Cannabis use and neuropsychological performance in healthy individuals and patients with schizophrenia.

BACKGROUND: The effects of cannabis use on neuropsychological indices that show characteristic disturbances in schizophrenia are unclear. The effect of cannabis use on these cognitive functions is of particular interest given the hypothesized association between cannabis use and schizophrenia. Therefore, this study aimed to examine the effects of cannabis use on attentional control, working memory and executive functioning, in both healthy individuals and patients with schizophrenia. METHOD: Neuropsychological performance was assessed in 36 cannabis users who were otherwise healthy, 35 healthy non-users, 22 cannabis-using patients with schizophrenia, and 49 non-using patients with schizophrenia. Participants were administered the Stroop task, the letter-number sequencing and spatial span subtests of the Wechsler Memory Scale, and the Wisconsin Card Sorting Test (WCST). RESULTS: Patients with schizophrenia (both cannabis users and non-users) showed significantly poorer performance across all neuropsychological tasks, relative to controls; however, there were no significant differences between schizophrenic cannabis users and schizophrenic non-users on any measures, with the exception of increased non-perseverative errors on the WCST in cannabis-using patients. Similarly, healthy cannabis users showed no significant differences from healthy non-users in any of the cognitive domains, with the exception of a schizophrenic-like increase in perseveration on the WCST. CONCLUSIONS: Amongst both healthy individuals and patients with schizophrenia there appears to be little difference in cognitive performance between cannabis users and non-users, suggesting that cannabis use has only subtle effects on the neurocognitive performance indices assessed here, which have been well established to be disturbed in schizophrenia.

Stimulus quality affects expression of the acoustic startle response and prepulse inhibition in mice.

The relationship between stimulus intensity and startle response magnitude (SIRM) can assess the startle reflex and prepulse inhibition (PPI) with advantages over more commonly used methods. The current study used the SIRM relationships in mice to determine differences between white noise and pure tone (5 kHz) stimuli. Similarly to rats, the SIRM relationship showed a sigmoid pattern. The SIRM-derived reflex capacity (RMAX) and response efficacy (slope) of the white noise and pure tone stimuli in the absence of prepulses were equivalent. However, the pure tone startle response threshold (DMIN) was increased whereas the stimulus potency (1/ES50) was decreased when compared to white noise. Prepulses of both stimulus types inhibited RMAX and increased DMIN, but the white noise prepulses were more effective. Both stimulus intensity gating and motor capacity gating processes are shown to occur, dependent on prepulse intensity and stimulus onset asynchrony. Prepulse intensities greater than 10 dB below the startle threshold appear to produce PPI via stimulus intensity gating, whereas a motor capacity gating component appears at prepulse intensities near to the startle threshold.

Entrainment of circadian rhythm to a photoperiod reversal shows retinal dystrophy in RPE65(-/-) mice.

Light entrainment of circadian rhythms is mediated by classical "visual" photoreceptors (rods and cones) as well as "nonvisual" photoreceptive elements (light-detecting cells that do not contribute to classical "vision"). This paper aimed to assess whether light entrainment of locomotor circadian rhythms in mice with impaired rods and cones differs from normal controls and whether this technique, alongside existing techniques, could be used to assess visual function. The study was primarily interested in differences between the entrainment of circadian rhythms of normal-sighted C57Bl/6J mouse and the C57Bl/RPE65 knockout mouse (RPE65(-/-)), although C3H/HeJ (rd/rd) mice were included as a preexisting model of retinal degeneration. Circadian rhythms of motor activity before and after a 12-h light reversal were assessed in custom-built cages that continuously monitored movement. The controls showed a significantly higher mesor and amplitude when compared to the RPE65(-/-) and rd/rd mice. Despite the loss of rods and cones, the RPE65(-/-) and rd/rd maintained a 24-h circadian rhythm entrained to light similar to controls and were capable of circadian reentrainment to a 12-h light reversal. Importantly, this light reentrainment of the circadian phase occurred at a significantly slower rate in the retinal degenerate models than in the controls. The RPE65(-/-) model demonstrates a retinal degenerate reentrainment phenotype when compared to the rd/rd model. It is suggested that these retinal degenerate mice retain the ability to detect light for the purposes of circadian rhythm entrainment. However, alterations of specific parameters of the circadian rhythm with loss of rods and cones may provide measures of loss of visual function (sight).

