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.

Calcium channel blockade interacts with a neuroleptic to attenuate the conditioning of amphetamine's behavioral effects in the rat.

Conditioned responses to drug-related cues appear to be related to the maintenance of stimulant addiction. These conditioned responses are not blocked by treatments that block the direct effects of stimulants and may contribute to the high rate of relapse of addicts. Rats administered (+)-amphetamine in a specific environment exhibit conditioned locomotion when subsequently placed in that environment without drugs. The neuroleptic haloperidol significantly attenuated amphetamine-induced locomotor activity but failed to reduce conditioned locomotion. Nimodipine, an L-type calcium channel antagonist, had no effect on amphetamine-induced unconditioned or conditioned locomotion. However, combined nimodipine and haloperidol treatment blocked the unconditioned and attenuated the conditioned locomotor response to amphetamine. Conjunctive therapy with nimodipine and haloperidol may provide an efficacious treatment for stimulant addiction. In addition, nimodipine may provide an important adjunctive therapy for schizophrenia, allowing the use of lower doses of neuroleptic to avoid extrapyramidal side effects.

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.

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.

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.

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.

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.

Role of dopamine D-1 and D-2 receptor subtypes in mediating dopamine agonist effects on food consumption in rats.

The effects of selective D-2 and D-1 dopamine (DA) receptor agonists on food consumption were investigated in free-feeding rats. A selective D-2 receptor agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), increased the consumption of standard food pellets in the dose range of 7.5-120 micrograms/kg, while SKF 38393 (5.0 mg/kg), a selective D-1 receptor agonist, decreased food pellet intake. The increase in food pellet intake produced by PHNO was blocked by haloperidol (an antagonist relatively selective for the D-2 receptor at the dose used, 0.05 mg/kg) and SCH 23390 (20 micrograms/kg, a D-1 receptor selective antagonist). Increasing "arousal" by disturbance associated with repeated food weighing also increased food pellet consumption, but did not diminish PHNO-elicited feeding. However, the same range of doses of PHNO (7.5-120 micrograms/kg) which increased food pellet intake decreased consumption of a liquid diet, and had no overall effect on a highly palatable liquid diet. The increase in consumption of solid food induced by PHNO appears to be secondary to enhancement of chewing behaviors. In contrast, the decrease in food intake induced by SKF 39393 may be due to a direct action of the drug on neural feeding mechanisms.

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.

Nimodipine and haloperidol attenuate behavioural sensitization to cocaine but only nimodipine blocks the establishment of conditioned locomotion induced by cocaine.

The classical conditioning of the behavioural effects of cocaine has been shown to contribute to behavioural sensitization. In the present experiments, it was demonstrated that the effects of cocaine in rats can be conditioned to contextual stimuli. Furthermore, sensitization to cocaine's locomotor effects were demonstrated, and shown to be context specific. Nimodipine (10 mg/kg, SC), an L-type dihydropyridine Ca2+ channel antagonist, appeared to completely block the establishment of conditioning of cocaine's effects, but only partially blocked sensitization to cocaine. Haloperidol (0.05 mg/kg, IP), a relatively specific D2 dopamine receptor antagonist, attenuated behavioral sensitization but had no influence on the establishment of the conditioned component of cocaine. These results indicate that the sensitization to, and the development of classical conditioning of, cocaine's behavioural effects can be pharmacologically dissociated, but that a non-associative process involved in sensitization is normally overridden by conditioning factors.

Chronic administration of a selective dopamine D-2 agonist: factors determining behavioral tolerance and sensitization.

The locomotor stimulant effects of sustained administration of a potent and selective dopamine (DA) D-2 receptor agonist, [+]-4-propyl-9-hydroxynaphthoxazine (PHNO), in rats were assessed 24 h a day during 12 h light-dark cycles. PHNO was administered continuously with subcutaneous implants of Alzet osmotic minipumps (5 micrograms/h), for 12 h a day with modified osmotic minipumps (5 micrograms/h), or by daily injections (15 micrograms, SC). Tolerance was observed to occur only with 24 h continuous infusions and only during the light period. The other treatment regimens produced sensitization of the locomotor response. Daytime tolerance to continuous infusions of PHNO was reversed following reversal of the light-dark cycle. A normally 'arousing' stimulus also reversed (temporarily) daytime tolerance. The present results indicate that the temporal pattern of administration of DA agonists, the phase of the circadian cycle and environmental stimuli associated with arousal are important determinants of the behavioral consequences of long-term treatment.

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.

6-Hydroxydopamine lesions of the medial prefrontal cortex fail to influence intravenous self-administration of cocaine.

It has been suggested that the initiation and maintenance of cocaine self-administration (SA) is critically dependent on the dopaminergic (DA) projection to the medial prefrontal cortex (mPFC). Evidence for this hypothesis has been obtained from intracranial SA of cocaine, but a role of the mPFC in IV cocaine SA has not been established. The present experiment investigated the effect of destruction of DA-containing terminals in the mPFC on the rate and pattern of IV cocaine SA. Rats were trained to self-administer cocaine during daily 3-h sessions. After stable response patterns were obtained, the rats received either bilateral injections of 6-hydroxydopamine (6-OHDA) into the mPFC, or sham operations. The lesions did not affect either the rate or pattern of IV cocaine SA, despite producing substantial DA depletions in the mPFC. Thus, the mPFC does not appear to be a critical substrate for the maintenance of IV cocaine SA. The 6-OHDA lesions of the mPFC resulted in an apparent increase in DA turnover in both the striatum and the nucleus accumbens, suggesting that DA terminals in the mPFC may have an inhibitory influence on the activity of subcortical DA projections.

