LSD-induced alterations of investigatory responding in rats

The effects of lysergic acid diethylamide (LSD) on investigatory responses of rats in a novel hole-board were assessed in a series of experiments. LSD (40–160 g/kg) altered the temporal distribution of nose-poke responses during a 24-min session; LSD-treated rats responded less than controls initially, yet increased their response rates late in the session. This dose-dependent effect was not related to the time course of the drug's action nor to alterations in general locomotor activity. Only partial tolerance was found after eight daily injections of 100 g/kg LSD. When handling stress was minimized by placing the animals in an anteroom for 10 min before starting the test, the distribution of responding was normal although the overall frequency was still reduced. Conversely, vigorous handling potentiated the LSD effect. These results are interpreted as indicating an increased sensitivity of the LSD-treated rats to the stimuli associated with being handled and placed into the novel hole-board rather than a direct effect on investigatory tendencies. This LSD-induced potentiation of defensive responses appears to compete with the active exploration of the novel environment.R. K. Light is presently at the Department of Psychology, Indiana University, Bloomington, Indiana.     

Effects of 5HT-1A agonists on locomotor and investigatory behaviors in rats differ from those of hallucinogens

Behavioral profiles composed of both locomotor activity and investigatory behavior were established for the 5HT-1A agonists 8OHDPAT, buspirone, gepirone, and ipsapirone using rats tested in a Behavioral Pattern Monitor. Typically these compounds dose-relatedly decreased horizontal locomotion and investigatory activity during the first half of the 1-h test session. Time-course studies revealed that the time interval between injection and placement of the animal in the testing chamber made no difference in the temporal distribution of locomotor activity following most 5HT-1A agonists. These results were compared and contrasted to the behavioral profiles previously established for hallucinogenic compounds such as LSD and DOM, the psychoactive properties of which have been suggested to be mediated by 5HT-2 binding sites. Examination of ipsapirone and 8OHDPAT in a familiar environment paradigm revealed that both drugs decreased behavioral responding independently of the animals' familiarity with the test environment, in contrast to the behaviorally suppressive effects of hallucinogenic 5HT-2 antagonists which disappear in a familiar environment. Additionally, d,l-propranolol was used as a 5HT-1 antagonist and was found to block the behavioral effects of the 5HT-1A agonists ipsapirone and buspirone without having significant effects by itself. Propranolol was also used to identify the contribution of the 5HT-1 binding site to the behavioral effects of LSD. Even at relatively high doses, propranolol only partially antagonized the effects of LSD, supporting the hypothesis that the behavioral effects of LSD reflect the activation of both 5HT-1 and 5HT-2 receptors. Together, these findings demonstrate that 5HT-1A agonists have a different profile of behavioral effects than 5HT-2 agonists and that the two classes of drugs can be differentiated using the same test paradigm. The results provide further support for the hypothesis that the previously described potentiation of neophobia induced by hallucinogens is due to the activation of 5HT-2 receptors.     

Behavioral effects of xylamine-induced depletions of brain norepinephrine: interaction with LSD

Male rats were treated with a combination of systemic fluoxetine and intraventricular xylamine (under ether anesthesia) to deplete brain norepinephrine (NE) in the projection areas of the locus coeruleus. Four days later, control and lesioned rats were tested following injections of either saline or 80 micrograms/kg LSD in a Behavioral Pattern Monitor which recorded the sequential patterns of their locomotor and investigatory (holepokes) responses. Liquid chromatographic measures of brain monoamines confirmed that xylamine reduced hippocampal NE by 80.8% and hypothalamic NE by 26% without affecting levels of serotonin or dopamine. Relative to controls, NE-depleted rats exhibited repetitive spatial patterns of locomotion with no alteration in the amount or rate of habituation of locomotor activity. Lesioned animals made fewer rearings and holepokes, particularly early in the hour test session. When given 80 micrograms/kg LSD, sham-lesioned rats exhibited the expected decreases in entries into and time spent in the center of the chamber, an increase in time spent in the corners, and fewer holepokes and rearings early in the session. With the exception of the effect on rearings and holepokes, the effects of LSD were diminished in rats depleted of brain NE. These results indicate that this profile of behavioral effects of LSD, which has been interpreted as a potentiation of neophobia, may be dependent upon the noradrenergic projections of the locus coeruleus.     