Differing effects of the cannabinoid agonist, CP 55,940, in an alcohol or Tween 80 solvent, on prepulse inhibition of the acoustic startle reflex in the rat.

It has been suggested that cannabinoid agonists increase dopamine (DA) transmission in the mesolimbic dopamine system. However, evidence for such an effect is inconsistent. Prepulse inhibition (PPI) of the acoustic startle reflex is a behavioural paradigm that is modulated by an increase of mesolimbic dopamine. This study sought to ascertain whether or not a cannabinoid agonist, CP 55,940, mimicked the effects of amphetamine (a drug which increases dopamine release) on PPI. The first experiment measured the PPI of 16 male Wistar rats injected (i.p.) with different doses of CP 55,940 in a Latin-square design. A second experiment replicated the effects of the first experiment in a between-subjects design, and also examined the effects of using a 5% alcohol solution as a solvent for cannabinoid agonists, in comparison to the more inert detergent, Tween 80. In both experiments, CP 55,940 in Tween 80 significantly reduced basal activity, increased startle onset latencies and increased PPI, effects opposite to those of amphetamine. These results suggest that the net behavioural effects of cannabinoids are opposite to those of amphetamine. In addition, it was found that 1 ml/kg of a 5% alcohol solution has significant behavioural effects on its own, and reverses the effects of CP 55,940 on PPI.

Pinealectomy blocks stress-induced motor stimulation but not sensitization and tolerance to a dopamine D2 receptor agonist.

RATIONALE: The motor stimulant effects of the selective dopamine D2 receptor agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), develop both tolerance and sensitization depending on circadian rhythms and time of day. Daytime tolerance can be transiently reversed by stress. Given that only tolerance develops when rats are kept under constant light conditions, it seems plausible that the pineal hormone melatonin may determine the circadian rhythm in tolerance and sensitization. OBJECTIVE: The effects of pinealectomy on the development of sensitization and stress-induced reversal of tolerance to sensitization to the motor stimulant effects of PHNO were determined. METHODS: Sprague-Dawley rats were pinealectomized or given sham operations and administered continuously with PHNO (5 microg/h) via subcutaneously implanted mini-pumps. Injections of 2-iodo-melatonin were subsequently administered to determine if sensitization to PHNO could be reinstated in the pinealectomized animals, assuming that sensitization would be reduced. RESULTS: Pinealectomy did not influence circadian rhythms in the development of sensitization and tolerance to PHNO. Pinealectomy blocked the motor activation effects of "injection-stress", and this effect was reinstated by treatment with 2-iodo-melatonin. CONCLUSIONS: Melatonin is not involved in the development of sensitization or tolerance to the behavioral effects of PHNO. However, melatonin modulates the stress-induced motor activity responses.

Does locomotor response to novelty in rats predict susceptibility to develop sensitization to cocaine and PHNO?

It has been suggested that the locomotor response of rats to novelty is positively correlated with motor stimulant effects of acute injections with psychomotor stimulants, and liability to self-administer these drugs. In addition, response to novelty appears to be inversely correlated with an individual's susceptibility to develop behavioural sensitization (an increase in the behavioural response to a given dose of stimulant after repeated treatments). To test some of these putative relationships, 96 rats were allocated to one of two subgroups based on a median split of locomotor responses to novelty. Animals then received 10 successive injections of either vehicle, cocaine (10 mg/kg), or the direct D2 agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO: 15 microg/kg), and locomotor activity was monitored. Conditioning tests and additional sensitization and cross-sensitization tests were conducted. Results showed that locomotor responses to novelty are not significantly correlated with locomotor effects of either acute injection with cocaine or PHNO, or rate of development of behavioural sensitization to these drugs. However, locomotor responses to novelty did predict level of locomotor and stereotypy responses to cocaine, and to a lessor extent to PHNO. Cocaine-treated, but not PHNO-treated, rats exhibited drug-conditioned-like effects. Cross-sensitization between cocaine and PHNO was not observed, indicating independent mechanisms for sensitization. It is concluded that the locomotor response to novelty can predict level of locomotion and stereotypy produced by cocaine and PHNO, but does not predict the degree or rate of behavioural sensitization to either of these drugs.

