Roland Douglas Shytle

Nicotinic acetylcholine receptors as targets for antidepressants

While the monoamine deficiency hypothesis of depression is still most commonly used to explain the actions of antidepressant drugs, a growing body of evidence has accumulated that is not adequately explained by the hypothesis. This article draws attention to contributions from another apparently common pharmacological property of antidepressant medications—the inhibition of nicotinic acetylcholine receptors (nAChR). Evidence is presented suggesting the hypercholinergic neurotransmission, which is associated with depressed mood states, may be mediated through excessive neuronal nicotinic receptor activation and that the therapeutic actions of many antidepressants may be, in part, mediated through inhibition of these receptors. In support of this hypothesis, preliminary evidence is presented suggesting that the potent, centrally acting nAChR antagonist, mecamylamine, which is devoid of monoamine reuptake inhibition, may reduce symptoms of depression and mood instability in patients with comorbid depression and bipolar disorder. If this hypothesis is supported by further preclinical and clinical research, nicotinic acetylcholine receptor antagonists may represent a novel class of therapeutic agents for treating mood disorders.

Mecamylamine (Inversine ): an old antihypertensive with new research directions

Mecamylamine (Inversine®), the first orally available antihypertensive agent, is now rarely used. Although celebrated in the 1950s, mecamylamine fell out of favour because of its widespread ganglionic side effects at antihypertensive doses (30–90 mg/day). However, recent studies suggest that mecamylamine is very effective at relatively low doses (2.5–5 mg b.i.d.) for blocking the physiological effects of nicotine and improving abstinence rates in smoking cessation studies, particularly for women. When these lower doses of mecamylamine are given, patients do not experience the severity of side effects that made the drug unpopular for the treatment of hypertension. Tobacco smoking is a strong risk factor for cardiovascular morbidity, including accelerated atherosclerosis and increased risk of heart attacks. Though currently untested, the available evidence suggests that low-dose mecamylamine therapy might reduce blood pressure variability and atherogenetic lipid profile in smokers. With this in mind, mecamylamine should be an important research tool in the field of hypertension research, particularly in recalcitrant smokers with mild to moderate hypertension.

locomotor behavioral effects of prenatal and postnatal nicotine exposure in rat offspring

The purpose of this study was to determine if prenatal/postnatal nicotine exposure results in hyperactive offspring. Rat offspring were exposed to nicotine, through implantation of osmotic minipumps in dams, at levels of 0.75, 1.5 and 3.0 mg/kg/day, for 19 days prenatally and 16 days postnatally. Offspring were measured for gestation length, body weight, litter size, sex difference and locomotor activity. No significant effects were shown for gestation length, litter size or male to female pup ratio. However, higher percentage of pup deaths resulted from nicotine-exposed dams than from control dams. Significantly less litter body weight was shown in nicotine-exposed offspring on postnatal day 1 when compared to controls. However, these offspring surpassed the control groups in litter body weight on postnatal day 14 and 21. Hyperactivity was shown in offspring exposed to prenatal/postnatal nicotine at levels of 0.75 and 3.0 mg/kg/day on postnatal day 14, but not on postnatal day 21 or at the 1.5 mg/kg/day condition. Results are consistent with the hypothesis that rat offspring are susceptible to the neurochemical and neurobehavioral effects of prenatal/postnatal nicotine exposure.

Transdermal Nicotine in Tourette’s Syndrome

In an open clinical trial, transdermal nicotine patch significantly ameliorated the frequency and severity of tics in patients with Tourette’s syndrome who were receiving dopamine receptor blockers. This effect, noted within 3 hours after application of the patch, persisted for a variable period of time after removal of the patch. In 2 patients, initially with incapacitating Tourette’s symptoms, the effect persisted from 3 weeks to 4 1/2 months without further administration of nicotine.

Potential new complication in drug therapy development for amyotrophic lateral sclerosis

ABSTRACT Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the brain and spinal cord. Treatment development for ALS is complicated by complex underlying disease factors. Areas covered: Numerous tested drug compounds have shown no benefits in ALS patients, although effective in animal models. Discrepant results of pre-clinical animal studies and clinical trials for ALS have primarily been attributed to limitations of ALS animal models for drug-screening studies and methodological inconsistencies in human trials. Current status of pre-clinical and clinical trials in ALS is summarized. Specific blood-CNS barrier damage in ALS patients, as a novel potential reason for the clinical failures in drug therapies, is discussed. Expert commentary: Pathological perivascular collagen IV accumulation, one unique characteristic of barrier damage in ALS patients, could be hindering transport of therapeutics to the CNS. Restoration of B-CNS-B integrity would foster delivery of therapeutics to the CNS.

Clinical Assessment of Tourette’s Syndrome

Gilles de la Tourette syndrome (TS) is a neuropsychiatric and behavioral disorder with childhood onset that is characterized largely by the expression of both motoric and vocal tics that can range from relatively mild to very severe over the course of a patient’s lifetime (Robertson, 1989). Although the exact pathogenesis is still not known, current hypotheses implicate disinhibition of cortical-striatal-thalamocortical minicircuits (Leckman et al., 1990). In addition, there is now strong evidence that TS is a hereditary motor disorder with the most accepted genetic model being an autosomal dominant mode of inheritance with incomplete penetrance and a variable expression (Price et al., 1988; van de Wetering and Heutink, 1993). Like many other hereditary psychiatric disorders, a major obstacle in linking a particular DNA sequence with the disorder in all affected family members is developing a clear and rigorous definition of the phenotype. This has been especially difficult with TS, since a growing body of evidence now indicates that, in addition to the expression of both motoric and vocal tics, many of these patients also exhibit other motoric abnormaliyies, including obsessive-compulsive disorder (OCD) attention-deficit-hyperactivity disorder (ADHD), and associated visualmotor deficits (Singer and Rosenberg, 1989; Silver and Hagin, 1990; Bornstein and Yang, 1991; Cohen and Leckman, 1994). Since tics can vary in intensity and can be voluntarily suppressed during a clinical examination (Koller and Biary, 1989), they can sometimes go unnoticed when other associated symptoms like hyperactivity, impulsiveness, or obsessions and compulsions dominate the clinical picture (van de Wetering and Heutink, 1993). Therefore, it is important to have precise criteria for consistent diagnosis among researchers as well as assessment tools that can characterize the overall clinical picture of these patients for the ultimate delineation of the gene(s) and environmental factors involved with the expression of the TS phenotype.