Depletion of brain serotonin by 5,7-dihydroxytryptamine alters the response to amphetamine and the habituation of locomotor activity in rats

Awake Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 g 5,7-dihydroxytryptamine (5,7-DHT) through chronically implanted cannulae. Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 5,7-DHT. In a separate set of animals, liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 80–90% and caudate 5HT by 30–42% as early as 24 h after administration of 5,7-DHT. One or 3 days after lesioning, locomotor and exploratory behavior was characterized with a Behavioral Pattern Monitor (BPM). Relative to controls, lesioned rats exhibited a decreased rate of habituation of both locomotor activity and investigatory holepokes. Although the amount of locomotor activity elicited by amphetamine (1.0 mg/kg) was unchanged by the 5HT depletion, lesioned animals exhibited highly stereotyped patterns of locomotion during the last 30-min test session, in contrast to the relatively random patterns characteristic of control animals given amphetamine. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats.     

Behavioral analysis of the effect of neurotensin injected into the ventral mesencephalon on investigatory and spontaneous motor behavior in the rat

The present experiments examined in detail the behavioral response to microinfusions of neurotensin (NT) into the ventral tegmental area (VTA), substantia nigra (SN) and hippocampus (HPC). The behavioral apparatus consisted of an eight-hole box in which investigatory and spontaneous motor behavior were recorded. Three doses (0.175, 0.5, 4.0 g) of NT were injected into the VTA. The main effect of NT was a strong augmentation of rearing (frequency and duration) both in the periphery and center of the arena, accompanied by a small increase in locomotion and decreased grooming. NT had no effect on the strategy, organization, or duration of exploration but did augment frequency of hole visits towards the end of the session. NT injected into the SN and HPC had no effect on investigatory and spontaneous behavior with the exception of an increase in peripheral locomotion after HPC-NT injections. The results are discussed in terms of a modulatory role of endogenous NT on mesolimbic dopamine neurons.     

Patterns of exploration in rats distinguish lisuride from lysergic acid diethylamide

In order to further validate a previously proposed animal model of the effects of LSD in humans, doses of 5, 15, 30 and 60 micrograms/kg lisuride (a non-hallucinogenic congener of LSD) were studied using a behavioral pattern monitor (BPM). The BPM provided both quantitative measures of crossovers, rearings, and holepokes and qualitative measures of spatial patterns of locomotion. A holeboard chamber connected to a homecage provided two test situations. Rats were tested either with (free exploration) or without access to the homecage (forced exploration). In both situations, lisuride exhibited a biphasic dose-response curve for horizontal locomotion (low dose suppression and high dose enhancement), while rearing was significantly reduced at all doses. Lisuride also produced a dose-dependent increase in the perseverative quality of locomotor patterns. A comparison of these results with our previous studies with lysergic acid diethalmide (LSD) indicate that, with the exception of rearings, lisuride fails to mimic LSD's characteristic effects on exploratory activity. Rather, lisuride exhibited many similarities to the dopamine angonist apomorphine.     

