The intranasal (IN-) administration of substances is attracting attention from scientists as well as pharmaceutical companies. The effects are surprisingly fast and specific. The present review ...explores our current knowledge about the routes of access to the cranial cavity. 'Direct-access-pathways' from the nasal cavity have been described but many additional experiments are needed to answer a variety of open questions regarding anatomy and physiology. Among the IN-applied substances oxytocin (OT) has an extensive history. Originally applied in women for its physiological effects related to lactation and parturition, over the last decade most studies focused on their behavioral 'prosocial' effects: from social relations and 'trust' to treatment of 'autism'. Only very recently in a microdialysis study in rats and mice, the 'direct-nose-brain-pathways' of IN-OT have been investigated directly, implying that we are strongly dependent on results obtained from other IN-applied substances. Especially the possibility that IN-OT activates the 'intrinsic' OT-system in the hypothalamus as well needs further clarification. We conclude that IN-OT administration may be a promising approach to influence human communication but that the existing lack of information about the neural and physiological mechanisms involved is a serious problem for the proper understanding and interpretation of the observed effects.
The cerebrospinal fluid (CSF) system provides nutrients to and removes waste products from the brain. Recent findings suggest, however, that in addition, the CSF contains message molecules in the ...form of actively released neuroactive substances. The concentrations of these vary between locations, suggesting they are important for the changes in brain activity that underlie different brain states, and induce different sensory input and behavioral output relationships.The cranial CSF displays a rapid caudally-directed ventricular flow followed by a slower rostrally-directed subarachnoid flow (mainly towards the cribriform plate and from there into the nasal lymphatics). Thus, many brain areas are exposed to and can be influenced by substances contained in the CSF. In this review we discuss the production and flow of the CSF, including the mechanisms involved in the regulation of its composition. In addition, the available evidence for the release of neuropeptides and other neuroactive substances into the CSF is reviewed, with particular attention to the selective effects of these on distant downstream receptive brain areas. As a conclusion we suggest that (1) the flowing CSF is involved in more than just nutrient and waste control, but is also used as a broadcasting system consisting of coordinated messages to a variety of nearby and distant brain areas; (2) this special form of volume transmission underlies changes in behavioral states.
Background
Pulsed radiofrequency treatment has recently been described as a non-neurodestructive or minimally neurodestructive alternative to radiofrequency heat lesions. In clinical practice ...long-lasting results of pulsed radiofrequency treatment adjacent to the cervical dorsal root ganglion for the management of chronic radicular spinal pain have been reported without neurologic complications. However, the mode of action is unclear. An early (3 h) effect of pulsed radiofrequency as measured by an increase of c-Fos in the pain-processing neurons of the dorsal horn of rats has been described in the literature. This effect was not mediated by tissue heating. The authors investigated a possible late or long-term effect of three different radiofrequency modalities.
Methods
Cervical laminectomy was performed in 19 male Wistar rats. The cervical dorsal root ganglion was randomly exposed to one of the four interventions: sham, continuous radiofrequency current at 67 centigrades, or pulsed radiofrequency current for 120 s or 8 min. The animals were sacrificed and the spinal cord was prepared for c-Fos labeling 7 days after the intervention.
Results
The number of c-Fos immunoreactive cells in the dorsal horn was significantly increased in the three different radiofrequency modalities as compared with sham. No significant difference was demonstrated between the three active intervention groups.
Conclusions
The authors demonstrated a late neuronal activity in the dorsal horn after exposure of the cervical dorsal root ganglion to different radiofrequency modalities, which was not temperature dependent.
Abstract The cerebrospinal fluid (CSF) usually is considered as a protective ‘nutrient and waste control’ system for the brain. Recent findings suggest, however, that the composition of CSF is ...actively controlled and may play an influential role in the changes in brain activity, underlying different behavioral states. In the present review, we present an overview of available data concerning the release of oxytocin into the CSF, the location of the oxytocin-receptive brain areas and the behavioral effects of intracerebroventricular oxytocin. About 80% of the oxytocin-receptive areas are located close to the ventricular or subarachnoid CSF, including the hypothalamic ‘Behavior Control Column’ (L.W.Swanson, 2003). As a conclusion we suggest that ‘CSF-oxytocin’ contributes considerably to the non-synaptic communication processes involved in hypothalamic-, brainstem- and olfactory brain areas and behavioral states and that the flowing CSF is used as a ‘broadcasting system’ to send coordinated messages to a wide variety of nearby and distant brain areas.