PHNO, a selective dopamine D2 receptor agonist, does not reduce prepulse inhibition of the startle reflex in rats.

RATIONALE: Dopamine agonists nonselective for dopamine receptor subtypes, such as apomorphine, reduce prepulse inhibition of the startle reflex. It has been suggested that either D2 or D3 dopamine receptors mediate this action of apomorphine. OBJECTIVE: The present study investigated whether a selective D2 agonist with relatively low affinity for D3 receptors can reduce prepulse inhibition. METHODS: Rats (n=48) were treated with vehicle or one of three doses ( 15, 30 or 60 microg/kg, s.c.) of the specific dopamine D2 receptor agonist (+)-4-propyl-9-hydroxynaphthoxazine (PHNO) for 11 days. On days 1, 6 and 11 of treatment, the rats (n=12 in each group) were tested for their acoustic startle reflexes (105-dB, 40-ms white noise) and for prepulse inhibition (5-kHz tone, 5 dB above a 65 dB background white noise). Prepulses were presented with a range of stimulus onset asynchronies (SOAs: 5-160 ms) or lead times between the onset of the prepulse and the onset of the startle stimulus. In a second experiment, two groups of rats (n=10 in each group) were tested in a similar manner after vehicle or apomorphine (0.8 mg/kg, s.c.) to verify the sensitivity of the present procedure to agonist-induced reductions in prepulse inhibition. RESULTS: At doses that increased motor activity, PHNO increased prepulse inhibition at SOAs less than 80 ms and had no effect on prepulse inhibition at SOAs of 80 ms or above. However, all doses decreased startle amplitudes on trials in which only the startle-eliciting stimulus was presented. Apomorphine reduced prepulse inhibition under the same conditions. CONCLUSIONS: These findings with PHNO are in contrast to the less-specific D2 agonist, quinpirole, which has been reported to decrease prepulse inhibition. It is concluded that activation of D2 dopamine receptors alone is not sufficient to attenuate prepulse inhibition of the startle reflex.

Circadian rhythm-dependent development of melatonin effects and tolerance to PHNO in rats.

Male Sprague-Dawley rats were given 12 days of continuous infusions of (+)-4-propyl-9-hyroxynapthoxazine (PHNO, 5microg/h), a highly selective dopamine D(2) receptor agonist, via subcutaneous ALZET((R)) osmotic pumps. Motor stimulant effects (locomotion and rearing) were monitored throughout the treatment period, including after the animals were injected with 2-iodo-melatonin (0.5 mg/kg) on days 8-10 and 13 after initiation of PHNO infusions. The rats (maintained on 12 L:12 D cycle) developed tolerance to the motor stimulant effects of PHNO during the day, and behavioral sensitization to PHNO during the night. Arousing rats with a vehicle injection transiently blocked the daytime tolerance. A more sustained environmental noise without handling of animals, which had a stronger effect on increasing motor activity of control rats, reversed tolerance to sensitization. Therefore, graded levels of arousal produce graded increases in motor activity in rats otherwise tolerant to the effects of PHNO. Daytime tolerance to PHNO was reversed to sensitization by 2-iodo-melatonin. This effect was more than an additive effect of drug + injection procedure stress. The differential development of nocturnal sensitization and diurnal tolerance to PHNO effects on motor activity may depend upon circadian rhythms in melatonin release, as well as on state of arousal.

Does sensitization occur to prepulse inhibition of the startle reflex effects of repeated apomorphine treatments in rats?