Cocaine-induced behavioral sensitization in the young rat

Rationale: Repeated psychostimulant treatment has been shown to sensitize the locomotor activity of young rats, but there is conflicting evidence suggesting that this sensitized response will persist across only a few drug abstinence days. Objective: The purpose of the present study was to determine whether: (a) young rats are capable of expressing a sensitized locomotor response after an extended drug abstinence period, and (b) the longevity of the sensitized response is critically affected by either the number of drug pretreatment days or environmental conditioning factors. Methods: Young rats were pretreated with saline or cocaine (15 mg/kg or 30 mg/kg, i.p.) for either five or ten consecutive days [i.e., on postnatal days (PD) 16–20 or PD 11–20]. After each daily injection, rats were placed in activity chambers, and locomotion was measured for 30 min. To assess environmental conditioning factors, some rats were injected with saline prior to being placed in the activity chambers and then injected with cocaine prior to being returned to the home cage. After one or seven abstinence days (i.e., on PD 22 or PD 28), rats received a challenge injection of saline or cocaine (15 mg/kg) in the activity chamber and locomotion was assessed. Results: Young rats exhibit cocaine-induced locomotor sensitization after either a short (1-day) or long (7-day) drug abstinence period. When a long abstinence period was used, locomotor sensitization was only apparent when cocaine pretreatment lasted for 10 days. Conditioning factors were also important for determining whether locomotor sensitization was expressed, because young rats pretreated with cocaine in the home cage did not show a sensitized locomotor response after seven abstinence days. Conclusions: Young rats are capable of showing cocaine-induced locomotor sensitization after an extended abstinence period. Both the number of drug pretreatment days and the environmental context in which cocaine was given (i.e., the activity chamber or home cage) influenced the longevity of cocaine-induced locomotor sensitization. Received: 30 August 1999 / Accepted: 21 December 1999     

Differences in the stimulus properties of barbital and hallucinogens.

The present investigation sought to determine whether drugs which produce markedly different perceptual effects in man, barbital and mescaline or LSD produce different stimuli in rats. In a standard 2 lever operant test chamber, rats received sweetened milk for correct responses according to a variable interval schedule. All sessions were preceded by 1 of 2 treatments; following Treatment A, only responses on Lever A were reinforced and, in a similar fashion, Lever B was correct following Treatment B. No responses were reinforced during the first 5 min of a daily 30 min session. It was found that barbital can serve as a discriminative stimulus when this drug is paired with saline. Previously, we had demonstrated that mescaline or LSD can serve as discriminative stimuli. When barbital was administered to animals trained to discriminate mescaline or LSD and saline, they made either random responses or responses appropriate to saline treatment. This observation suggests that the stimulus properties of barbital are difference from those of the hallucinogens. A subsequent demonstration of discriminated responding when barbital and mescaline or LSD were paired as discriminative stimuli supports this conclusion. The present results extend previous findings which suggest that the degree of similarity or difference of drug stimuli in rats is congruent with the degree of similarity or difference of perceptual drug effects in man.     

5HT-2 mediation of acute behavioral effects of hallucinogens in rats

In rats tested during their first exposure to a Behavioral Pattern Monitor chamber, acute injections of the 5HT-2 agonists mescaline, quipazine, 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), or 2,5-dimethoxy-4-ethylamphetamine (DOET) produced an inhibition of locomotor and investigatory behavior during the first 30 min of the test session. This suppression of exploratory behavior was attenuated when rats were familiarized with the testing chamber prior to the administration of DOI. Hence, as previously observed with both LSD and DOM, 5HT-2 agonists appear to potentiate the normal neophobic reaction to a novel environment. The mixed 5HT-1 and 5HT-2 agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT) also produced a decrease in activity when animals were tested in the novel environment. However, as previously found with 5HT-1A agonists, this effect was unchanged when animals were tested in the familiar environment and may therefore reflect a generalized sedation. The receptor specificity of these differential effects of 5HT-1 and 5HT-2 agonists in this paradigm was tested by assessing the ability of selective 5HT-2 antagonists to block the effects of the agonists. A dose of the 5HT-2 antagonist ketanserin which had no effect by itself significantly reduced the behavioral effects of mescaline, DOM, and quipazine. Similarly, the selective 5HT-2 antagonist ritanserin blocked the effect of quipazine. In contrast, ketanserin had no significant effect on the suppression of activity produced by the 5HT-1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8OHDPAT). These results demonstrate that the behavioral effects of 5HT-1 and 5HT-2 agonists can be differentiated both phenomenologically and pharmacologically within a single paradigm. The findings provide further support for the hypothesis that the potentiation of neophobia produced by hallucinogens in rats is attributable to their agonist actions at 5HT-2 receptors.     

