The effects of chronic ethanol self-administration on hippocampal serotonin transporter density in monkeys.

Evidence for an interaction between alcohol consumption and the serotonin system has been observed repeatedly in both humans and animal models yet the specific relationship between the two remains unclear. Research has focused primarily on the serotonin transporter (SERT) due in part to its role in regulating extracellular levels of serotonin. The hippocampal formation is heavily innervated by ascending serotonin fibers and is a major component of the neurocircuitry involved in mediating the reinforcing effects of alcohol. The current study investigated the effects of chronic ethanol self-administration on hippocampal SERT in a layer and field specific manner using a monkey model of human alcohol consumption. [(3)H]Citalopram was used to measure hippocampal SERT density in male cynomolgus macaques that voluntarily self-administered ethanol for 18 months. Hippocampal [(3)H]citalopram binding was less dense in ethanol drinkers than in controls, with the greatest effect observed in the molecular layer of the dentate gyrus. SERT density was not correlated with measures of ethanol consumption or blood ethanol concentrations, suggesting the possibility that a threshold level of consumption had been met. The lower hippocampal SERT density observed suggests that chronic ethanol consumption is associated with altered serotonergic modulation of hippocampal neurotransmission.

Disruptions in serotonergic regulation of cortical glutamate release in primate insular cortex in response to chronic ethanol and nursery rearing.

Early-life stress has been shown to increase susceptibility to anxiety and substance abuse. Disrupted activity within the anterior insular cortex (AIC) has been shown to play a role in both of these disorders. Altered serotonergic processing is implicated in controlling the activity levels of the associated cognitive networks. We therefore investigated changes in both serotonin receptor expression and glutamatergic synaptic activity in the AIC of alcohol-drinking rhesus monkeys. We studied tissues from male rhesus monkeys raised under two conditions: Male rhesus monkeys (1) "mother reared" (MR) by adult females (n=9) or (2) "Nursery reared" (NR), that is, separated from their mothers and reared as a separate group under surrogate/peer-reared conditions (n=9). The NR condition represents a long-standing and well-validated nonhuman primate model of early life stress. All monkeys were trained to self-administer ethanol (4% w/v) or an isocaloric maltose-dextrin control solution. Subsets from each rearing condition were then given daily access to ethanol, water, or maltose-dextrin for 12 months. Tissues were collected at necropsy and were further analyzed. Using real time RT-PCR we found that ethanol-naive, NR monkeys had lower AIC levels of 5-HT(1A) and 5-HT(2A) receptor mRNA compared with ethanol-naive, MR animals. Although NR monkeys consumed more ethanol over the 12-month period compared with MR animals, both MR and NR animals expressed greater 5-HT(1A) and 5-HT(2A) receptor mRNA levels following chronic alcohol self-administration. The interaction between nursery-rearing conditions and alcohol consumption resulted in a significant enhancement of both 5-HT(1A) and 5-HT(2A) receptor mRNA levels such that lower expression levels observed in nursery-rearing conditions were not found in the alcohol self-administration group. Using voltage clamp recordings in the whole cell configuration we recorded excitatory postsynaptic currents in both ethanol-naive and chronic self-administration groups of NR and MR monkeys. Both groups that self-administered ethanol showed greater glutamatergic activity within the AIC. This AIC hyperactivity in MR alcohol-consuming monkeys was accompanied by an increased sensitivity to regulation by presynaptic 5-HT(1A) receptors that was not apparent in the ethanol-naive, MR group. Our data indicate that chronic alcohol consumption leads to greater AIC activity and may indicate a compensatory upregulation of presynaptic 5-HT(1A) receptors. Our results also indicate that AIC activity may be less effectively regulated by 5-HT in ethanol-naive NR animals than in NR monkeys in response to chronic ethanol self-administration. These data suggest possible mechanisms for increased alcohol seeking and possible addiction potential among young adults who had previously experienced early-life stress that include disruptions in both AIC activity and serotonin system dynamics.

The native T-type calcium current in relay neurons of the primate thalamus.