There are conflicting reports as to whether or not the effects of dopamine agonist effects at reducing prepulse inhibition of the acoustic startle reflex develop sensitization with repeated treatments. In this experiment, rats (12 per each dose group) were treated for 10 days prior to startle-testing on each day with 0 (vehicle), 50, 200 or 800 microg/kg of apomorphine. Startle testing was conducted with each rat receiving no stimulus trials (null trials), startle pulse only trials (40 ms 105 dB white noise), prepulse only trials (20 ms 72 dB 5 kHz tone) and prepulse+pulse trials with a 100 ms stimulus onset asynchrony (SOA, i.e. the lead time from onset of prepulse to onset of pulse). The rats were then challenged after 5-7 days of withdrawal from the treatment regimen with a vehicle and apomorphine (200 microg/kg) injection with the order of injection counterbalanced. A range of SOAs and two different prepulse intensities (68 and 70 dB) were presented to every rat on the challenge tests. Sensitization developed during treatment to the increase in motor activity produced by the two higher doses, and to the increase in an orienting response produced by the prepulse stimulus in the highest dose group, but not to the prepulse inhibition effect of the drugs. The 50 microg/kg inhibitory autoreceptor selective dose decreased responses on the first of three blocks of both null trials and prepulse only trials. The two higher doses dose-dependently increased startle reflex amplitudes on the prepulse+pulse trials (reduced prepulse inhibition), but this effect did not exhibit sensitization during treatment. The lowest dose significantly increased prepulse inhibition relative to the vehicle-treated group on the first block of trials over days. After apomorphine challenge, sensitization to the effects of apomorphine on reducing prepulse inhibition was apparent for some dose groups at some SOAs. Sensitization to the effects of apomorphine on prepulse inhibition can be demonstrated upon a subsequent drug challenge if pretreatments are associated exclusively with the startle testing environment.

Unbiased cocaine conditioned place preferences (CPP) obscures conditioned locomotion, and nimodipine blockade of cocaine CPP is due to conditioned place aversions.

The effect of nimodipine (0, 0.1, 1.0 and 10 mg/kg, SC), a dihydropyridine L-type Ca2+ channel antagonist, on the establishment of cocaine-(10 mg/kg IP) conditioned place preferences (CPP) was investigated. Nimodipine produced conditioned place aversions (CPA) on its own; reductions in cocaine CPP are apparently due to this CPA. There is a high negative correlation between time spent in the CS+ compartment and the difference in locomotion rates between the CS+ and the non-drug (CS-) compartments, independent of drug effects. This relationship is responsible for an increased rate of locomotion observed in the CS- compartment in cocaine-conditioned rats. Analysis of covariance indicated that cocaine CPP occurred independently of cocaine's effects on locomotion. Furthermore, cocaine produces an increase in the rate of locomotion in the CS+ compartment when time spent in this compartment is equated with time spent in the CS- compartment. This suggests that cocaine's effects on CPP and "conditioned" locomotion are due to separate mechanisms of action. On the other hand, nimodipine-induced place aversions and locomotor rates are not independent of each other, indicating a common mechanism of action, or that one is a consequence of the other. It is concluded that place preferences and place aversions can sometimes be secondary to compartment-specific locomotor changes, and locomotion effects can be confounded by differential times spent in each compartment. The relationships between these two behaviours must be controlled for before conclusions of CPP or CPA can be drawn in drug conditioning studies.

Behavioral sensitization to cocaine, but not cocaine-conditioned behavior, is associated with increased dopamine occupation of its receptors in the nucleus accumbens.

Rats had repeated treatments with cocaine associated with a specific context (paired group). Evidence for classical conditioning of cocaine's motor-activity effects and context-specific behavioral sensitization to cocaine was obtained, relative to vehicle-treated (control) and pseudoconditioned (unpaired) groups. Only the paired group exhibiting context-specific behavioral sensitization had more dopamine bound to both D1-like and D2-like receptors in the nucleus accumbens than did rats in the control group receiving cocaine on the test day. No effects on receptor occupation were found in rats showing a classical conditioned response to a context previously paired with cocaine. Thus, sensitization to cocaine, but not classical conditioning of cocaine's behavioral effects, was associated with greater dopaminergic neurotransmission selectively in the nucleus accumbens.

