Stimulant and reinforcing effects of cocaine in monoamine transporter knockout mice.

A large body of evidence supports the hypothesis that the reinforcing effects of cocaine depend on its ability to block the dopamine transporter (DAT), thereby increasing dopamine extracellular concentration within the mesocorticolimbic system. However, the fact that cocaine similarly binds to the serotonin and norepinephrine transporters (SERT and NET, respectively), raises the possibility that modulation of mesocorticolimbic dopaminergic transmission might be achieved through alternate pathways. The successful disruption of the genes coding for the DAT, the SERT and the NET offered ideal tools to determine the extent of the participation of these transporters and respective monoaminergic systems in the reinforcing effects of cocaine. Studies of cocaine-induced motor activation and maintenance of intravenous (i.v.) self-administration in DAT- and in NET-knockout (KO) mice are reviewed here, and discussed in light of new observations obtained from double monoamine transporters KO mice (i.e., DAT-KO/SERT-KO, NET-KO/SERT-KO). The reinforcing potency of cocaine is maintained in the absence of the DAT but decreased in the absence of the NET; its motivational rewarding effect is observed in the absence of the SERT, but not when both DAT and SERT are lacking. Moreover, a dichotomy between cocaine motor activating and reinforcing effects is reported. Such dichotomy is suggestive of independent mechanisms underlying the psychomotor stimulant and reinforcing effects of cocaine. Overall, these studies provide evidence that cocaine dynamically acts at multiple sites through pathways that might be exchangeable under certain circumstances.

Monoamine transporters: from genes to behavior.

Modulation of fast neurotransmission by monoamines is critically involved in numerous physiological functions and pathological conditions. Plasma membrane monoamine transporters provide one of the most efficient mechanisms controlling functional extracellular monoamine concentrations. These transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), which are expressed selectively on the corresponding neurons, are established targets of many psychostimulants, antidepressants, and neurotoxins. Recently, genetic animal models with targeted disruption of these transporters have become available. These mice have provided opportunities to investigate the functional importance of transporters in homeostatic control of monoaminergic transmission and to evaluate, in an in vivo model system, their roles in physiology and pathology. The use of these mice as test subjects has been helpful in resolving several important issues on specificity and mechanisms of action of certain pharmacological agents. In the present review, we summarize recent advances in understanding the physiology and pharmacology of monoamine transporters gained in mice with targeted genetic deletion of DAT, SERT, and NET.

Pineal gland hormone and idiopathic scoliosis: possible effect of melatonin on sleep-related postural mechanisms.