The generation of thalamic bursts depends upon calcium currents that flow through transiently open (T)-type calcium channels. In this study, we characterized the native T-type calcium current underlying thalamic burst responses in the macaque monkey. Current clamp recordings from lateral geniculate nucleus (LGN) slices showed characteristic burst responses when relay cells were depolarized from relatively hyperpolarized membrane potentials. These bursts could also be elicited by stimulation of excitatory synaptic inputs to LGN cells. Under voltage clamp conditions, the inactivation kinetics of native currents recorded from primate LGN neurons showed consistency with T-type currents recorded in other mammals and in expression systems. Real-time reverse transcriptase PCR performed on RNA isolated from the LGN (including tissues isolated from magnocellular and parvocellular laminae) detected voltage-dependent calcium channel (Ca(v)) 3.1, Ca(v) 3.2, and Ca(v) 3.3 channel transcripts. Ca(v) 3.1 occurred at relatively higher expression than other isoforms, consistent with in situ hybridization studies in rats, indicating that the molecular basis for burst firing in thalamocortical systems is an important conserved property of primate physiology. Since thalamic bursts have been observed during visual processing as well as in a number of CNS disorders, studies of the expression and modulation of these currents at multiple levels are critical for understanding their role in vision and for the discovery of new treatments for disruptions of thalamic rhythms.

MR Imaging of BK virus encephalitis.

BK virus infection is most often associated with urologic disease in patients who have undergone renal or bone marrow transplantation. We report a rare case of biopsy-confirmed BK virus encephalitis in an immunocompromised patient with hemorrhagic cystitis, in whom dramatic imaging findings were present despite relatively mild clinical symptoms. MR imaging demonstrated widespread increased signal intensity on T2- and fluid-attenuated inversion recovery-weighted images, with restricted diffusion, in the cerebellum, cerebral white matter, and deep gray matter structures. The simultaneous presence of urologic abnormalities and neurologic deficits in certain immunocompromised patients should prompt consideration of BK virus encephalitis.

Ethanol modulation of excitatory and inhibitory synaptic transmission in rat and monkey dentate granule neurons.

BACKGROUND: The physiological mechanisms underlying the behavioral and cognitive effects of ethanol are not fully understood. However, there is now compelling evidence that ethanol acts, at least in part, by modulating the function of a small group of proteins that mediate excitatory and inhibitory synaptic transmission. For example, intoxicating concentrations of ethanol have been shown to enhance GABAergic synaptic inhibition and depress glutamatergic excitatory neurotransmission in a number of brain regions. Because all of these electrophysiological studies have been performed in rodent brain slice or neuronal culture preparations, direct evidence that ethanol exerts similar effects on synaptic transmission in the primate central nervous system is lacking. METHODS: We have therefore developed methods to perform patch-clamp electrophysiological recordings from neurons in acutely prepared monkey (Macaca fascicularis) hippocampal slices. We have used these methods to compare the acute effects of ethanol on excitatory and inhibitory synaptic transmission in rat and monkey dentate granule neurons. RESULTS: Under our recording conditions, ethanol significantly potentiated gamma-aminobutyric acid type A inhibitory postsynaptic currents in both rat and monkey neurons. In addition, ethanol significantly inhibited NMDA, but not AMPA, excitatory postsynaptic currents in dentate granule neurons from both species. Notably, no significant differences were observed in any of the pharmacological properties of inhibitory or excitatory synaptic responses recorded from rat and monkey neurons. CONCLUSIONS: These data suggest that the differences in the behavioral effects of ethanol that have been observed between rats and higher-order mammals, such as monkeys and humans, may not reflect differences in the sensitivity of some of the major synaptic sites of ethanol action. Moreover, our results provide empirical evidence for the use of rodent brain slice preparations in elucidating synaptic mechanisms of ethanol action in the primate central nervous system.

Fellowship and practice trends in neuroradiology training programs in the United States.

BACKGROUND AND PURPOSE: Neuroradiology has become an increasingly diverse and subspecialized discipline. We evaluated the current status and trends affecting fellowship programs and the practice of clinical neuroradiology at academic medical centers, with emphasis on invasive procedures. METHODS: All 85 program directors at Accreditation Council for Graduate Medical Education-approved fellowships in neuroradiology were sent a detailed questionnaire pertaining to various demographic aspects of their program and the performance of certain radiologic examinations of the brain and spine. RESULTS: Sixty-seven programs (79%) responded. As many as 50% of programs are 1 year in length. Twenty-five percent of 2-year fellows leave their program after 1 year of training. During the past 5 years, 36% of programs have decreased in size and 73% reported a decline in the number of applicants. The majority (55%) of programs have had applicants renege on their commitment to begin a fellowship. Twenty percent of 2-year programs do not offer training in endovascular interventional procedures. Neurosurgeons perform endovascular interventional procedures at 18% of centers. There is an 18-fold variation in the volume of neuroangiographic procedures performed each year and a 150-fold variation in the volume of myelographic procedures performed. In 29% of programs, neuroradiologists are nonparticipants in nonvascular interventional spinal procedures; in 40%, they share these procedures with musculoskeletal radiologists/nonradiologists. CONCLUSION: Interest in fellowship programs in neuroradiology is declining. An applicant's commitment to either begin a fellowship or complete 2 years of training cannot be regarded with assurance, and there is a lack of uniformity in many areas of the training experience, particularly in invasive diagnostic and therapeutic procedures.