Classically conditioned motor effects do not occur with cocaine in an unbiased conditioned place preferences procedure.

Classical conditioning and behavioural sensitisation of motor activity induced with cocaine (10mg/kg, i.p.) were examined using an unbiased two-compartment conditioned place preference (CPP) procedure. Habituation of the rats to the testing environment prior to training was varied (i.e. either the rats were habituated to the environment for three 30min sessions or they were not) in order to examine a possible influence of latent inhibition on conditioned locomotion or behavioural sensitisation. Furthermore, rats were either trained with an explicit CS+ (cocaine-paired compartment) and CS- (vehicle-paired compartment), or else they were trained with no barrier between the compartments (effectively a single-compartment procedure with no explicit CS-) in order to examine a possible influence of stimulus change (training rats while confined to one compartment, but testing with no barrier between compartments). On a drug-free test day with free access to both compartments, rats previously exposed to cocaine in one compartment (CS+) and vehicle in the second compartment (CS-) spent more time in the CS+ compartment (conditioned place preference). However, under no circumstance was the rate of motor activity higher in the CS+ compartment than in the CS- compartment, as would be expected if cocaine-induced motor activity was classically conditioned to contextual cues. Whether or not increased activity extinguished with repeated drug-free exposures to previously drug-paired contexts depended on habituation experience. In addition, both habituation and current access to compartments (free or restricted) determined the presence of post-extinction sensitisation to a challenge dose of cocaine (7.5mg/kg). Classical conditioning and non-associative sensitisation, independently or together, cannot account for this pattern of results.

Spontaneous behaviours of rats are differentially affected by substantia nigra infusions of brain-derived neurotrophic factor and neurotrophin-3.

The effects on spontaneous behaviour after 7 and 14 days of continuous unilateral infusion of brain-derived neurotrophic factor (BDNF, 12 micrograms/day) and neurotrophin-3 (NT-3, 12 micrograms/day) into the rat substantia nigra were investigated during the day and night. Animals subjected to these treatments were compared to untreated controls and vehicle-infused controls that were weight-matched for the decreases in body weight produced by BDNF and NT-3. BDNF increased feeding and food retrieval, indicating that BDNF did not decrease appetite. BDNF but not NT-3 markedly decreased drinking, suggesting that weight loss in BDNF-treated rats may be secondary to hypodypsia, whereas in NT-3-treated rats weight loss was more likely a direct consequence of decreased feeding. Exploratory behaviours, limb flicks and contralateral postural bias were increased by BDNF. The behavioural profile of BDNF-treated rats is consistent with an increase in dopaminergic activity. In addition, BDNF increased backwards walking, a behaviour that requires the activation of both dopamine and serotonin systems. In contrast, NT-3 selectively increased behaviours that are mediated primarily by serotonin, such as wet-dog shakes. NT-3 increased limb flicks and mouth movements, but had a smaller effect than BDNF on exploratory behaviour. Vehicle infusions produced behavioural effects consistent with cannula- or infusion-induced damage to the nigrostriatal dopamine system, and some of these effects were reversed by BDNF. Most of the behavioural effects of the neurotrophins are consistent with the view that BDNF increases activity of both dopaminergic and serotonergic systems within the nigrostriatal system, and that NT-3 increases serotonin activity. Effects of BDNF and NT-3 on grooming behaviours, possibly indicative of actions on nigral neuropeptides, provide further evidence of consistencies between reported neurochemical and behavioural effects of neurotrophins.

Pavlovian conditioning of psychomotor stimulant-induced behaviours: has convenience led us astray?