Experimental and clinical evidences indicate that endocrine mechanisms, particularly involving the pineal gland, exert a role in the development of postural deficits leading to the occurrence of idiopatic scoliosis (IS). In particular, experiments performed in bipedal animals have shown that removal of the pineal gland, which secretes melatonin (M), induced a scoliosis, and that in such preparations, administration of this hormone prevented the development of this deformity (cf. 131). It appears also that adolescents with IS showed a reduced level of serum M with respect to age-related control subjects. The possible mechanisms involved in the M regulation of the tonic contraction of the axial musculature have been discussed. It is known that the pineal gland is implicated in the control of circadian rhythms, including the sleep-waking cycle, and that during this cycle there are prominent changes in postural activity, which affect not only the limbs, but also the axial musculature. These changes are characterized by a decrease followed by a suppression of postural activity, which occur particularly during transition from wakefulness to synchronized sleep and, more prominently, to rapid eye movement (REM) sleep. Episodes of postural atonia may also occur during the cataplectic episodes, which are typical of narcolepsy. Cholinergic and/or cholinoceptive neurons located in the dorsal pontine reticular formation (pRF) and the related medullary inhibitory reticulospinal (RS) system, intervene in the suppression of posture during REM sleep, as well as during the cataplectic episodes which occur in narcolepsy. These structures are under the modulatory (inhibitory) influence of the dorsomedial and the dorsolateral pontine tegmentum, where serotoninergic raphe nuclei (RN) neurons and noradrenergic locus coeruleus (LC) neurons are located. We postulated that M may act not only on the circadian pacemaker, but also directly on the pontine tegmental structures involved in the regulation of posture during the animal states indicated above. This hypothesis is supported by the facts that: 1) the dorsal pRF may contain specific binding sites for M; 2) this structure is particularly sensitive to M in adolescents, as well as in adult subjects affected by narcoleptic disturbances leading to cataplexy; 3) M increases the release of serotonin (5-HT), a neurotransmitter which enhances the postural tone by acting on the dorsal pRF: on the other hand, deficits in M levels may lower the activity of the serotoninergic raphe system, thus leading to a decrease or suppression of postural activity similar to that occurring either during REM sleep or during the cataplectic episodes typical of narcoleptic patients; 4) IS patients may show episodes of sleep apnea, a phenomenon which has been attibuted to a reduced tonic contraction of primary and accessory respiratory muscles during REM, resulting from a reduced release of 5-HT at dorsal pontine level. It has been postulated that, if the reduced M and 5-HT levels are subliminal to produce a complete suppression of posture under the conditions reported above, the reduced postural tone, which results from this condition may lead to the development of IS, due to hypotonia which affects the axial musculature. M secretion could be regulated not only by the activity of the serotoninergic raphe neurons projecting to the pineal gland, but probably also by the activity of noradrenergic LC neurons. It is likely that the development of IS, which results from a reduced level of M and 5-HT, may occur provided that the noradrenergic LC inhibition of the pontine structures is impaired. Such impairment could depend upon genetic factors, similar to those postulated to play a role in narcolepsy. In conclusion, the possibility exists that an impaired activity of brain monoaminergic systems may lead to disfunction in the production of M, which is apparently an important factor in the etiopathogenesis of IS.

A biogenic amine-synapse mechanism for mental retardation and developmental disabilities.

Recent studies have demonstrated that biogenic amines have a function of facilitating formation and maintenance of synapses in diverse regions of the central nervous system in developing and adult animals. The normal number of synapses maintained by biogenic amines are crucial to acquire learning and memory. The level of biogenic amines was reported to decrease in the brain by several neurodevelopmental disorders associated with mental retardation and developmental disabilities such as Rett syndrome, autism and Down syndrome. Taken into consideration this fact together with the function of biogenic amines for synapses, the density of synapses appears to decrease considerably in the brains of patients suffered from the neurodevelopmental disorders. The synaptic overproduction during the critical period of development especially 1 year after birth has been considered as a background mechanism to provide plasticity for the developing brain. Synaptic overproduction does not appear to occur in the brains of patients suffered from the neurodevelopmental disorders, which they are observed mental retardation occurring in the first 1 year after birth. Along with the neurodevelopmental disorders, environmental factors (stress, drugs and nutrition) during pre- and post-natal critical developmental periods are known to change levels of biogenic amines in the brain. In fact, maternal stress has been shown to decrease the levels of serotonin and the density of synapses in the hippocampus of the offspring, and they showed developmental disabilities in the spatial learning and memory. A cascade appears to exist from either the child neurological disorders or the environmental factors to mental retardation and developmental disabilities by decreases in the levels of biogenic amines and synaptic density.

Neurophysiology of Rett syndrome.

Neurophysiological studies on Rett syndrome (RTT) are reviewed, and pathophysiology of RTT is discussed. The electroencephalography (EEG), sensory evoked potentials (SEP), sleep-wake rhythm study and polysomnography (PSG) study showed age-dependent characteristics. PSG revealed the brainstem and midbrain monoaminergic systems are deranged from early developmental stage, that is serotonin and noradrenaline systems seem to be hypoactive and dopaminergic system is also hypoactive associated with receptor supersensitivity. These monoaminergic systems are known to influence the maturation of the higher neuronal systems at specific areas and at specific ages. Particularly the synaptogenesis of the cerebral cortex is modulated by region or layer specifically from an early stage of the development. The observations made in EEG and SEP studies also suggested specific subcortical and cortical involvements taking place during the development. The age-dependent appearance of characteristic clinical features of RTT, and the variation of the clinical severities, e.g. classical, variant, form fruste, etc., can also be explained by the specific features of these monoaminergic systems. Furthermore, analysis of the components of rapid eye movement sleep suggested the onset of RTT lies between 36 gestational weeks to 3-4 months postnatally. The discovery of the mutations of methyl-CpG-binding protein 2 (MECP2) gene as the causative gene of RTT is an epoch helping not only to understand the pathophysiology of RTT but also various neurodevelopmental disorders.