Role of enhanced MRI in the follow-up of patients with medically refractory trigeminal neuralgia undergoing stereotactic radiosurgery using the gamma knife: initial experience.

PURPOSE: The purpose of this work was to evaluate the early posttreatment MR findings, and their clinical utility, in patients with trigeminal neuralgia undergoing stereotactic radiosurgery using the gamma knife. METHOD: Twenty-six patients with medically refractory trigeminal neuralgia underwent stereotactic radiosurgery. A single dose of 70-90 Gy was administered to the proximal root entry zone (n = 21) or the retrogasserian portion (n = 5) of the trigeminal nerve. Posttreatment enhanced MRI and clinical assessment were performed at 3-6 months. RESULTS: Five patients did not have radiologic follow-up. There were no changes identified in the treated trigeminal nerve or adjacent brainstem in 19 of 21 patients. Two patients with multiple sclerosis developed abnormal signal and enhancement in the brainstem and/or trigeminal nerve; neither had clinical complications. Onset of therapeutic effect ranged from 3 weeks to 3 months; 19 patients had a beneficial response. CONCLUSION: Results of enhanced MRI 3-6 months after stereotactic radiosurgical treatment of trigeminal neuralgia do not correlate with the clinical response. Because beneficial clinical responses or treatment failures are apparent by 3 months, routine posttreatment MRI in these patients is not warranted.

Progression of changes in dopamine transporter binding site density as a result of cocaine self-administration in rhesus monkeys.

The present study examined the time course of alterations in levels of dopamine transporter (DAT) binding sites that accompany cocaine self-administration using quantitative in vitro receptor autoradiography with [(3)H]WIN 35,428. The density of dopamine transporter binding sites in the striatum of rhesus monkeys with 5 d, 3.3 months, or 1.5 years of cocaine self-administration experience was compared with DAT levels in cocaine-naive control monkeys. Animals in the long-term (1.5 years) exposure group self-administered cocaine at 0.03 mg/kg per injection, whereas the initial (5 d) and chronic (3.3 months) treatment groups were each divided into lower dose (0.03 mg/kg per injection) and higher dose (0.3 mg/kg per injection) groups. Initial cocaine exposure led to moderate decreases in [(3)H]WIN 35,428 binding sites, with significant changes in the dorsolateral caudate (-25%) and central putamen (-19%) at the lower dose. Longer exposure, in contrast, resulted in elevated levels of striatal binding sites. The increases were most pronounced in the ventral striatum at the level of the nucleus accumbens shell. At the lower dose of the chronic phase, for example, significant increases of 21-42% were measured at the caudal level of the ventral caudate, ventral putamen, olfactory tubercle, and accumbens core and shell. Systematic variation of cocaine dose and drug exposure time demonstrated the importance of these factors in determining the intensity of increased DAT levels. With self-administration of higher doses especially, increases were more intense and included dorsal portions of the striatum so that every region at the caudal level exhibited a significant increase in DAT binding sites (20-54%). The similarity of these findings to previous studies in human cocaine addicts strongly suggest that the increased density of dopamine transporters observed in studies of human drug abusers are the result of the neurobiological effects of cocaine, ruling out confounds such as polydrug abuse, preexisting differences in DAT levels, or comorbid psychiatric conditions.

Chronic cocaine-mediated changes in non-human primate nucleus accumbens gene expression.

Chronic cocaine use elicits changes in the pattern of gene expression within reinforcement-related, dopaminergic regions. cDNA hybridization arrays were used to illuminate cocaine-regulated genes in the nucleus accumbens (NAcc) of non-human primates (Macaca fascicularis; cynomolgus macaque), treated daily with escalating doses of cocaine over one year. Changes seen in mRNA levels by hybridization array analysis were confirmed at the level of protein (via specific immunoblots). Significantly up-regulated genes included: protein kinase A alpha catalytic subunit (PKA(calpha)); cell adhesion tyrosine kinase beta (PYK2); mitogen activated protein kinase kinase 1 (MEK1); and beta-catenin. While some of these changes exist in previously described cocaine-responsive models, others are novel to any model of cocaine use. All of these adaptive responses coexist within a signaling scheme that could account for known inductions of genes(e.g. fos and jun proteins, and cyclic AMP response element binding protein) previously shown to be relevant to cocaine's behavioral actions. The complete data set from this experiment has been posted to the newly created Drug and Alcohol Abuse Array Data Consortium (http://www.arraydata.org) for mining by the general research community.