In order to classically condition the behavioural effects of psychomotor stimulants within a test context, rats were treated for 10 days with (+)-amphetamine (1.5mg/kg), (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 30µg/kg) or vehicle prior to a 1h placement into a test box. Conditioned behavioural effects were then measured in the previously drug-paired context after a vehicle injection (drug-free test day). Each rat was videotaped for the 1h test box exposure on days 1, 4, 7 and 10 of the drug conditioning trials, and on the drug-free test day. Eleven of 28 behaviours that were scored for frequency, duration and mean bout duration (bout length) were significantly influenced by at least one of the two drugs. Amphetamine predominantly increased bout lengths while PHNO predominantly increased bout frequency. Only two measures that were influenced by the drugs exhibited clear increases over controls in a manner consistent with a classical conditioning interpretation. Behavioural sensitization clearly occurred to some of the effects of amphetamine and PHNO, but these were not the same effects as those increased on the non-drug day testing for classical conditioning. Most behavioural effects of amphetamine and PHNO are not classically conditioned, and behavioural sensitization to these drugs, while perhaps context-specific, is not due to classical conditioning. Automated measures of behaviours have provided misleading evidence concerning the similarity among behavioural effects of stimulants, sensitization and effects of exposure to an environment previously paired with stimulants. Analysis of transitions between behaviours does not support the view that stimulants increase switching or response competition, or that behavioural reorganization is responsible for sensitization. Rather, it is suggested that stimulants selectively facilitate current stimulus-guided behaviours.

Behavioral sensitization and tolerance to cocaine and the occupation of dopamine receptors by dopamine.

Data from the authors' laboratory on the neural substrates of Pavlovian conditioning and behavioral sensitization to psychomotor stimulants are reviewed. The findings of a recent experiment on the role of occupation of dopamine receptors by dopamine and its association to behavioral sensitization are reported. Daily intermittent injections of cocaine produced behavioral sensitization to the locomotor response in rats, whereas continuous cocaine infusions produced behavioral tolerance. Behavioral sensitization to cocaine was blocked by coadministration of nimodipine, an L-type calcium channel blocker. The increase in locomotion produced by cocaine was associated with an increase in the occupation of striatal dopamine D1 and D2 receptors, measured as the density of receptors protected from denaturation by N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ). This association was not observed when rats were given a challenge injection of cocaine 10 d after withdrawal from similar treatment regimens. Rats given a cocaine challenge after withdrawal from either intermittent or continuous cocaine treatments regimens exhibited increased occupation of striatal D1 and D2 receptors. This increase was similar in magnitude to that observed in rats without a history of cocaine treatments after a challenge injection of cocaine. This suggests that the differences in occupancy of striatal dopamine receptors by dopamine observed in the prewithdrawal condition are likely the results of differences in brain levels of cocaine achieved by the two treatment regimens. Occupancy of striatal dopamine D1 and D2 receptors does not appear to be related to the development of sensitization to the motor-stimulating effects of cocaine.

Clinical and chronobiological effects of light therapy on nonseasonal affective disorders.

Light therapy (bright or dim light) was given at different times (morning or evening) to 27 unmedicated patients with nonseasonal depression (according to DSM-III-R criteria) and 16 normal volunteers. Circadian rhythms in body temperature were measured before and after light therapy. Bright light significantly improved clinical symptoms of depression, as measured by the Hamilton Rating Scale for Depression (HRSD), independent of the time of phototherapy. Dim light therapy had no effect on HRSD scores. Circadian rhythms of body temperatures in patients with affective disorder were more sensitive to the entraining effects of bright light than those of normal subjects, but these effects were not related to clinical improvement. Bright light exposure has an antidepressant effect on patients with nonseasonal depression, but the effect is unlikely to be mediated via the same circadian system that regulates body temperature.

Conditioned place preferences, conditioned locomotion, and behavioral sensitization occur in rats treated with diethylpropion.

