Speed of saccade execution and inhibition associated with fractional anisotropy in distinct fronto‐frontal and fronto‐striatal white matter pathways

Fast cancellation or switching of action plans is a critical cognitive function. Rapid signal transmission is key for quickly executing and inhibiting responses, and the structural integrity of connections between brain regions plays a crucial role in signal transmission speed. In this study, we used the search‐step task, which has been used in nonhuman primates to measure dynamic alteration of saccade plans, in combination with functional and diffusion‐weighted MRI. Functional MRI results were used to identify brain regions involved in the reactive control of gaze. Probabilistic tractography was used to identify white matter pathways connecting these structures, and the integrity of these connections, as indicated by fractional anisotropy (FA), was correlated with search‐step task performance. Average FA from tracts between the right frontal eye field (FEF) and both right supplementary eye field (SEF) and the dorsal striatum were associated with faster saccade execution. Average FA of connections between the dorsal striatum and both right SEF and right inferior frontal cortex (IFC) as well as between SEF and IFC predicted the speed of inhibition. These relationships were largely behaviorally specific, despite the correlation between saccade execution and inhibition. Average FA of connections between the IFC and both SEF and the dorsal striatum specifically predicted the speed of inhibition, and connections between the FEF and SEF specifically predicted the speed of execution. In addition, these relationships were anatomically specific; correlations were observed after controlling for global FA. These data suggest that networks supporting saccade initiation and inhibition are at least partly dissociable. Hum Brain Mapp 37:2811–2822, 2016. © 2016 Wiley Periodicals, Inc .     

Mapping neural dynamics underlying saccade preparation and execution and their relation to reaction time and direction errors

Our ability to control and inhibit automatic behaviors is crucial for negotiating complex environments, all of which require rapid communication between sensory, motor, and cognitive networks. Here, we measured neuromagnetic brain activity to investigate the neural timing of cortical areas needed for inhibitory control, while 14 healthy young adults performed an interleaved prosaccade (look at a peripheral visual stimulus) and antisaccade (look away from stimulus) task. Analysis of how neural activity relates to saccade reaction time (SRT) and occurrence of direction errors (look at stimulus on antisaccade trials) provides insight into inhibitory control. Neuromagnetic source activity was used to extract stimulus‐aligned and saccade‐aligned activity to examine temporal differences between prosaccade and antisaccade trials in brain regions associated with saccade control. For stimulus‐aligned antisaccade trials, a longer SRT was associated with delayed onset of neural activity within the ipsilateral parietal eye field (PEF) and bilateral frontal eye field (FEF). Saccade‐aligned activity demonstrated peak activation 10ms before saccade‐onset within the contralateral PEF for prosaccade trials and within the bilateral FEF for antisaccade trials. In addition, failure to inhibit prosaccades on anti‐saccade trials was associated with increased activity prior to saccade onset within the FEF contralateral to the peripheral stimulus. This work on dynamic activity adds to our knowledge that direction errors were due, at least in part, to a failure to inhibit automatic prosaccades. These findings provide novel evidence in humans regarding the temporal dynamics within oculomotor areas needed for saccade programming and the role frontal brain regions have on top‐down inhibitory control.     

Dissociations in dopamine release in medial prefrontal cortex and ventral striatum during the acquisition and extinction of classical aversive conditioning in the rat