Antidepressant-induced sexual dysfunction adversely affects the quality of life of antidepressant users and reduces compliance with treatment. Animal models provide an instructive approach for ...examining potential sexual side effects of novel drugs. This review discusses the stability and reproducibility of our standardized test procedure that assesses the acute, subchronic and chronic effects of psychoactive compounds in a 30minute mating test. In addition, we present an overview of the effects of several different (putative) antidepressants on male rat sexual behavior, as tested in our standardized test procedure. By comparing the effects of these mechanistically distinct antidepressants (paroxetine, venlafaxine, bupropion, buspirone, DOV 216,303 and S32006), this review discusses the putative mechanism underlying sexual side effects of antidepressants and their normalization.
This review shows that sexual behavior is mainly inhibited by antidepressants that increase serotonin neurotransmission via blockade of serotonin transporters, while those that mainly increase the levels of dopamine and noradrenaline are devoid of sexual side effects. Those sexual disturbances cannot be normalized by simultaneously increasing noradrenaline neurotransmission, but are normalized by increasing both noradrenaline and dopamine neurotransmission. Therefore, it is hypothesized that the sexual side effects of selective serotonin reuptake inhibitors may be mediated by their inhibitory effects on dopamine signaling in sex brain circuits. Clinical development of novel antidepressants should therefore focus on compounds that simultaneously increase both serotonin and dopamine signaling.
•Antidepressants (AD) that block SERT inhibit sexual behavior.•AD that increase dopamine and noradrenaline do not inhibit sexual behavior.•SERT-mediated inhibition is counteracted by increasing dopamine and noradrenaline.•SSRI-induced sexual side effects may be due to inhibition of dopamine signaling.
Serotonin plays an important role in male sexual behavior. Many studies have been performed on the pivotal role of 5-HT1A receptors in sexual behavior. Overall, 5-HT1A receptors do not appear to be ...involved under normal circumstances, but become very important under conditions of elevated serotonin levels in sexual behavior. 5-HT1A receptor agonists facilitate ejaculatory behavior in male rats, while inhibiting copulatory behavior. Three different phases can be distinguished in rats' sexual cycle, the introductory (precopulatory), the copulatory and the executive (ejaculatory) phases. Different mechanisms and brain regions are involved in these phases. The mechanisms, brain regions and the possible involvement of 5-HT and 5-HT1A receptors in the appropriate phases in male rat sexual behavior will be discussed in the current review.
•We discuss the mechanisms of serotonin in male sexual behavior.•5-HT1A receptors are important under conditions of elevated serotonin levels.•Three phases can be distinguished in the sexual cycle in males.•Different mechanisms are involved in the different phases.
Beta-endorphin (β-END) is an opioid neuropeptide which has an important role in the development of hypotheses concerning the non-synaptic or paracrine communication of brain messages. This kind of ...communication between neurons has been designated volume transmission (VT) to differentiate it clearly from synaptic communication. VT occurs over short as well as long distances via the extracellular space in the brain, as well as via the cerebrospinal fluid (CSF) flowing through the ventricular spaces inside the brain and the arachnoid space surrounding the central nervous system (CNS). To understand how β-END can have specific behavioral effects, we use the notion behavioral state, inspired by the concept of machine state, coming from Turing (Proc London Math Soc, Series 2,42:230-265, 1937). In section 1.4 the sequential organization of male rat behavior is explained showing that an animal is not free to switch into another state at any given moment. Funneling-constraints restrict the number of possible behavioral transitions in specific phases while at other moments in the sequence the transition to other behavioral states is almost completely open. The effects of β-END on behaviors like food intake and sexual behavior, and the mechanisms involved in reward, meditation and pain control are discussed in detail. The effects on the sequential organization of behavior and on state transitions dominate the description of these effects.