Dissociation of multiple effects of acute LSD on exploratory behavior in rats by ritanserin and propranolol

Rats tested for 1 h in the Behavioral Pattern Monitor (BPM) after injection of the mixed serotonergic agonistd-lysergic acid diethylamide (LSD) exhibit a behavioral profile similar to that produced by various hallucinogenic 5HT-2 agonists. The characteristic effects of the hallucinogens include suppression of locomotor and exploratory behavior and a preferential decrease in entries into the center of the BPM during the initial half of the test session. After LSD, the initial suppression of responding is followed by a subsequent increase in locomotor activity that is not observed with other serotonergic agonists. In the present studies, the 5HT-1 andβ-adrenergic antagonistd,1-propranolol and the 5HT-2 antagonist ritanserin were administered individually or in combination prior to the acute administration of LSD to test for the involvement of these receptor subtypes in the mediation of the effects of LSD in the BPM paradigm. Propranolol (20 mg/kg) abolished the initial suppression of activity induced by 60 μg/kg LSD without affecting the subsequent increase in locomotion. Conversely, 2.0 mg/kg ritanserin failed to block the initial suppressive effects of 60 or 120 μg/kg LSD, but attenuated the LSD-induced increases in activity during the second half of the session. The combination of propranolol and ritanserin prevented both these effects of LSD. By contrast, the more selective 5HT-2 agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) (0.27 mg/kg) produced an initial suppression of activity in the BPM that was blocked by 2.0 mg/kg ritanserin and was not followed by a subsequent increase in activity. These findings suggest that the initial suppressive effects of LSD in the BPM paradigm are dissociable from the subsequent increases in locomotion and that the two effects are mediated via different serotonergic orβ-adrenergic receptors.     

Individual differences in behavioral measures: correlations with nucleus accumbens dopamine measured by microdialysis.

Rats were placed in one of two novel test environments for behavioral observation. In one, exploratory behavior (assessed by hole pokes) and locomotion were assessed during a 10-min test session. In the other, the chewing of varied objects on the cage floor was rated over a 20-min session. Within 2-18 days, animals were anesthetized and microdialysis probes were implanted into the nucleus accumbens for measurement of basal and d-amphetamine-stimulated levels of dopamine (DA). These measures were then correlated with the individual behavioral rating collected earlier from the drug-free animals. We found a significant correlation between duration of exploratory behavior and amphetamine-induced DA release. Locomotor activity did not correlated with either basal or amphetamine-stimulated DA release. Duration of chewing episodes correlated with basal levels of DA, as well as with amphetamine-induced DA release. Our studies indicate that differences in the dopaminergic responsivity of the nucleus accumbens (or other circuitry influencing nucleus accumbens DA function) may contribute to individual differences in certain behaviors displayed by the animals when placed in a novel environment.     

A correlative evaluation of cyclazocine,LSD and naloxone on continuous discriminated avoidance in rats

Cyclazocine, a long acting narcotic antagonist, induces disorientation, hyperirritability and hallucinations. In contrast, naloxone is devoid of any psychotomimetic affects. Cyclazocine (2.5 mg/kg) and LSD (1.0 mg/kg) induced strikingly similar behavioural disruptions on well-established discriminated (Sidman) avoidance performance in rats. Cyclazocine and LSD administration resulted in periods of response-inhibition and a subsequent enhancement of response rates. In the presence of the warning signal rats often failed to lever-press and as a consequence received more shocks. Naloxone (30 mg/kg) had little effect on avoidance responding. The effects of cyclazocine and LSD in rats may be mediated through similar mechanisms.     