Dual perfusion in vivo brain microdialysis was used to monitor extracellular levels of dopamine in the medial prefrontal cortex and ventral striatum during the acquisition and extinction of a classical aversive conditioning paradigm in rats. The main finding was a dissociation in the pattern of release in the two brain areas. The first stimulus–footshock pairing elicited large increases in cortical dopamine over baseline levels that were much greater than the increases elicited by different stimuli of equivalent salience that were unpaired with footshock. In contrast, dopamine levels in ventral striatum were unchanged under these conditions. Over the next two pairings, there was a decline in the cortical response and an increase in the response in ventral striatum. The first presentation of the aversive conditioned stimulus in a separate context elicited the largest response in ventral striatum. Post-conditioning, the cortical response to the conditioned stimulus was smaller than that elicited by the initial stimulus–footshock pairing and was equivalent in magnitude to that elicited by stimuli unpaired with footshock. Over the final two conditioned stimuli presentations, in the absence of the footshock reinforcer (extinction), responses declined in both brain areas. Simultaneous monitoring of behaviour indicated that the neurochemical events were accompanied by effective aversive learning, as indexed by conditioned freezing responses. The data are discussed in terms of the hypothesis that medial prefrontal cortex is especially engaged during novel circumstances which may, potentially, require new learning, whilst ventral striatal dopamine more closely follows the expression of conditioned responding during learning and extinction.     

Neural correlates of reward and attention in macaque area LIP

Saccade reaction times decrease and the frequency of target choices increases with the size of rewards delivered for orienting to a particular visual target. Similarly, increasing rewards for orienting to a visual target enhances neuronal responses in the macaque lateral intraparietal area (LIP), as well as other brain areas. These observations raise several questions. First, are reward-related modulations in neuronal activity in LIP, as well as other areas, spatially specific or more global in nature? Second, to what extent does reward modulation of neuronal activity in area LIP reflect changes in visual rather than motor processing? And third, to what degree are reward-related modulations in LIP activity independent of performance-related modulations thought to reflect changes in attention? Here we show that increasing the size of fluid rewards in blocks reduced saccade reaction times and improved performance in monkeys performing a peripherally-cued saccade task. LIP neurons responded to visual cues spatially segregated from the saccade target, and for many neurons visual responses were systematically modulated by expected reward size. Neuronal responses also were positively correlated with reaction times independent of reward size, consistent with re-orienting of attention to the saccade target. These observations suggest that motivation and attention independently contribute to the strength of sustained visual responses in LIP. Our data thus implicate LIP in the integration of the sensory, motor, and motivational variables that guide orienting.     

Ontogeny of soluble and particulate prolyl endopeptidase activity in several areas of the rat brain and in the pituitary gland

We have analyzed the activity of prolyl endopeptidase (PEP) in several areas of the rat brain (brain cortex, striatum, brain stem, cerebellum and hypothalamus) and in the pituitary gland during ontogeny. In all of these areas, we observed a reduction in PEP activity during development. However, the temporal profile of these alterations was found to be area specific and differences in the ontogeny of the soluble and particulate forms of PEP were observed. Thus, by postnatal day 20 (PD20), soluble PEP activity had began to decrease in the brain cortex and striatum, whereas decreased soluble PEP activity was observed earlier, at PD15, in the brain stem and cerebellum. Changes in the particulate fraction were even more pronounced. Senescence was associated with decreased soluble PEP activity in the striatum, but in contrast, particulate PEP activity was found to be increased in the senescent brain stem. The present results indicate that alterations in the levels of activity of PEP may represent an important event in the development and aging of the central nervous system.     

Phosphatases and cathepsin D activities after vasogenic oedema: an experimental study

The role of two phosphatases (acid and alkaline phosphatase) and a lysosomal aspartyl endopeptidase (cathepsin D) in producing rat brain oedema was studied in 3 different rat cerebral areas (i.e. frontal cortex, hippocampus and striatum) at 1, 2 and 3 d after vasogenic brain oedema induction. The percentage of water content in the frontal cortex increased immediately, 1 d after oedema induction and remained high for 2 and 3 d after oedema induction. In the hippocampus and the striatum the water content only increases 3 d after oedema induction. In the oedematous hemisphere (right), when compared to the contralateral hemisphere (left), the acid phosphatase activity decreases in the hippocampus, while the alkaline phosphatase increases in the frontal cortex and striatum; cathepsin D increases only in the striatum. The changes caused by the enzymatic activities were significant only 2 and 3 d after oedema induction. The results of this study show that: (i) the vasogenic oedema induced in experimental conditions was not sufficient to cause a massive liberation of lysosomal enzymes and (ii) brain areas adjacent (below) to the site of the experimental oedematous lesion (frontal cortex) were influenced by oedema induction.     

