Chronic Drug Regimens Research Articles

The Beneficial Effects of Dietary Interventions on Gut Microbiota—An Up-to-Date Critical Review and Future Perspectives

Different dietary interventions, especially intermittent fasting, are widely used and promoted by physicians; these regimens have been studied lately for their impact on the gut microbiota composition/function and, consequently, on the general physiopathological processes of the host. Studies are showing that dietary components modulate the microbiota, and, at the same time, the host metabolism is deeply influenced by the different products resulting from nutrient transformation in the microbiota compartment. This reciprocal relationship can potentially influence even drug metabolism for chronic drug regimens, significantly impacting human health/disease. Recently, the influence of various dietary restrictions on the gut microbiota and the differences between the effects were investigated. In this review, we explored the current knowledge of different dietary restrictions on animal and human gut microbiota and the impact of these changes on human health.

Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing

Recent data suggest that Alzheimer's patients who discontinue treatment with cholinesterase inhibitors have a significantly delayed cognitive decline as compared to patients receiving placebo. Such observations suggest cholinesterase inhibitors to provide a disease-modifying effect as well as symptomatic relief and, moreover, that this benefit remains after drug withdrawal. Consistent with this suggestion, we now demonstrate that chronic administration of tacrine, nefiracetam, and deprenyl, drugs that augment cholinergic function, increases the basal frequency of dentate polysialylated neurons in a manner similar to the enhanced neuroplasticity achieved through complex environment rearing. While both drug-treated and complex environment reared animals continue to exhibit memory-associated activation of hippocampal polysialylated neurons, the magnitude is significantly reduced suggesting that such interventions induce a more robust memory pathway that can acquire and consolidate new information more efficiently. This hypothesis is supported by our findings of improved learning behavior and enhanced resistance to cholinergic deficits seen following either intervention. Furthermore, the level of enhancement of basal neuroplastic status achieved by either drug or environmental intervention correlates directly with improved spatial learning ability. As a combination of both interventions failed to further increase basal polysialylated cell frequency, complex environment rearing and chronic drug regimens most likely enhanced cognitive performance by the same mechanism(s). These findings suggest that improved memory-associated synaptic plasticity may be the fundamental mechanism underlying the disease modifying action of drugs such as cholinesterase inhibitors. Moreover, the molecular and cellular events underpinning neuroplastic responses are identified as novel targets in the search for interventive drug strategies for the treatment of neurodegenerative and neuropsychiatric disorders.

Antihypertensive medication and quality of life--silent treatment of a silent killer?

Hypertension is one of the major killers in the modern world and one of the great ironies of the disease is that it has little or no immediate effect on affected individuals' quality of life (QOL). This makes treatment very difficult, as most medications will affect QOL negatively, either through side effects or through the change in life-style associated with chronic drug regimens. This review describes some of the conceptual background for QOL measurements and looks at the effects on QOL of different antihypertensive treatments available today. The latest addition to the range of antihypertensive drugs, angiotensin II-receptor blockers, may be a significant step forward in treatment, as their ease of dosing and excellent tolerability minimise negative effects on patients while their possible benefits on factors such as sexual function may even improve QOL in hypertensive patients.

The antidepressant drug phenelzine produces antianxiety effects in the plus-maze and increases in rat brain GABA.

Research on the effects of antidepressant/ antipanic drugs in animal models of anxiety has yielded equivocal results, even after chronic drug regimens. In contrast, we found that the antidepressant/antipanic drug phenelzine, given acutely, produced a clear anxiolytic effect in the elevated plus-maze, a widely-used animal model of "anxiety" that is primarily sensitive to benzodiazepine-type anxiolytics (e.g., diazepam). Furthermore, the effective dose of phenelzine (15 mg/kg) administered to rats was associated with more than a 2- fold increase in whole brain levels of gamma-aminobutyric acid (GABA), whereas an ineffective dose of phenelzine (5.1 mg/kg) did not significantly change GABA levels. The N-acetylated metabolite of phenelzine, N2-acetylphenelzine, produced neither an anxiolytic effect in the elevated plus-maze nor a significant change in whole-brain levels of GABA. However, both phenelzine and N2-acetylphenelzine potently inhibited monoamine oxidase, a mechanism commonly thought to be involved in the therapeutic effects of monoamine oxidase inhibitors such as phenelzine in the treatment of depression in humans. These results suggest that the mechanism whereby phenelzine produces anxiolytic effects in the plus-maze model is unique to a facilitatory action on brain levels of GABA, in contrast to classical benzodiazepines, which produce anxiolytic effects by enhancing the affinity of the GABAA-receptor for GABA.