Threshold differences for naloxone and naltrexone in the hypothalamus and midbrain using fixed ratio brain self-stimulation in rats

Scopolamine reversed the reduction in avoidance responding caused by spiperone and antagonized the inhibitory effects of spiperone on the behavioral actions of d-amphetamine or apomorphine. Scopolamine-induced locomotor activity was greater in 6-hydroxydopamine (6-OHDA)-treated animals than in controls. This increase was prevented by administration of -methyltyrosine, but not by inhibition of dopamine--hydroxylase, indicating that this action of scopolamine was associated with presynaptic dopaminergic fibers. Therefore, the possibility that pre-synaptic dopaminergic function was the locus of the antagonism of spiperone by scopolamine was examined using drug interaction studies in 6-OHDA-treated rats. However, when 6-OHDA-treated rats were given -methyltyrosine, scopolamine still reversed the spiperone blockade of apomorphine-induced locomotion. Although these data provided evidence for a post-synaptic action for this cholinergic blocking agent, scopolamine affected neither dopamine-stimulated adenylate cyclase activity nor ³H-spiperone binding in vitro. Furthermore, scopolamine did not alter the level of specific ³H-spiperone binding found in brain after in vivo administration. This suggests that the postsynaptic mechanism affected by scopolamine is different from the site affected by spiperone. Thus, it is concluded that scopolamine can affect both pre- or post-synaptic events associated with dopaminergic function and that both may contribute to the reversal of the actions of spiperone.     

The effect of δ 9-tetrahydrocannabinol and LSD on the acquisition of an active avoidance response in the rat

The course of active avoidance learning of rats in a symmetrical Y-maze under the influence of 1, 3, and 9 mg/kg of ⁹-THC i.p., and 5, 20, and 100 g/kg of LSD was investigated. ⁹-THC in a dosage of 1 mg/kg had no effect on avoidance learning. Three and to a lesser extent 9 mg/kg produced more rapid learning with a significantly better performance. Learning under ⁹-THC proved to be statedependent. The withdrawal of ⁹-THC caused a decrease in the avoidance rate, which was dependent on the dosage. Upon renewal of the THC doses, the animals reattained their earlier performance. In the course of the experiment there was rapid tolerance development, especially of the sedative properties of THC.LSD retarded the rate of acquisition of the active avoidance response. Whereas the control animals displayed over 80% successful active avoidance from the 14th session onwards, this was achieved by the LSD groups only after the 20th session. However, in contrast to the control group the LSD animals were able to increase their avoidance rate to over 90%, and this was maintained to the end of the experiment (a total of 24 sessions with LSD). The sudden withdrawal of LSD produced a fall in avoidance rate, which was dependent on the previous training dosage; as with ⁹-THC state-dependent learning can also be assumed for LSD.     

On the elevated plus-maze the anxiolytic-like effects of the 5-HT1A agonist, 8-OH-DPAT, but not the anxiogenic-like effects of the 5-HT1A partial agonist, buspirone, are blocked by the 5-HT1A antagonist, WAY 100635