Pathophysiology of Rett syndrome from the stand point of clinical characteristics.

In this report, we reviewed the characteristics of motor development and motor symptoms of Rett Syndrome (RTT) and demarcated the early and pathognomonic motor symptom which correlates to the impairment of the higher cortical function (HCF) assessed by the ability of language. It is suggested that failure of locomotion in late infancy is the primary and pathognomonic symptom. Thus, the impairment of the neurons or neuronal systems involving locomotion is suggested as the primary lesion in the pathophysiology of RTT not only for motor dysfunction but also for the failure in the development of language and cognitive function. On the other hand the neuronal systems involving the loss of purposeful hand use and the stereotyped hand movement, the most characteristic and diagnostic symptoms of RTT appearing in early childhood, are affected later or secondarily but induce further degradation of the HCF. Hypofunction of the aminergic neurons in the brainstem and midbrain is suggested as the cause of dysfunction of these neuronal systems, for those of locomotion, the noradrenarlin (NA) and/or the serotonin (5HT) neurons and for the stereotyped hand movement the dopamine (DA) neurons. The NA and/or the 5HT neurons in the brain stem may be involved primarily and may cause dysfunction of the midbrain DA neuron directly or indirectly through affecting the pedunculopontine nuclei.

Treatable neurotransmitter deficiency in mild phenylketonuria.

The authors describe a case of neurologic involvement in mild hyperphenylalaninemia (HPA), not due to tetrahydrobiopterin (BH(4)) deficiency, with low levels of monoamine neurotransmitter metabolites in CSF. The combined BH(4)-Phe loading test suggested a BH(4) response, confirmed by clinical improvement after BH(4) therapy. Molecular study revealed a compound heterozygosity of the phenylalanine hydroxylase alleles: a mild HPA-associated mutation (T380M) and the new mutation D151E. This case demonstrates that even mild HPA, generally considered a benign disorder, may present neurologic impairment.

Dramatic brain aminergic deficit in a genetic mouse model of phenylketonuria.

Clinical data suggest that brain catecholamines and serotonin are deficient in phenylketonuria (PKU), an inherited metabolic disorder that causes severe mental retardation and neurological disturbances. To test this hypothesis, brain tissue levels of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT) and their metabolites were evaluated in the genetic mouse model of PKU (Pah(enu2)). Results indicated a significant reduction of 5-HT levels and metabolism in prefrontal cortex (pFC), cingulate cortex (Cg), nucleus accumbens (NAc), caudate putamen (CP), hippocampus (HIP) and amygdala (AMY). NE content and metabolism were reduced in pFC, Cg, AMY and HIP. Finally, significantly reduced DA content and metabolism was observed in pFC, NAc, CP and AMY. In pFC, NAc and CP there was also a marked reduction of DA release.

Presentation, diagnosis, and treatment of the disorders of monoamine neurotransmitter metabolism.

For many years, all of the described cases of monoamine neurotransmitter deficiency were associated with hyperphenylalaninemia that was generally detected at neonatal screening. It is now clear that inherited deficiency of monoamines often occurs in the absence of hyperphenylalaninemia and that the normal battery of screening tests used to investigate individuals with suspected metabolic disease will not detect these cases. Diagnosis in this situation must rely heavily on clinical suspicion. This article, therefore, describes the presentation and clinical symptoms that result from defective monoamine neurotransmission; outlines therapeutic approaches; and explains how cerebrospinal fluid profiles of monoamine metabolites, their precursors, and the cofactor required for monoamine synthesis can be used to pinpoint the exact site of the metabolic lesion.