Hypoxia promotes and antisense oligonucleotides inhibite endothelin production

Rats were trained to discriminate an injection of pentylenetetrazol (PTZ), 20 mg/kg, from saline using a two-lever operant procedure with food as a reinforcer. In substitution tests, rats selected the PTZ-appropriate lever after PTZ, but not after cocaine (20 mg/kg). A higher dose of cocaine (40 mg/kg) was behaviorally disruptive which resulted in no lever selection during the test session. Subsequently, training and testing were halted, and cocaine, 20 mg/kg/8-hr, was administered for 7 days. Following this chronic drug regimen, substitution of PTZ for the PTZ stimulus was increased. Furthermore, cocaine (40 mg/kg) substituted for the PTZ stimulus. Following redetermination of the PTZ and cocaine dose-response curves, chronic cocaine injections were terminated and spontaneous withdrawal was assessed by determining its substitution for the PTZ stimulus. Cocaine withdrawal progressively substituted for the PTZ stimulus reaching a peak 120 hrs after the last cocaine injection. Diazepam, 5 mg/kg, blocked adminitration of cocaine produced sensitization for 1) chronic administration of cocaine produced sensitization for the PTZ stimulus, 2) tolerance developed to the behaviorally disruptive effects of cocaine, and 3) cocaine withdrawal produced a PTZ-like stimulus which was blocked by diazepam.

Technique for the continuous infusion of high doses of cocaine by osmotic minipump

The present article describes a procedure for modifying osmotic minipumps to avoid the local, toxic, necrotic effects of high concentrations of drug at the exit portal during the chronic, continuous infusion of cocaine. The present procedure eliminates the occurrence of necrotic skin lesions otherwise produced by SC administration of cocaine and/or other vasoconstrictive agents. The method of administration will therefore be useful for administration of other chronic drug regimens.

Clozapine's functional mesolimbic selectivity is not duplicated by the addition of anticholinergic action to haloperidol: a brain stimulation study in the rat

This study examined whether the anticholinergic potency of the clinically superior antipsychotic drug clozapine contributes to clozapine's anatomically-selective functional inhibition of the mesolimbic dopamine (DA) system, using an electrical brain-stimulation reward (BSR) paradigm in rats that has been previously shown to be highly sensitive to clozapine's mesolimbic functional selectivity. Rats were chronically administered saline, clozapine, haloperidol, or haloperidol plus the anticholinergic compound trihexyphenidyl, and threshold sensitivity of the mesolimbic and nigrostriatal DA systems was assessed using the BSR paradigm, to infer degree of functional DA blockade produced by the chronic drug regimens. Chronic saline produced no change in either DA system. Congruent with previous findings, chronic clozapine powerfully inhibited the mesolimbic DA system but spared the nigrostriatal DA system. Also congruent with previous findings, chronic haloperidol powerfully inhibited both DA systems. Compared to chronic haloperidol alone, chronic haloperidol plus chronic trihexyphenidyl exerted diminished anti-DA action in both the mesolimbic and nigrostriatal DA systems. These results suggest that clozapine's anticholinergic potency is not an adequate explanation for its functional mesolimbic selectivity.

Cardiac Arrhythmias in Childhood

Determining safe and effective antiarrhythmic therapy in paediatric patients requires definition of the mechanism of the arrhythmia, determination of associated risk factors for treatment (such as the presence of congenital cardiac defects, myocarditis or cardiomyopathy), and monitoring for potential drug side effects related to the treatment. A number of modalities for non-invasive evaluation of arrhythmias is available, including ECG, 24-hour ambulatory Holter monitoring, and transtelephonic ECG transmission. Arrhythmias requiring medical treatment in children with normal cardiac anatomy and function include supraventricular tachycardia (SVT), ventricular tachycardia (VT) and primary atrial tachycardias. SVT is treated acutely with vagal manoeuvres or drugs which slow AV conduction [adenosine (adenine riboside), edrophonium, phenylephrine or verapamil]. When medical conversion is not achieved, transoesophageal overdrive pacing or direct current (DC) cardioversion may be required. Long term drug therapy for SVT includes first-line treatment with digoxin, verapamil or propranolol. Ventricular tachycardia is managed acutely with DC cardioversion and intravenous lidocaine (lignocaine). Chronic drug regimens include mexiletine, propranolol or amiodarone. In children with structural congenital heart disease or myocardial dysfunction, hazards of drug therapy for arrhythmias include depression of cardiac function, proarrhythmia (drug-induced worsening of arrhythmias), and conduction abnormalities. Care must be taken to choose medication regimens which are likely to be effective with minimum risk of potentiating abnormal haemodynamics or conduction.