This review focuses on the role of serotonin and especially 5-HT1A receptors in female rat sexual behavior. In addition, the differences and/or similarities with male rats are discussed. Overall, in ...both males and females 5-HT1A receptors do not appear to be involved in sexual behavior under normal circumstances, but become very important under conditions of elevated serotonin levels. 5-HT1A receptor agonists facilitate sexual behavior in male rats, but inhibit female sexual activity. At first sight, this seems quite conflicting, but could be due to our definitions of different elements of sexual behavior. Three different phases can be distinguished in rats' sexual cycle, the introductory (precopulatory), the copulatory and the executive (ejaculatory) phases. Different mechanisms and brain regions are involved in these phases. If the appropriate phases of males and females are properly compared, the role of 5-HT1A receptors in rats might be more similar than assumed thus far.
•5-HT1A receptors are important under conditions of elevated serotonin levels.•During low levels of hormones 5-HT1A receptors are important.•Three phases can be distinguished in the sexual cycle in males and females.•Different phases of sexual behavior have different regulatory mechanisms.•Male and female sexual behavior is more similar than normally expected.
There is increasing evidence that non-synaptic communication by volume transmission in the flowing CSF plays an important role in neural mechanisms, especially for extending the duration of ...behavioral effects. In the present review, we explore the mechanisms involved in the behavioral and physiological effects of β-endorphin (β-END), especially those involving the cerebrospinal fluid (CSF), as a message transport system to reach distant brain areas. The major source of β-END are the pro-opio-melano-cortin (POMC) neurons, located in the arcuate hypothalamic nucleus (ARH), bordering the 3rd ventricle. In addition, numerous varicose β-END-immunoreactive fibers are situated close to the ventricular surfaces. In the present paper we surveyed the evidence that volume transmission via the CSF can be considered as an option for messages to reach remote brain areas. Some of the points discussed in the present review are: release mechanisms of β-END, independence of peripheral versus central levels, central β-END migration over considerable distances, behavioral effects of β-END depend on location of ventricular administration, and abundance of mu and delta opioid receptors in the periventricular regions of the brain.
Neural activation following sexual behavior was studied in the male and female rat brain, using Fos-immunoreactivity (Fos-IR) as a measure. In accordance with the available literature, we observed ...increased expression of c-fos in the medial preoptic nucleus (MPN), in the posteromedial subdivision of the bed nucleus of the stria terminalis, in the posterodorsal part of the medial amygdala, and in the caudal thalamus, in the parvicellular part of the subparafascicular nucleus. After performance of different behavioral elements (anogenital investigation, mounting, intromission or ejaculation) not only the numbers of Fos-IR neurons varied considerably, but also their distribution. Especially after ejaculation, but in females already after intromissions, dense groups of Fos-IR neurons appeared in specific subdivisions of the areas mentioned above. That these groups of dense Fos-IR appeared as a result of the ejaculation per se, was assessed by administrating the 5-HT1A agonist 8-OH-DPAT to the males, whereupon they ejaculated within a few seconds, without the usual amount of preceding behavioral elements. Since the pattern of Fos-IR was similar to the normal ejaculation pattern, we have described the dense activation areas as ‘ejaculation-related clusters’. Our review discusses the stimuli and pathways probably involved in the observed pattern of Fos-IR and we conclude that the ‘deep viscero-genital’ activation, occurring at the moment of ejaculation, running along the pelvic nerve and ascending from the spinal cord, is most probably responsible. We show that the location of the Fos-IR neurons in the medial subparafascicular nucleus perfectly coincides with the location of Galanin-IR fibers, ascending from the spinal cord. The application of anterograde and retrograde neuroanatomical tracers into the MPN, in combination with Fos-IR showed that the medial preoptic nucleus has very specific relationships with the Fos-IR sub-areas, involved in ejaculation. We conclude that within the larger brain structures involved in sexual and other social activities, a specific ejaculation-related subcircuit exists, which may, under normal conditions in the rat, serve a ‘sexual-satiety function’.
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