Event-related functional magnetic resonance imaging of reward-related brain circuitry in children and adolescents.

BACKGROUND: Functional disturbances in reward-related brain systems are thought to play a role in the development of mood, impulse, and substance-abuse disorders. Studies in nonhuman primates have identified brain regions, including the dorsal/ventral striatum and orbital-frontal cortex, in which neural activity is modulated by reward. Recent studies in adults have concurred with these findings by observing reward-contingent blood oxygen level-dependent (BOLD) responses in these regions during functional magnetic resonance imaging (fMRI) paradigms; however, no previous studies indicate whether comparable modulations of neural activity exist in the brain reward systems of children and adolescents. METHODS: We used event-related fMRI and a behavioral paradigm modeled on previous work in adults to study brain responses to monetary gains and losses in psychiatrically healthy children and adolescents as part of a program examining the neural substrates of anxiety and depression in youth. RESULTS: Regions and time-courses of reward-related activity were similar to those observed in adults with condition-dependent BOLD changes in the ventral striatum and lateral and medial orbital-frontal cortex; specifically, these regions showed larger responses to positive than to negative feedback. CONCLUSIONS: These results provide further evidence for the value of event-related fMRI in examining reward systems of the brain, demonstrate the feasibility of this approach in children and adolescents, and establish a baseline from which to understand the pathophysiology of reward-related psychiatric disorders in youth.     

Functional deactivations: multiple ipsilateral brain areas engaged in the processing of somatosensory information

Somatosensory signals modulate activity throughout a widespread network in both of the brain hemispheres: the contralateral as well as the ipsilateral side of the brain relative to the stimulated limb. To analyze the ipsilateral somatosensory brain areas that are engaged during limb stimulation, we performed functional magnetic resonance imaging (fMRI) in 12 healthy subjects during electrical median nerve stimulation using both a block- and an event-related fMRI design. Data were analyzed through the use of model-dependent (SPM) and model-independent (ICA) approaches. Beyond the well-known positive blood oxygenation level-dependent (BOLD) responses, negative deflections of the BOLD response were found consistently in several ipsilateral brain areas, including the primary somatosensory cortex, the supplementary motor area, the insula, the dorsal part of the posterior cingulate cortex, and the contralateral cerebellum. Compared to their positive counterparts, the negative hemodynamic responses showed a different time course, with an onset time delay of 2.4 s and a peak delay of 0.7 s. This characteristic delay was observed in all investigated areas and verified by a second (purely tactile) event-related paradigm, suggesting a systematic difference for brain areas involved in the processing of somatosensory information. These findings may indicate that the physiological basis of these deactivations differs from that of the positive BOLD responses. Therefore, an altered model for the negative BOLD response may be beneficial to further model-dependent fMRI analyses.     

Common biology of craving across legal and illegal drugs - a quantitative meta-analysis of cue-reactivity brain response

The present quantitative meta-analysis set out to test whether cue-reactivity responses in humans differ across drugs of abuse and whether these responses constitute the biological basis of drug craving as a core psychopathology of addiction. By means of activation likelihood estimation, we investigated the concurrence of brain regions activated by cue-induced craving paradigms across studies on nicotine, alcohol and cocaine addicts. Furthermore, we analysed the concurrence of brain regions positively correlated with self-reported craving in nicotine and alcohol studies. We found direct overlap between nicotine, alcohol and cocaine cue reactivity in the ventral striatum. In addition, regions of close proximity were observed in the anterior cingulate cortex (ACC; nicotine and cocaine) and amygdala (alcohol, nicotine and cocaine). Brain regions of concurrence in drug cue-reactivity paradigms that overlapped with brain regions of concurrence in self-reported craving correlations were found in the ACC, ventral striatum and right pallidum (for alcohol). This first quantitative meta-analysis on drug cue reactivity identifies brain regions underlying nicotine, alcohol and cocaine dependency, i.e. the ventral striatum. The ACC, right pallidum and ventral striatum were related to drug cue reactivity as well as self-reported craving, suggesting that this set of brain regions constitutes the core circuit of drug craving in nicotine and alcohol addiction.     