 Nicotine has been shown to maintain intravenous self-administration behaviour in humans and laboratory animals. However, factors critical in the initiation of nicotine self administration are not well defined. In particular genetic differences and effects of pre-exposure to nicotine have not been examined. Male Sprague-Dawley or Long-Evans rats were surgically prepared with indwelling jugular catheters and 3 days later received chronic injections of nicotine (0.4 mg/kg SC) or vehicle (saline, 1 ml/kg) for 7 days in their home cage. The next day, 2-h daily test sessions were initiated, during which rats were given the opportunity to nose-poke for nicotine infusions (0.015, 0.03 or 0.06 mg/kg per infusion) under a one-response fixed-ratio (FR-1) schedule of reinforcement with a 20-s time out after each infusion. One hole was defined as active while pokes in the other hole were recorded but had no scheduled consequence. The response requirement was increased progressively to five (FR-5) over successive sessions. Both saline- and nicotine-pretreated Sprague-Dawley rats showed a preference for the active hole, while only the saline-pretreated Long-Evans rats acquired the self-administration as defined by significant differences between responding in the active versus the inactive holes. The Fisher (F344) and Lewis inbred strains also failed to acquire self-administration of nicotine under these conditions. With Sprague-Dawley and Long-Evans rats that acquired the self-administration, and showed stable levels of maintained responding for nicotine, substituting saline for the nicotine or pretreating with mecamylamine (2.0 mg/kg SC) extinguished the behaviour. When dose per infusion was varied, an inverted U-shaped dose-response curve was obtained. These results support previous reports that nicotine can serve as a reinforcer in rodents and demonstrate that environmental factors such as prior nicotine exposure or genetic factors such as rat strain can affect acquisition of nicotine self-administration. Received: 29 March 1996 / Final version: 20 August 1996     

The role of 5-HT(1A) receptors in the locomotor-suppressant effects of LSD: WAY-100635 studies of 8-OH-DPAT, DOI and LSD in rats

The selective 5-HT(1A) antagonist WAY-100635 was employed to further clarify the respective contributions of 5-HT(1A) receptors to the effects of the 5-HT(1A) agonist 8-OH-DPAT, the 5-HT(2) agonist DOI, and the mixed 5-HT(1A/2) agonist LSD on exploratory locomotion in rats. In nocturnal studies of well-handled rats during their first exposure to the Behavioral Pattern Monitor, which enables analyses of quantitative and qualitative changes in locomotor activity, locomotor and investigatory responses were reduced by treatment with either 8-OH-DPAT, DOI, or LSD. The hypoactivity produced by 8-OH-DPAT, but not that produced by DOI, was antagonized by pretreatment with WAY-100635. These results substantiate the effectiveness and functional specificity of WAY-100635 as a 5-HT(1A) antagonist. Furthermore, these results are inconsistent with a functional interaction between 5-HT(1A) and 5-HT(2) receptors in the control of locomotor behavior. The decreases in locomotion produced by LSD were attenuated by pretreatment with WAY-100635, indicating that the effects of LSD in this paradigm are due partly to agonist actions at 5-HT(1A) receptors. Therefore, 5-HT(1A) receptors appear to play a direct role in mediating the effects of LSD on rodent locomotion.     

Effects of anxiolytic and antidepressant drugs on long-lasting behavioural deficits resulting from one short stress experience in male rats

Exposure of male Wistar rats to one single session of ten inescapable footshocks induces changes in the behavioural responses to environmental stimuli as measured in the noise test 14 days later. Shocked (S) rats showed decreased locomotion and rearing during the first 3 min of exposure to a novel environment compared to control (C) rats. When the 85 dB background noise was switched off a marked immobility response emerged in S rats, concomitant with a further decrease in locomotion and rearing. In response to noise off, C rats showed hardly any immobility and a much smaller reduction in locomotion and rearing compared to S rats. These long-lasting changes in behaviour were not reversed by acute treatment with the antidepressants fluvoxamine (3.0–30.0 mg/kg) and desmethylimipramine (DMI, 2.5–10.0 mg/kg) injected IP 30 min before the noise test on day 14 following the shock session. Chronic treatment (day 1 to day 14) with flvoxamine or DMI did not reverse the behavioural deficits induced by shock exposure. Diazepam (0.6–5.0 mg/kg) administered acutely only reversed the effects of shock on locomotion during the first 3 min of the noise test. Chronic treatment with diazepam normalized the shock-induced decrease in locomotion and attenuated the rearing decrease during the first 3 min of the test, and partially restored shock-induced changes in behavioural response to switching off the noise. The most potent drug in this study was the 5-HT_1A receptor agonist flesinoxan (0.3–3.0 mg/kg). Both acute and chronic drug treatment were equally effective in reversing the shock-induced locomotion deficits as well as the marked immobility response in S rats, although rearing was not reversed. However, flesinoxan also increased locomotion and reduced rearing in C rats, suggesting some nonspecific stimulating effects of flesinoxan. In conclusion, the footshock-induced long-lasting behavioural changes are sensitive to treatment with (putative) anxiolytic agents, whereas no beneficial effect of the antidepressant drugs was found.     

