Phenylpropanolamine: reinforcing and subjective effects in normal human volunteers

The reinforcing and subjective effects of phenylpropanolamine (PPA, 25 and 75 mg, PO) were compared with those of d-amphetamine (AMP, 5 mg) in a group of normal, healthy adults (eight males, nine females) with no history of drug abuse. A discrete-trial choice procedure was used in which subjects first sampled placebo and a dose of one of the drugs. Subjects were then allowed to choose between self-administration of drug or placebo on three separate occasions. The relative frequency with which active drug was chosen over placebo was used as the primary index of the drug's reinforcing efficacy. Subjective effects were measured with the Profile of Mood States, a short version of the Addiction Research Center Inventory and a series of visual analog scales. Ratings of drug liking, drug labelling, general activity level and strength of drug preference were also obtained. As expected, AMP was chosen significantly more often than expected by chance (69% of occasions). AMP also increased ratings of drug liking, preference strength, and activity level, and produced a profile of subjective effects consistent with its well-established stimulant and euphorigenic properties. The low dose of PPA was without effect on most measures. PPA 75 mg was chosen significantly less often than expected by chance (39% of occasions). This dose of PPA was most frequently labelled as a stimulant, and produced significant increases on ratings of Anxiety and stimulated, and decreases on ratings of sedated and hungry. Unlike AMP, PPA did not affect ratings of drug liking or mood scales reflecting euphoria. In sum, these results indicate that PPA does not possess AMP-like dependence potential.     

Cocaine: Excitatory effects on sensorimotor reactivity measured with acoustic startle

Cocaine (2.5–10 mg/kg) caused a dose-related increase in the amplitude of the acoustic startle reflex in rats. In contrast, procaine (5–40 mg/kg) caused a dose-related decrease in startle, indicating that the effects of cocaine could not be ascribed to its local anesthetic effects. Cocaine's excitatory effects were blocked by pretreatment with haloperidol (0.5 mg/kg) but not by cyproheptadine or prazosin. The excitatory effects of cocaine (10 mg/kg) were markedly attenuated by pretreatment with reserpine (5 mg/kg 24 and 18 h earlier) but not by -methyl-p-tyrosine (100 mg/kg 1 h earlier). In contrast, comparably sized excitatory effects of d-amphetamine were blocked by -methyl-p-tyrosine and greatly enhanced by pretreatment with reserpine. Neither pretreatment blocked excitatory effects of apomorphine on startle. The data indicate that cocaine increases startle by acting through reserpine-sensitive pools of dopamine and provide further support for the conclusion that acoustic startle is enhanced by activation of dopamine receptors.     

Caffeine and nicotine improve visual tracking by rats: a comparison with amphetamine,cocaine and apomorphine

Psychomotor stimulant drugs such as caffeine, nicotine, amphetamine and cocaine, have been shown to improve vigilance in man under conditions of fatigue. Nicotine has also been shown to improve performance in some cognitive tests in patients with Alzheimer's disease. In rodents these drugs increase activity which may confound performance enhancing effects in rodent models. However, improvements have been found in a number of tests that do not seem to be directly dependent upon an enhancement of locomotor activation. In one example, Evenden and Robbins (1985) reported consistent improvements in a visual tracking test following amphetamine. The present study was undertaken to determine whether these performance enhancing effects of amphetamine could also be obtained with cocaine and apomorphine, which both have psychomotor stimulant effects through their actions as, respectively, indirect and direct dopamine agonists, and by caffeine and nicotine, which do not have a direct dopaminergic mechanism of action. The results of the study indicate that all five drugs improved tracking performance at one or more doses. The most consistent effects were obtained with amphetamine which, like cocaine and nicotine, improved tracking at a dose which did not produce other changes in behaviour. Taking into account previous studies (Evenden and Robbins 1983, 1985), these results were interpreted as indicating that psychomotor stimulant drugs produce ageneral activation of behaviour. At all but the highest doses of such drugs, the form of behaviour that is observed depends upon the environment. The results of this study support the conclusion that in the situation where stimuli are present which exert a strong control over behaviour in the undrugged state, then the stimulated behaviour will be directed towards those, and may result in an enhancement of performance.     

Desmethylimipramine attenuates cocaine withdrawal in rats

Depression and anhedonia are two major symptoms of cocaine withdrawal in humans. Hence, pharmacological treatments effective in depression might also alleviate the symptoms of cocaine withdrawal. In the present study, the effects of acute and repeated administration of a tricyclic antidepressant, desmethylimipramine (DMI), were investigated in naive and cocaine-withdrawing rats. An animal model of cocaine withdrawal was used that employs the elevation in intracranial self-stimulation (ICSS) thresholds following the termination of prolonged periods of cocaine self-administration as a measure of an animal's anhedonic state. The influence of chronic DMI treatment on-adrenergic receptor binding and affinity was also correlated with the behavioral signs of cocaine withdrawal. Neither acute nor repeated DMI treatment influenced reward functions in rats that were not undergoing cocaine withdrawal. However, repeated DMI treatment significantly down-regulated-adrenergic receptors, and shortened the duration of the post-cocaine anhedonia (elevation in thresholds). Furthermore, the magnitude of the-adrenergic receptor down-regulation correlated significantly with the degree of effectiveness of DMI treatment in reversing the post-cocaine anhedonia. However, chronic DMI treatment did reduce the amount of cocaine self-administered by the animals. The reversal of the post-cocaine anhedonia in this animal model of cocaine withdrawal by chronic DMI treatment demonstrates the potential usefulness of the model in identifying new pharmacotherapies for cocaine withdrawal. In addition, the results indicate that tricyclic antidepressants may be able to ameliorate some of the symptoms of cocaine withdrawal.     