Non-visual information does not drive saccade gain adaptation in monkeys

Recent experiments have characterized the dependence of saccade gain adaptation on the characteristics of the visual error following inaccurate saccades. We currently know little about the potential role of non-visual information in driving saccade adaptation. The brain could use non-visual signals from the saccade burst generator or extraocular muscle (EOM) proprioceptors to determine if the eye had rotated the appropriate distance to aim at a target. Both saccade-related burst signals and EOM proprioceptive information reach the posterior vermis of the cerebellum, a brain area strongly implicated in saccade adaptation. In the experiment described here we determined if non-visual information has a significant affect on saccade adaptation. We made monkey saccades hypometric with intra-saccade target movements and then tested the recovery of saccade gain toward normal under three conditions: (1) when the target was continuously visible, (2) when the target extinguished for 1000 ms beginning during the saccade, and (3) when the monkey remained in the dark. In the first condition both visual and non-visual indications of hypometria were available. In the second, only non-visual information was available. In the third, the monkey made no visually guided saccades and very few spontaneous saccades in the dark so neither visual nor non-visual information could drive adaptation. We found that, though it was hypometric, saccade size during recovery changed the same small amount when monkeys made saccades to extinguishing targets or remained in the dark. Saccade size changed significantly (approximately 5x) more during recovery when the monkey tracked continuously visible targets. Thus non-visual information has no influence on adaptation and visual post-saccade error is the only known driver of saccade adaptation.     

Exploring the anatomy of negative motor areas (NMAs): Findings in awake surgery

Positive motor responses have been used in neurosurgery for the identification of motor structures. With the term “negative motor responses” (NMRs) a complete inhibition of movement without loss of muscle tone or consciousness is meant. Papers already exist in the literature regarding cortical areas in which such NMRs are evoked, the so-called “negative motor areas” (NMAs), but their location and functional meaning are still poorly understood. This paper discusses the anatomy of the NMAs of the human brain, in light of our brain mapping experience. 21 patients underwent awake surgery and direct electrical stimulation (DES) was performed using bipolar electrodes. Excision was interrupted when functional responses were intraoperatively identified through DES. The labeled mapping sites were recorded by photography prior to and following tumor resection. Results depicting a probabilistic map of negative motor network anatomy were retrospectively analyzed. Our findings strongly support the fact that the precentral gyrus, classical site of the of the Primary Motor Areas, is also strongly involved in generating NMRs. The distribution of NMAs was noted not to be as rigid as previously described, ranging in different brain areas with a somatotopic arrangement. Presented anatomical results are consistent with the literature, but the exact functional meaning of NMAs and their subcortical connectivity is still far from being completely understood.     

Neck muscle responses evoked by transcranial magnetic stimulation of the human frontal eye fields

Transcranial magnetic stimulation (TMS) provides a non-invasive means of investigating brain function. Whereas TMS of the human frontal eye fields (FEFs) does not induce saccades, electrical stimulation of the monkey FEF evokes eye-head gaze shifts, with neck muscle responses evoked at stimulation levels insufficient to evoke a saccade. These animal results motivated us to examine whether TMS of the FEF (TMS-FEF) in humans evokes a neck muscle response. Subjects performed memory-guided saccades to the left or right while TMS (two pulses at 20?Hz) was delivered on 30% of trials to the left FEF coincident with saccade instruction. As reported previously, TMS-FEF decreased contralateral saccade reaction times. We simultaneously recorded the activity of splenius capitis (SPL) (an ipsilateral head turner). TMS-FEF evoked a lateralized increase in the activity of the right SPL but not the left SPL, consistent with the recruitment of a contralateral head-turning synergy. In some subjects, the evoked neck muscle response was time-locked to stimulation, whereas in others the evoked response occurred around the time of the saccade. Importantly, evoked responses were greater when TMS was applied to the FEF engaged in contralateral saccade preparation, with even greater evoked responses preceding shorter latency saccades. These results provide new insights into both the nature of TMS and the human oculomotor system, demonstrating that TMS-FEF engages brainstem oculomotor circuits in a manner consistent with a general role in eye-head gaze orienting. Our results also suggest that pairing neck muscle recordings with TMS-FEF provides a novel way of assaying the covert preparation of oculomotor plans.     