Extended access oxycodone self-administration and neurotransmitter receptor gene expression in the dorsal striatum of adult C57BL/6 J mice

Rationale

Although non-medical use of oxycodone continues to be a growing problem in the United States, there are no animal studies examining the effects of long-term oxycodone self-administration (SA).

Objectives

The current study was designed to examine chronic oxycodone SA by mice (14 days), in novel extended (4 h) SA sessions and its effect on selective striatal neurotransmitter receptor mRNA expression.

Methods

Adult male C57/BL6J mice were either allowed to self-administer oxycodone (0.25 mg/kg/infusion, FR1) or served as yoked-saline controls in an extended access paradigm. Mice self-administered oxycodone for 4 h/day for 14 consecutive days. Comparison groups with 14-days exposure to 1-h SA sessions were also studied. Within 1 h of the last extended SA session, mice were sacrificed, dorsal striatum was isolated and selective neurotransmitter receptor mRNA levels were examined.

Results

The oxycodone groups poked the active hole significantly more times than the yoked controls. The number of nose pokes at the active hole rose over the 14 days in the oxycodone group with extended access. The expression of 13 neurotransmitter receptor mRNAs was significantly altered in the dorsal striatum, including the gamma-aminobutyric acid (GABA) A receptor beta 2 subunit (Gabrb2) showing experiment-wise significant decrease, as a result of extended oxycodone SA.

Conclusion

C57BL/6 J mice escalated the amount of oxycodone self-administered across 14 consecutive daily extended sessions, but not 1-h sessions. Decreases in Gabrb2 mRNA levels may underlie escalation of oxycodone intake in the extended access SA sessions.     

Stimulation of avoidance behavior by buprenorphine in rats

The effects of buprenorphine and morphine on rates and temporal patterns of avoidance responding were studied in rats. Responding was maintained under a schedule of electric shock avoidance with 30-s response-shock and shock-shock intervals during 4-h sessions. Morphine (0.3–3.0 mg/kg) increased response rates, but a dose of 10 mg/kg disrupted bar pressing. Buprenorphine increased response rates (0.003–0.03 mg/kg) and produced maximal effects that plateaued over a greater than 300-fold dose range (0.03–10 mg/kg). Disruption of bar pressing was not observed with buprenorphine. Both drugs also produced dose-related shifts in the interresponse time distribution toward increased conditional probabilities of shorter interresponse times. Morphine (10 mg/kg) and buprenorphine (0.3–10 mg/kg) virtually abolished the temporal patterning of responding in that the conditional probability of a response occurring in any class interval from 0.5 to 25.5 s was close to 0.5. These results demonstrate that lower doses of buprenorphine and morphine produce similar effects on avoidance behavior in rats. At higher doses, the effects of morphine differ from those of buprenorphine in that morphine disrupts bar pressing behavior, whereas the rate-increasing effects of buprenorphine platcau over a broad dose range.     

Residual effects of prolonged cannabis administration on exploration and DRL performance in rats

Chronic oral administration of cannabis extract to rats (daily ⁹ dose 20 mg/kg) was examined for its residual effect on open field activity and DRL (differential reinforcement of low-rate responding) performance, following a 2–3-month drug-free period. Locomotor activity during the latter part of an open field test was markedly increased in rats previously treated for either 6 months or 3 months with the drug. The same treatments also produced a significant impairment on a DRL-20 task relative to control subjects' performance. These and other findings (impaired maze learning and facilitated two-way shuttle box avoidance) might mean that cannabis produces long-lasting hippocampal, dysfunction in rats.