Diethylpropion is a centrally acting appetite-suppressing drug thought to act primarily through catecholamine pathways in the brain. In the present study, four doses of diethylpropion (0, 10, 20, and 40 mg/kg, intraperitoneally) were administered to rats to examine the hypothesis that the drug has psychomotor stimulant properties such as the ability to induce conditioned behaviors and behavioural sensitization. The rats were administered drug and then vehicle on alternating days, and confined to a "drug" or vehicle-paired side of a two-compartment box for 16 pairings. Only the 10-mg/kg dose of diethylpropion increased spontaneous locomotor activity in comparison to vehicle; the 20- and 40-mg/kg doses significantly decreased spontaneous locomotion. All doses of diethylpropion decreased spontaneous rearing, and the 20-and 40-mg/kg doses produced significantly less rearing than the 10-mg/kg one. At the 10-mg/kg dose, conditioned place preferences, conditioned locomotion, and conditioned rearing were observed. The 40-mg/kg dose produced conditioned rearing and conditioned defecation. In response to a 5-mg/kg challenge injection of diethylpropion, behavioural sensitization in locomotion and rearing occurred in rats that had previously received any one of the three doses of diethylpropion. Over 36 days, decreased weight gain was observed only in the 20- and 40-mg/kg groups. The rats were killed 48 h after the last drug injection, and whole brain was analyzed for levels of the catecholamines, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), 5-HT (not a catecholamine), and 5-hydroxyindoleacetic acid (5-HIAA) by HPLC with electrochemical detection.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative behavioural and neurochemical studies with a psychomotor stimulant, an hallucinogen and 3,4-methylenedioxy analogues of amphetamine.

Spontaneous behaviours were assessed in freely moving rats after treatment with equimolar doses of drugs that share a basic amphetamine structure. The drugs used included a psychomotor stimulant [(+)-amphetamine (AMPH)], an hallucinogen [para-methoxyamphetamine (PMA)] and the entactogens 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxy-N-ethylamphetamine (MDE). A detailed analysis of the frequency and duration of 30 different behaviours and the temporal organization of the behaviours was conducted in addition to measuring motor activity with an automated device. Levels of the biogenic amines and their acid metabolites in discrete brain regions and brain drug levels were also obtained. The automated motor activity measures discriminated among entactogens, the stimulant and the hallucinogen, but failed to distinguish between the hallucinogen and vehicle. Principal components analysis and cluster analysis of the frequencies and durations of the behaviours did not improve the classification of the drugs over the automated motor activity measures. Only the cluster analysis of the transitions between individual behaviours succeeded in differentiating the drug classes from each other and from vehicle treatment. All the behavioural measures classified one entactogen (MDE) as an hallucinogen. Cortical 5-hydroxytryptamine (5-HT) measures grouped MDE with the other entactogens but did not distinguish AMPH from vehicle. However, striatal dopamine measures differentiated AMPH from vehicle treatment. Variations in the durations of behavioural effects across drugs were associated with large differences in drug levels 3 h after injection. Although the neurochemical data provided a classification system that most closely parallels human subjective effects of these drugs, both the neurochemical and the behavioural measures supported the existence of an entactogen class distinct from a psychomotor stimulant and an hallucinogen.

Effects of nimodipine and/or haloperidol on the expression of conditioned locomotion and sensitization to cocaine in rats.

The development of classical conditioning of cocaine's locomotor effects can be dissociated from the development of sensitization to cocaine by co-administration of haloperidol, a dopamine D2-like receptor antagonist, and nimodipine, an L-type calcium channel antagonist. The effects of these agents on the expression of conditioning and sensitization are described in the present report. Rats were given injections of vehicle or cocaine (10 mg/kg, IP) for 10 days before placement in a specific context in which locomotor activity was recorded. Neither haloperidol (0.05 mg/kg, IP) nor nimodipine (10 mg/kg, SC) influenced the expression of classical conditioning of cocaine's locomotor effects to the situational context on a subsequent cocaine-free test. Combined treatment of rats with both drugs did block classical conditioning with cocaine. Nimodipine, but not haloperidol, blocked the expression of behavioural sensitization to cocaine after a cocaine challenge. It is concluded that the expression of cocaine-induced classical conditioning can be pharmacologically dissociated from the expression of behavioural sensitization to cocaine. Furthermore, the effects of nimodipine and haloperidol on the expression of conditioning and sensitization are different from their effects on the development of these phenomena.