Attention modulates the dorsal striatum response to love stimuli

In previous functional magnetic resonance imaging (fMRI) studies concerning romantic love, several brain regions including the caudate and putamen have consistently been found to be more responsive to beloved‐related than control stimuli. In those studies, infatuated individuals were typically instructed to passively view the stimuli or to think of the viewed person. In the current study, we examined how the instruction to attend to, or ignore the beloved modulates the response of these brain areas. Infatuated individuals performed an oddball task in which pictures of their beloved and friend served as targets and distractors. The dorsal striatum showed greater activation for the beloved than friend, but only when they were targets. The dorsal striatum actually tended to show less activation for the beloved than the friend when they were distractors. The longer the love and relationship duration, the smaller the response of the dorsal striatum to beloved‐distractor stimuli was. We interpret our findings in terms of reinforcement learning. By virtue of using a cognitive task with a full factorial design, we show that the dorsal striatum is not activated by beloved‐related information per se, but only by beloved‐related information that is attended. Hum Brain Mapp 35:503–512, 2014. © 2012 Wiley Periodicals, Inc.     

Event-related power modulations of brain activity preceding visually guided saccades

To analyze the characteristics of the event-related desynchronization (ERD) and synchronization (ERS) of cortical rhythms during the preparation and execution of a lateralized eye movement, EEG was recorded in normal subjects during a visually guided task. Alpha and beta bands were investigated in three temporal intervals: a sensory period, a delay period and a saccade preparation period time locked with saccade onset. Modulations of ERD/ERS power, coupled with the task, reached the largest amplitudes over the frontal and parieto-occipital regions. Differences of oscillatory activity in the alpha bands revealed an intriguing pattern of asymmetry in parieto-occipital areas. Rightward saccades induced a larger desynchronization with respect to the leftward saccades in the left hemisphere, but not in the right. If representative, these findings are congruent to the established right-hemisphere dominance of the brain areas that direct attention. Moreover differences between the two alpha types emerged in the frontal areas before and during the saccade preparation periods, indicative of differential engagement of these areas depending on the task demands. In conclusion, the present approach shows that planning eye movements is linked with covert orienting of spatial attention and may supply a useful method for studying eye movements and selective attention-related processes.     

Reducing vascular variability of fMRI data across aging populations using a breathholding task

The magnitude and shape of blood oxygen level-dependent (BOLD) responses in functional MRI (fMRI) studies vary across brain regions, subjects, and populations. This variability may be secondary to neural activity or vasculature differences, thus complicating interpretations of BOLD signal changes in fMRI experiments. We compare the BOLD responses to neural activity and a vascular challenge and test a method to dissociate these influences in 26 younger subjects (ages 18-36) and 24 older subjects (ages 51-78). Each subject performed a visuomotor saccade task (a vascular response to neural activity) and a breathholding task (vascular dilation induced by hypercapnia) during separate runs in the same scanning session. For the saccade task, signal magnitude showed a significant decrease with aging in FEF, SEF, and V1, and a delayed time-to-peak with aging in V1. The signal magnitudes from the saccade and hypercapnia tasks showed significant linear regressions within subjects and across individuals and populations. These two tasks had weaker, but sometimes significant linear regressions for time-to-peak and coherence phase measures. The significant magnitude decrease with aging in V1 remained after dividing the saccade task magnitude by the hypercapnia task magnitude, implying that the signal decrease is neural in origin. These findings may lead to a method to identify vascular reactivity-induced differences in the BOLD response across populations and the development of methods to account for the influence of these vasculature differences in a simple, noninvasive manner.     

