro- 1H-3-benzazepine], the D2 antagonist eticlopride and the dopamine D1/D2 antagonist flupenthixol produced dose-dependent blockade of gnawing induced by either cocaine or methylphenidate.(ABSTRACT TRUNCATED AT 250 WORDS)

Verticalization of behavior elicited by dopaminergic mobilization is qualitatively different between C57BL/6J and DBA/2J mice.

Behavioral effects of dopaminergic stimulation were evaluated in C57BL/6J mice and compared to the effects occurring in DBA/2J mice, an inbred strain with reduced densities of striatal dopamine receptors. Effects of apomorphine (0.5-64 mg/kg) alone and in combination with cocaine (30 mg/kg) were assessed using a time-sampling technique that classified climbing and leaning in separate categories. Locomotion was also assessed in a separate experiment. Climbing occurred in DBA/2J mice only at doses of apomorphine that were 16 times higher than the smallest effective dose in C57BL/6J mice; nevertheless, relative to baseline values, effects were fairly comparable. By contrast, whereas DBA/2J mice showed dose-dependent leaning under apomorphine, C57BL/6J mice exhibited little leaning even at doses not producing climbing, and only after the highest apomorphine dose was leaning significantly increased. Apomorphine was equipotent in inducing gnawing across strains, although somewhat less efficacious in DBA/2J mice. When given alone, cocaine produced significant climbing, but not leaning or gnawing, in either strain. Whereas cocaine potentiated apomorphine-induced climbing and gnawing in both strains, apomorphine-induced leaning was not consistently changed by cocaine in either strain. These effects were not indirectly due to hyperkinesia, since neither apomorphine alone nor apomorphine and cocaine in combination was stimulant; apomorphine alone reduced locomotor activity and attenuated cocaine-induced hyperkinesia. The present data do not support a unitary, purely quantitative, account of insensitivity to dopaminergic stimulation based upon low densities of striatal dopamine receptors in DBA/2J mice. Rather, this constellation of results is suggestive of qualitative interstrain dissimilarities in dopaminergic responsiveness that could reflect organizational differences in receptor populations.

Transient hypersensitivity to apomorphine-induced gnawing after termination of acute effects of a single high dose of cocaine.

Physical dependence on cocaine has not been fully characterized or definitively identified. Since behavioral changes are typically not observed after cocaine withdrawal in animal studies, we sought to amplify or reveal any such changes in behavior by administration of the dopamine agonist apomorphine. C57BL/6J mice were tested for behavioral effects (climbing, gnawing, and locomotor activity) of apomorphine at various times after acute administration of cocaine. When tested at a time when most of the administered cocaine had disappeared from brain and when behavioral effects of cocaine had dissipated, at 2 and 4h post cocaine administration, effects of apomorphine on gnawing were increased 4-fold. This dopaminergic hypersensitivity was induced by acute treatment with doses of 15mg/kg cocaine and higher. Effects of apomorphine were not enhanced at later time periods (6 to 24h after cocaine), indicating a rapid waning of the dopaminergic hypersensitivity. Hypersensitivity to apomorphine was not further augmented by 8 days of daily cocaine injections. Cocaine did not influence climbing and hypomotility induced by apomorphine 4h after its injection, demonstrating selectivity in the behavioral expression of the dopaminergic hypersensitivity. Further, cocaine did not induce sensitization to its own effects indicating that the hypersensitivity to apomorphine was not due to a typical sensitization phenomenon. The results of these experiments demonstrate a short-lived dopaminergic supersensitivity after termination of the acute effects of a single high dose of cocaine, the implications of which remain to be discovered.

Behavioral sensitization and tolerance to the D2 agonist RU 24213: dissociation between several behavior patterns in mice.

Previous studies have shown that different components of behavioral effects of indirect agonists given chronically to laboratory rodents can follow different courses during treatment. Whether repeated injections of a D2 agonist can lead to the same phenomenon was investigated in mice using the D2 agonist N-n-propyl-N-phenylethyl-p-(3-hydroxy-phenyl)-ethylamine (RU 24213). Five mutually exclusive behaviors were examined over seven intermittent administrations (every other day over 13 daily injections) of RU 24213 (2.5 mg/kg SC) in mice. Rapid tolerance to the clearest initial effect of RU 24213, stillness, was found. Suppression of grooming also showed tolerance later in the treatment regimen (from the fourth test). From the third test, parallel time courses of sensitization were obtained for ambulation and rearing. Sleeping position was strongly depressed throughout the chronic treatment. These results show that the development in time of the behavioral effects of RU 24213 injected chronically strongly depend upon the behavioral measure. This supports the use of multiple measures in the same animal in the behavioral analysis of chronically injected dopaminergic drugs.