Mathew T. Martin-Iverson

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.

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 cocaines 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 cocaines 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, cocaines behavioural effects can be pharmacologically dissociated, but that a non-associative process involved in sensitization is normally overridden by conditioning factors.

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

The development of classical conditioning of cocaines 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 theexpression 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 cocaines 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.

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.

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, anL-type calcium channel blocker. The increases 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 byN-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 treatment regimens exhibited increased occupations 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 tnat the differences in occupancy of striatal dopamine receptors by dopamine observed in the prewithdrawal condition are likely the result of differences in brain levels of cocaine achieved by the two treatment regimens. Occupancy of striatals dopamine D1 and D2 receptors does not appear to be related to the development of sensitization to the motor-stimulating effects of cocaine.

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.

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.

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 cocaines 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 cocaines behavioral effects, was associated with greater dopaminergic neurotransmission selectively in the nucleus accumbens.

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

Abstract 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.

Presynaptic dopaminergic neurotransmission mediates amphetamine-induced unconditioned but not amphetamine-conditioned locomotion and defecation in the rat

A series of experiments were conducted to investigate the role of presynaptic dopamine (DA) and noradrenaline (NA) neurotransmission in stimulant-unconditioned and conditioned locomotion and defecation. (+)-Amphetamine (AMP, 1.5 mg/kg, s.c.) increased both locomotion and defecation in rats, and both of these effects were conditioned to environmental stimuli. Some groups of rats were treated with DSP4 (50 mg/kg, i.p.), a selective, long-lasting NA neurotoxin, given 7 days prior to conditioning with AMP. This treatment depleted forebrain NA to between 1% and 54% of control levels, depending on the brain region, but did not attenuate either AMP-unconditioned or conditioned locomotion. These results indicate that NA does not mediate either AMP unconditioned or conditioned locomotion. alpha-Methyl-para-tyrosine methyl ester (alpha MPT, 25-50 mg/kg, s.c.), a selective inhibitor of catecholamine synthesis given during conditioning with AMP, attenuated unconditioned AMP-induced locomotion and defecation but did not influence AMP-conditioned locomotion and defecation. Thus, alpha MPT blocked AMP-induced unconditioned locomotion, supporting the hypothesis that the locomotor and defecation stimulant effects of AMP are mediated by DA release. In spite of the attenuation of the direct effects of AMP, alpha MPT did not attenuate AMP-conditioned locomotion or defecation. It is concluded that AMP-induced release of dopamine is responsible for the unconditioned behavioral effects of amphetamine but not for the conditioning of amphetamine-induced locomotion and defecation.