Alterations of A1 adenosine receptors in different mouse brain areas after pentylentetrazol-induced seizures, but not in the epileptic mutant mouse 'tottering'

Single and repeated Pentylentetrazol (PTZ)-induced convulsions are associated with significant changes of A1 adenosine receptors (detected using the radioligand [3H]cyclohexyladenosine, [3H]CHA) in 4 different brain areas of the mouse, namely cortex, hippocampus, cerebellum and striatum. In hippocampus and cerebellum, a rapid increase in [3H]CHA binding, by 26% and 30% respectively, was observed 1 h after a single PTZ convulsion. In striatum, on the contrary, a significant decrease by 30% in [3H]CHA binding was seen, whereas in cortex no significant change could be detected. After daily repeated PTZ convulsions, a significant increase of A1 receptors by 26% appeared also in cortex, while the changes of A1 receptors observed in the other brain areas after a single PTZ convulsion were maintained in almost the same range. All the alterations observed were due to changes of the total number of A1 receptors (Bmax) without changes in receptor affinity (Kd). A significant increase in the latency of PTZ seizure (time between the PTZ-injection and the beginning of the seizure) was also observed after repeated PTZ-induced convulsions at the time when the changes in A1 adenosine receptors were noted. Considered together, these results provide further evidence for an A1 receptor-mediated modulation of seizure susceptibility and indicate that specific brain areas may play different roles in this modulation. The binding of [3H]CHA to membranes from different cortical and subcortical areas of the epileptic mutant mouse 'tottering' was not different from that in control animals.     

'Functional' neuroanatomical tract tracing: analysis of changes in gene expression of brain circuits of interest

Neuroanatomical tracing when considered as an isolated method produces relatively straightforward answers. Although single-, double- or even triple-tracing paradigms produce valuable data on the organization of brain circuits, the final outcome often is too simplistic since it is not possible to elucidate the activity of these circuits. In this regard, emerging technologies contribute with additional information about the status of neuronal circuits. The laser-guided capture microdissection microscope (LCM) allows the accurate dissection of small brain areas under the microscope that could be further analyzed for gene expression or proteomics. In order to elucidate the gene expression of a given circuit of interest, we have developed a combination of methods comprising (i) fluorescent non-radioactive in situ hybridization for the detection of vGLUT2 mRNA expression combined with retrograde tracing with Fluoro-Gold (FG; analysis performed under the confocal microscope) and (ii) laser-guided capture microdissection of brain areas containing neurons retrogradely labeled with FG followed by the measurement of changes in mRNA levels encoding for vGLUT2 by real-time PCR. Our goal was to detect changes in gene expression of the thalamostriatal pathway in unilaterally 6-OHDA lesioned rats. Taking advantage of this procedure, we found a three-fold increase in vGLUT2 mRNA expression within thalamic neurons projecting to the dopamine-depleted striatum when compared with the activity of the thalamic neurons innervating the control striatum.     