Effects of haloperidol and d-amphetamine on perceived quantity of food and tones.

The hypothesis that dopamine (DA) receptor agonists and antagonists affect "hedonia" associated with natural rewards was tested, using a psychophysical procedure previously shown to be sensitive to both the sweetness of food and the motivational state of rats. Rats were first trained to discriminate between two different quantities of a rewarding stimulus by pressing one of two levers. Perceived quantity was subsequently derived from generalization trials of intermediate quantities. Haloperidol (0.03-0.083 mg/kg), a DA receptor antagonist, did not influence perceived food quantity, an indirect marker of hedonic value. On the other hand, d-amphetamine (0.25-1.0 mg/kg) affected perceived food quantity in a dose-dependent fashion, and in the same direction as occurs after increasing hunger or food sweetness. Both haloperidol and amphetamine influenced the perceived quantity of a stimulus without natural reinforcing properties (a tone), but the effect of amphetamine on the perceived quantity of this initially neutral stimulus was opposite in direction to that observed with food. These results suggest that whereas amphetamine affects hedonic processes, haloperidol does not. In addition, it seems that haloperidol probably produces its actions through effects on motor mechanisms or by interfering with the response-facilitating properties of rewards.

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.

The effects of haloperidol on amphetamine- and methylphenidate-induced conditioned place preferences and locomotor activity.

Place preferences induced by the indirect dopamine (DA) receptor agonists amphetamine (AMP) and methylphenidate (MPD) were investigated using an unbiased compartment procedure. In this procedure, prior to drug conditioning, rats did not exhibit preferences for either of the two compartments in a shuttle box. Both stimulants produced place preferences. Repeated testing of the MPD conditioned animals revealed an extinction-like decrease in preferences, suggesting that place preferences produced by MPD result from conditioning of MPD's reinforcing properties to environmental cues. During conditioning, the DA receptor antagonist haloperidol was administered prior to drug (S+) treatments, or prior to both drug and vehicle (S-) treatments. Haloperidol pretreatment blocked place preferences induced by AMP but not by MPD. In contrast, haloperidol blocked locomotor activity stimulated by either AMP or MPD. These results suggest that the reinforcing properties of MPD and AMP may be mediated by different mechanisms, while the locomotor stimulant effects of the two drugs have common neural substrates.

Selective dopamine D1 and D2 agonists independently affect different components of the free-running circadian rhythm of locomotor activity in rats.

The effects of selective dopamine D1 (SKF 38393) and D2 (4-propyl-9-hydroxynaphthoxazine or PHNO) agonists on free-running rhythms of locomotor activity in rats were investigated under either constant light (LL) or dark (DD) condition. Rats under the DD condition exhibited clear circadian patterns of activity, while circadian patterns of activity in animals kept under the LL condition were more ambiguous. Under the DD condition, SKF 38393 significantly increased the length of the period of free-running rhythms of locomotor activity but had no effect on the amplitude and the mesor, while PHNO significantly increased the amplitude and the mesor of free-running rhythms but had no effect on the length of the period.

Stimulant-conditioned locomotion is not affected by blockade of D1 and/or D2 dopamine receptors during conditioning.

A series of experiments were conducted to investigate the role of dopamine (DA) D1 and D2 receptor subtypes in stimulant-conditioned locomotion in rats. Expt. 1 demonstrated that locomotion could be induced by a testing situation when that situation was previously paired with (+)-amphetamine (1.5 mg/kg, s.c.) or a D2 receptor selective agonist (PHNO, 15 or 30 micrograms/kg, s.c.), but not when the drug treatments were given 3 h after exposure to the situation. The selective D2 receptor antagonist, haloperidol (50 micrograms/kg, i.p.), and the D1 receptor antagonist, SCH 23390 (20 micrograms/kg, s.c.), blocked amphetamine-induced locomotion during the pairing process, but failed to block amphetamine-conditioned locomotion as assessed during a drug-free test in Expt. 2. This was true when the antagonists were given separately or together. The results of Expts. 3 and 4 showed that doses of the D1 (20 micrograms/kg, s.c.) and D2 antagonist (250 micrograms/kg, i.p.) that blocked the unconditioned locomotor effects of PHNO failed to block its conditioned locomotion. It is concluded that neither D1 nor D2 DA receptors are essential for the development of stimulant-conditioned locomotion.

Increased occupation of D1 and D2 dopamine receptors accompanies cocaine-induced behavioral sensitization.

In rats exhibiting behavioural sensitization after daily cocaine (10 mg/kg, i.p.) injections, the occupation of D1 and D2 dopamine receptors by dopamine, measured as protection from N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) receptor denaturation, was increased by about 100% compared to animals receiving cocaine in a treatment regimen that produced behavioural tolerance. Co-administration with nimodipine, an agent that blocks the impulse-dependent increase in synaptic concentrations of dopamine caused by cocaine, not only blocked sensitization but also blocked the increase in occupation of receptors. These findings strongly support the hypothesis that enhanced dopamine release and subsequent interaction with dopamine receptors is a substrate for behavioural sensitization to cocaine and have implications for the pharmacotherapy of cocaine abuse.