Electrophysiological correlates of response inhibition in children and adolescents with ADHD: influence of gender, age, and previous treatment history

Deficits in response inhibition may be at the core of the cognitive syndrome in ADHD. Here, inhibitory control mechanisms were studied in 36 ADHD-combined type and 30 healthy children by exploring the event-related brain activity during the Stop Signal task. The influence of age, gender, and previous treatment history was evaluated. The ADHD group showed reduced N200 wave amplitudes. For successful inhibitions, the N200 reduction was greatest over right inferior frontal scalp, and only the control group showed a success-related enhancement of such right frontal N200. Source analysis identified a source of the N200 group effect in right dorsolateral prefrontal cortex. Finally, a late positive wave to failed inhibitions was selectively reduced only in treatment-naïve ADHD children, suggesting that chronic stimulants may normalize late conscious error recognition. Both effects were independent of gender and age.     

Effects of stimulant medications on the EEG of children with attention-deficit/hyperactivity disorder

Abstract Rationale. Stimulant medications are the most commonly used treatments for attention deficit/hyperactivity disorder (ADHD) in North America and Australia, although it is still not entirely known how these medications work. Objectives. This study aimed to investigate the effects of stimulant medications on the EEG of children with the Combined subtype of ADHD. Method. An initial EEG was recorded during an eyes-closed resting condition and Fourier transformed to provide absolute and relative power estimates for the delta, theta, alpha and beta bands. Theta/alpha and theta/beta ratios were also calculated. Subjects were placed on a 6-month trial of a stimulant and a second EEG was recorded at the end of the trial. Results. The ADHD group had significantly greater absolute delta and theta, less posterior absolute beta, more relative theta, and less relative alpha than the control group, which is typical of EEG studies of children with ADHD. The use of stimulant medications resulted in normalisation of the EEG, primarily evident in changes in the theta and beta bands. Conclusions. These results suggest that stimulants act to increase cortical arousal in children with ADHD, normalising their brain activity. Electronic Publication     

Caffeine reduces amphetamine-induced activity in asymmetrical interaction

Caffeine-amphetamine interactions were studied to determine whether attenuation of amphetamine-induced activity by caffeine pretreatment (30 mg/kg) is the result of increased or decreased sensitivity to amphetamine. Caffeine pretreatment attenuated amphetamine activity in the rats without producing a horizontal shift in the dose-response curve. Results support a reduction in sensitivity to amphetamine. A cross-tolerance design revealed an asymmetrical interaction between caffeine and amphetamine. Multiple caffeine treatments (30 mg/kg) produced tolerance and attenuation of subsequent amphetamine activity (1.5 mg/kg). Amphetamine did not produce tolerance or affect subsequent caffeine-induced activity.     

A selective test for antidepressant treatments using rats bred for stress-induced reduction of motor activity in the swim test

Rationale and objective This paper describes a new procedure for detecting effective antidepressant treatments. The procedure uses the swim-test susceptible (Susceptible) rat which has been selectively bred to show decreased struggling behavior in a swim test after exposure to a mild stressor. The ability of treatments to block this decrease in swim-test activity was assessed as a method for detecting effective antidepressants. Results In both male and female Susceptible rats, chronic (14-day) treatment with different antidepressant drugs delivered via osmotic minipump [i.e., three tricyclics (desmethylimipramine, imipramine, amitriptyline), two selective serotonin reuptake inhibitors (fluoxetine and sertraline), a monoamine oxidase inhibitor (phenelzine), and two atypical antidepressants (venlafaxine and bupropion)] all prevented the stress-induced decrease in swim-test struggling normally shown by these rats. Electroconvulsive shock had a similar effect. Unlike antidepressant drugs, 14-day treatment with various nonantidepressant drugs [i.e., a stimulant (amphetamine), an anxiolytic (chlordiazepoxide), an antihistamine (chlorpheniramine), and an anticholinergic (scopolamine)] did not have this effect. Antidepressant drug treatment for 1 day (i.e., acute treatment) was also ineffective in this test. The procedure described above requires use of the Susceptible rat—swim test resistant rats (i.e., rats selectively bred to be resistant to decreased swim-test activity after exposure to stressful conditions) showed no significant differences in swim-test behavior between stress and nonstress conditions after 14-day drug treatment, and randomly bred Sprague–Dawley rats did not show a decrease in swim-test activity following exposure to the mild stressor that is the basis for the test. Conclusion These results suggest that the procedure described here, which uses a rat subject that has been bred for vulnerability to stressful conditions, may be a selective screening technique for effective antidepressant treatments.