(R)‐ and (S)‐ketamine induce differential fMRI responses in conscious rats

(R,S)‐ketamine exerts robust antidepressant effects in patients with depression when given at sub‐anesthetic doses. Each of the enantiomers in this racemic mixture, (R)‐ketamine and (S)‐ketamine, have been reported to exert antidepressant effects individually. However, the neuropharmacological effects of these enantiomers and the mechanisms underlying their antidepressive actions have not yet been fully elucidated. Therefore, we investigated the effect of (R,S)‐, (R)‐, and (S)‐ketamine on brain activity by functional MRI (fMRI) in conscious rats and compared these with that of N‐methyl‐D‐aspartate receptor (NMDAR) antagonist MK‐801 (n = 5~7). We also assessed their pharmacokinetic profiles (n = 4) and their behavioral effects (n = 7~9). This pharmacological MRI study revealed a significant positive response to (S)‐ketamine specifically in the cortex, nucleus accumbens and striatum. In contrast, negative fMRI responses were observed in various brain regions after (R)‐ketamine administration. (R,S)‐ketamine, evoked significant positive fMRI responses specifically in the cortex, nucleus accumbens and striatum, and this fMRI response pattern was comparable with that of (S)‐ketamine. MK‐801‐induced similar fMRI response pattern to (S)‐ketamine. The fMRI responses to (S)‐ketamine and MK‐801 showed differential temporal profiles, which corresponded with brain concentration profiles. (S)‐ketamine and MK‐801 significantly increased locomotor activity, while (R)‐ketamine produced no noticeable change. (R,S)‐ketamine tended to increase locomotor activity. Our novel fMRI findings show that (R)‐ketamine and (S)‐ketamine induce completely different fMRI response patterns on rat, and that the response produced by the latter is similar to that elicited by an NMDAR antagonist. Our findings provide insight into the antidepressant mechanism of (R,S)‐ketamine.     

A systematic regional study of brain salsolinol levels during and immediately following chronic ethanol ingestion in rats

Regional contents of salsolinol and catecholamines in the brain of normal and ethanol-treated rats were studied. Male Sprague Dawley rats were given ethanol solution as sole drinking fluid for 3, 4, 5 or 6 months. Salsolinol determined by gas chromatography mass spectrometry was found to be present in the hypothalamus and the striatum of control rats. The levels of salsolinol in these regions increased significantly by long-term ethanol drinking and rapidly decreased to control levels following its removal. Salsolinol levels in other regions of rat brain were extremely low or negative and unaltered upon chronic ethanol treatment. In ethanol-treated rats the hypothalamic salsolinol, although generally higher than in the striatum, increased along with the ethanol exposure, whereas the striatal salsolinol was constant during those periods of study. Brain dopamine (DA) and norepinephrine contents remained unaltered during and immediately after chronic ethanol treatments. No correlation of salsolinol levels with DA contents or blood ethanol concentrations was observed. The occurrence of salsolinol in selected areas of rat brain with lack of changes in catecholamine level but as a result of an in vivo formation by long-term ethanol drinking was considered to be due to an alteration of acetaldehyde metabolism in the liver and brain.     

Effect of chronic lithium on cholinergically mediated responses and [3H]QNB binding in rat brain

Lithium (Li) has been previously reported to increase acetylcholine turnover and release in rat brain and to potentiate the neurotoxicity of cholinergic agents. We studied the effect of chronic Li administration, alone and in combination with the muscarinic antagonist, scopolamine, on two cholinergically-mediated responses and on muscarinic cholinergic receptor (MCR) binding in rat brain. Administered separately, Li and scopolamine enhanced the cataleptic and hypothermic responses to pilocarpine; combined administration resulted in an additive effect on both these measures. [3H]Quinuclidinyl benzilate ([3H]QNB) binding was increased by Li in the corpus striatum but not in the cortex, hippocampus and hypothalamus. Scopolamine increased [3H]QNB binding in the striatum, cortex and hippocampus; Li and scopolamine effects on striatal MCR were not additive. Contrary to a previous report, antagonist-induced MCR supersensitivity was not prevented by concurrent Li administration in any of the brain areas studied. The additive effect of Li and scopolamine on pilocarpine-induced catalepsy and a trend in this direction for pilocarpine-induced hypothermia suggest that the actions of the two agents to enhance cholinergically mediated responses may be achieved by different mechanisms. Supersensitive responses following scopolamine may be attributed to antagonist-induced up-regulation of postsynaptic muscarinic receptors as demonstrated in the binding studies. The effects of Li to enhance cholinergically-mediated catalepsy and hypothermia are interpreted as extending previous reports that Li stimulates brain cholinergic function by a presynaptic increase in acetylcholine turnover and release.