Stimulants chronic effects

The acute effects of psychomotor stimulant overdoses are related to their CNS stimulant properties and may include euphoria, dizziness, tremor, irritability, and insomnia. At higher doses, convulsions and coma may ensue. These drugs are cardiac stimulants and may cause headache, palpitation, cardiac arrhythmias, anginal pain, and either hypotension or hypertension. Dextroamphetamine produces somewhat less cardiac stimulation. Chronic intoxication, in addition to these symptoms, commonly results in weight loss and a psychotic reaction that is often diagnosed as schizophrenia. 

Greenhill, L.L. and MTA Cooperative Group. (1999) Chronic stimulant treatment effects of weight acquisition rates of ADHD children. 39 26-27. 

Recent investigations into intracellular events have begun to define the postsynaptic events through which TCAs appear to exert their effects (Morinobu et ah, 1995). One of the observations made was down-regulation of transcription factors for early gene products such as c-Fos. C-Fos is normally produced in response to periods of stress. In research with rats, TCAs as well as other antidepressants have been shown to decrease the expression of c-Fos in areas of frontal cortex after chronic but not acute treatment. Other psychotropic medications (e.g., cocaine and haloperidol) with similar acute effects on norepinephrine/serotonin neurotransmission have not shown this same chronic effect. It has been speculated that the decreased production of c-Fos is the end product of a cascade of events stimulated by increased norepinephrine levels (Morinobu et ah, 1995). 

Arousal and attention have been investigated in 180 healthy nursery infants before hospital discharge and at 1 month of age (281). Cocaine-exposed infants showed a lack of arousal-modulated attention and preferred faster frequencies of stimulation, regardless of arousal condition compared with non-exposed infants. There were similar differences 1 month after birth, showing that these effects persisted beyond the period of presence of cocaine or its metabolites at birth. These effects were independent of absence of prenatal care, alcohol use, minority status, or sex, suggesting a direct and even chronic effect of intrauterine cocaine exposure on arousal-modulated attention and presumably on the developing nervous system of the infants. 

May be useful in decreasing the hypertension, tachycardia, and tremulousness associated with alcohol withdrawal, but not the seizures or delirium tremens In complicated alcohol withdrawal Clonidine may Improve social relationships, affectual responses, and sensory responses In autistic disorder Clonidine may reduce the Incidence of menopausal flushing Growth hormone response to clonidine may be reduced during menses Clonidine stimulates growth hormone secretion (no chronic effects have been observed)... 

Chronic use of morphine and other opioids is marked by acquired tolerance to the depressant agonist effects, e.g. analgesic action and respiratory depression (the fatal dose becomes higher), but not to some stimulant agonist effects, e.g. constipation and miosis, which persist. 

Studies have revealed consequences of P-AR stimulation beyond regulating the rate and strength of myocyte contraction. Chronic stimulation of the PrAR induces myocyte apoptosis, although the signaling pathway is controversial (12,63,64). In vitro studies suggest that this process requires PKA-independent activation of intracellular Ca2+ through L-type Ca2+ channels, which leads to Ca2+ release from sarcoplasmic reticulum and subsequent activation of calmodulin kinase II in adult cardiac myocytes (65). However, this prAR-stimulated proapoptotic effect appears to be blocked by PKA inhibition in adult rat myocytes (63). In contrast, activation of P2-ARs has an antiapoptotic effect, which is mediated by the Py-subunits of G, in both rat and mouse adult cardiac myocytes... 

Chronic effects of administration of cannabinoids have been studied in slices prepared from 40-day-old rats born to mothers who received daily subcutaneous injections of WlN55,212-2 throughout gestation (Mereu et al. 2003). LTP in these slices was reduced as compared to control slices prepared from rats born to untreated mothers. The slices also showed impaired basal and K+ -stimulated glutamate release. 

Effects As described in Chapter 7, these agents produce increased muscarinic and nicotinic stimulation. The effects include pinpoint pupils, sweating, salivation, bronchoconstric-tion, vomiting and diarrhea, CNS stimulation followed by depression, and muscle fascicula-tions, weakness, and paralysis. The most common cause of death is respiratory failure. Chronic exposure to some organophosphates (not carbamates) has resulted in a delayed neurotoxicity with axonal degeneration. The toxic mechanism appears to involve phosphorylation of a neuropathy target esterase (NTE). 

Cholinergic—stimulated by or releasing acetylcholine or a related compound Cholinesterase—enzyme that hydrolyzes acetylcholine into choline and acetic acid and is important in the functioning of the nervous system Chromatid—one of the two spiral filaments making up the chromosome Chromosomes—structures in the cell nucleus that contain DNA Chronic effect—biological change persisting over a major portion of a lifetime... 

The characteristic behavioral effects of acute and chronic psychomotor stimulant diugs are locomotor activation, stereotypy, and conditioned reward and stimulus-reward learning. The most important brain regions involved in these effects are summarized in Table 3. 

Stimulants induce both tolerance and sensitization to their behavioral effects. Tolerance develops to the anorectic and euphoric effects of stimulants (Schuster 1981) however, chronic intermittent use of low doses of stimulants delays the development of tolerance. With the doses commonly used in clinical practice, patients treated for narcolepsy or for depressive or apathetic states find that the stimulant properties usually persist without development of tolerance however, the persistence of antidepressant effects remains a matter of controversy. Sensitization has been linked to the development of amphetamine-induced psychosis (Yui et al. 1999). Sensitization to the induction of psychosis is suggested because psychosis is induced by progressively lower doses and shorter periods of consumption of amphetamine following repeated use over time (Sato 1986). Sensitization for amphetamine-induced psychosis may persist despite long periods of abstinence. 

The development of effective pharmacotherapy has lagged behind progress in understanding the reward mechanisms and chronic impairments underlying stimulant abuse. Pharmacological and behavioral treatment approaches that have been used for cocaine abuse have not been as widely tested for the treatment of amphetamine abuse, limiting what can be offered for treatment of this disorder. No treatment agents are approved by the FDA for treatment of cocaine or amphetamine dependence. 

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