Drug discrimination training during chronic drug treatment affects the development of tolerance.

The purpose of this experiment was to evaluate the extent to which continued drug discrimination training during chronic drug treatment affects the development of tolerance. Rats were trained to discriminate distilled water from 0.75 mg/kg amphetamine in a two-lever drug discrimination task. Two groups were then given a chronic drug regimen of 13 daily injections of either distilled water or 10 mg/kg amphetamine. Drug discrimination training was continued for half of each chronic drug group. Tolerance was apparent only in the group that was not trained during the chronic amphetamine treatment. The data support the conclusion that continued training throughout the chronic drug treatment provides the opportunity for reinforced correct responding as both nondrug- and drug-cue states are gradually shifted by the chronic drug regimen.

Anxiogenic properties of cocaine withdrawal

Rats were trained to discriminate an injection of pentylenetetrazol (PTZ), 20 mg/kg, from saline using a two-lever operant procedure with food as a reinforcer. In substitution tests, rats selected the PTZ-appropriate lever after PTZ, but not after cocaine (20 mg/kg). A higher dose of cocaine (40 mg/kg) was behaviorally disruptive which resulted in no lever selection during the test session. Subsequently, training and testing were halted, and cocaine, 20 mg/kg/8-hr, was administered for 7 days. Following this chronic drug regimen, substitution of PTZ for the PTZ stimulus was increased. Furthermore, cocaine (40 mg/kg) substituted for the PTZ stimulus. Following redetermination of the PTZ and cocaine dose-response curves, chronic cocaine injections were terminated and spontaneous withdrawal was assessed by determining its substitution for the PTZ stimulus. Cocaine withdrawal progressively substituted for the PTZ stimulus reaching a peak 120 hrs after the last cocaine injection. Diazepam, 5 mg/kg, blocked adminitration of cocaine produced sensitization for 1) chronic administration of cocaine produced sensitization for the PTZ stimulus, 2) tolerance developed to the behaviorally disruptive effects of cocaine, and 3) cocaine withdrawal produced a PTZ-like stimulus which was blocked by diazepam.

Chapter 21 Functional consequences of coexistence of classical and peptide neurotransmitters

Publisher Summary The chapter examines the effects of acute and chronic drug regimens, which are known to influence the turnover and tissue level of classical neurotransmitters with respect to their effect on the peptide neurotransmitters that coexist with the affected classical neurotransmitter. It was hypothesized that if these drug regimens change the firing rate or the release per pulse of a neuron, then these changes may alter the levels of all neurotransmitters stored and released from the neuron. The magnitude of change of tissue levels of the classical neurotransmitters and coexisting peptides may be different. The differential action of a drug is made likely by the fact that the mode and site(s) of synthesis of the coexisting classical neurotransmitters and peptides are different. A pure peptide-containing vesicle once transported from the soma via axonal transport to the terminal and released its content cannot be refilled with the peptide in the terminal as the neurotransmitter(s) elaborated there are the low-molecular-weight classical neurotransmitters. Thus, the retrieval of a peptidergic vesicle means that it can be loaded to become a classical neurotransmitter-containing vesicle.

Amphetamine-haloperidol discrimination: Effects of chronic drug treatment

Rats responding for food reinforcement were trained in a 2-lever drug discrimination task. Groups of rats were trained to discriminate one of four doses of amphetamine (0.0, 0.1, 0.3, or 0.5 mg/kg) from haloperidol (0.02 mg/kg). Both the rate of acquisition and level of discrimination at asymptote were a function of amphetamine training dose. Following acquisition of this discrimination, choice behavior was assessed in the absence of drug during two test sessions. Twenty-four hours following the second drug-free test session, chronic drug treatment commenced. Half of the animals received 10 mg/kg amphetamine for 10 consecutive days while the other half received 1 mg/kg haloperidol during the same period. Choice behavior was assessed during three 2.5-minute unreinforced drug-free test sessions 24, 48, and 72 hours following the chronic drug regimen. Following chronic haloperidol, animals responded as though a small dose of amphetamine had been administered, while following chronic amphetamine, they responded as though a small dose of haloperidol had been administered. Collectively, these results suggest that animals trained to discriminate amphetamine from haloperidol respond on the basis of a continuum of dopaminergic function. Further, this continuum can be used to elucidate the net effect of pharmacologically-induced alterations in dopaminergic function, as well as the effect of nonpharmacological manipulations that may result in dopaminergic changes.

Effects of chronic phencyclidine on fixed-ratio responding: No relation to neurotransmitter receptor binding in rat cerebral cortex

The effects of chronic phencyclidine (3.2 mg/kg for 25 days) on responding maintained under a fixed-ratio 30 schedule of food presentation were studied in rats. Initially phencyclidine produced large decreases in the overall rate of responding. This decrease was due primarily to long pauses in responding and secondarily to a decrease in local rates of responding. Although tolerance developed to the rate-decreasing effects of phencyclidine in each subject, the extent and pattern of its development differed among the subjects. After the chronic drug regimen, the rats were sacrificed. Ligand binding to muscarinic cholinergic, opiate, adrenergic, and serotonergic receptors in cortex was then compared to that in rats which received saline with operant training, phencyclidine alone, or saline alone. Neither operant behavior alone, phencyclidine alone, nor the interaction of phencyclidine and operant behavior was found to alter binding to these receptors. The results indicate that behavioral tolerance develops to phencyclidine, but it is not accompanied by changes in binding to the receptors studied.

Morphine dependence in rats assessed in a shock discrimination task.

The effects of chronic morphine sulfate (5 mg/kg/day for 14 days) on shock discrimination performance of rats was assessed in Experiment 1. Significant tolerance developed to the disruptive effects of morphine on performance. A significant increase in discrimination performance was found 48 h after the last injection in tests conducted without the injection environment cues present. Ten days after the chronic drug regimen, tests conducted 30 min after exposure to the injection-environment cues revealed no differences between animals previously administered morphine and control animals administered saline. In Experiment II, shock discrimination performance was assessed in a separate group of rats after exposure to a single injection of morphine sulfate (30 mg/kg), which eliminated associative processes, e.g., Pavlovian or instrumental conditioning, as factors in the subsequent behavioral tests for hyperalgesia. Significant changes in discrimination performance (primarily enhanced percent correct to the high shock stimulus) indicative of increased pain sensitivity were obtained in tests conducted 1, 2, and 3, but not 9 days after the injection. These experiments indicate that increased pain sensitivity, as opposed to hyperresponsivity operationally measured in traditional analgesia tests (e.g., hot plate, jump-flinch, and tail flick), is a component of morphine withdrawal of a nonassociative origin.

Extinction-induced mirror responding as a baseline for studying drug effects on aggression

Pigeons worked individually in a chamber containing a response key and a mirror. Responding on the key was controlled by a multiple schedule in which a brief period of continuous food reinforcement alternated with a 5 min period of extinction. Under baseline conditions, aggressive behavior (responding on the mirror) occured at the onset of each extinction period. After 10 saline control sessions, 5 mg/kg of chlordiazepoxide was injected IM 30 min pressesion for 60 daily sessions. The drug initially produced a marked decrease in aggressive behavior but had little or no effect on key pecking. The aggressive behavior generally remained suppressed during the chronic drug regimen and returned to control levels when the drug was withdrawn. It was concluded that the technique of extinction-induced mirror responding in pigeons provides a stable, sensitive and recoverable baseline for objectively assessing selective drug effects on aggression.

Effects of chronic exposure to delta9-tetrahydrocannabinol on delayed matching-to-sample in chimpanzees.

Three groups of four chimpanzees were trained on a 20-sec delayed matching-to-sample task and then were exposed to a 152 day chronic drug regimen. Two of the chimpanzees in each group were drug naive. The other two chimpanzees in each group had experienced 45 doses of Δ 9-tetrahydrocannabinol (Δ 9-THC) four months prior to the present experiment. One group of animals served as nondrug controls. A second control group received an oral dose of 1.0 mg Δ 9-THC per kilogram of body weight following each matching-to-sample session. The experimental group was given the same dose of Δ 9-THC prior to each daily session. The initial administrations of the drug before but not after each session produced a significant decrease in matching-to-sample accuracy. During the course of the chronic drug regimen, animals in the experimental group recovered very slowly from this initial impairment in matching-to-sample performance. The extent to which the experimental animals recovered seemed to depend upon their pre-experimental drug histories. The drug-experienced animals developed complete tolerance within five weeks while the previously drug-naive animals did not so do even after five months exposure to the drug. However, no residual or long-term effects were observed following termination of the chronic drug regimen.