Stereotactic radiosurgical pallidotomy and thalamotomy with the gamma knife: MR imaging findings with clinical correlation--preliminary experience.

PURPOSE: To evaluate the temporal evolution and appearance of a radiosurgical lesion at magnetic resonance (MR) imaging and the clinical response in patients undergoing stereotactic radiosurgical pallidotomy or thalamotomy with the gamma knife. MATERIALS AND METHODS: Seventeen patients with medically refractory movement disorders underwent stereotactic radiosurgical pallidotomy (n = 2) or thalamotomy (n = 15). A single dose of 120-140 Gy was administered to a target in the globus pallidus interna or ventralis intermedius thalamic nucleus. Postprocedure gadolinium-enhanced MR imaging and clinical assessment were performed at 1 month and 3 months. RESULTS: At 3 months, the radiosurgical lesion most commonly (n = 11) appeared as a ring-enhancing focus 5 mm or less in diameter surrounded by vasogenic edema that extended less than 7 mm in radius beyond the target. Five patients had ring-enhancing lesions 7 mm or more in diameter; four of these developed symptomatic perilesional edema at 3 (n = 2) or 8 (n = 2) months after the procedure. Onset of therapeutic effect began approximately 4 weeks after treatment. In the 15 patients with tremor, there was a mean decline of 2.1 on the Tremor Rating Scale. CONCLUSION: Findings in this pilot study suggest that radiosurgical thalamotomy is a promising treatment for medically refractory tremor. Three-month follow-up MR studies show a ring-enhancing lesion surrounded by a variable amount of vasogenic edema. Visualization of the radiosurgical lesion and the clinical response are delayed compared to that with radio-frequency procedures.

The relationship between the functional abilities of patients with cervical spinal cord injury and the severity of damage revealed by MR imaging.

BACKGROUND AND PURPOSE: The appearance of the damaged spinal cord after injury correlates with initial neurologic deficit, as determined by the American Spinal Injury Association grade and manual muscle test score, as well as with recovery, as assessed by manual muscle test scores. The purpose of this study was to determine whether the presence of spinal cord hemorrhage and the size and location of spinal cord edema on MR images is predictive of functional recovery in survivors of cervical spinal cord injury (SCI). METHODS: The degree of damage to the cervical spinal cord was measured on the MR images of 49 patients who underwent imaging within 72 hours of sustaining SCI. The effects of hemorrhage and length/location of edema on changes in the value of the motor scale of the functional independence measure (FIM) were assessed on admission to and discharge from rehabilitation. RESULTS: Patients without spinal cord hemorrhage had significant improvement in self-care and mobility scores compared with patients with hemorrhage. There was no significant effect of spinal cord hemorrhage on changes in locomotion and sphincter control scores. The rostral limit of edema positively correlated with admission and discharge self-care scores and with admission mobility and locomotion scores. Edema length had a negative correlation with all FIM scales at admission and discharge. CONCLUSION: The imaging characteristics of cervical SCI (hemorrhage and edema) are related to levels of physical recovery as determined by the FIM scale. Imaging factors that correlate with poor functional recovery are hemorrhage, long segments of edema, and high cervical locations.

Effect of cocaine self-administration on dopamine D2 receptors in rhesus monkeys.

The present study used autoradiography to examine the effects of chronic self-administration of cocaine on the density of dopamine D2 receptors in nonhuman primates. Three rhesus monkeys intravenously self-administered an average of 1.35 mg/kg cocaine per day for 18-22 months until they were euthanized immediately after a self-administration session. Binding site density of the D2 ligand [3H]raclopride (2 nM) was assessed in these monkeys as well as three untreated controls, using quantitative in vitro receptor autoradiography. As compared to untreated controls, D2 binding site density was significantly lower in the animals that self-administered cocaine in all regions of the striatum rostral to the anterior commissure. These regions include the anterior and central regions of the caudate nucleus, putamen, olfactory tubercle, and both the shell and core of the nucleus accumbens. Within the substantia nigra and ventral tegmental area, by contrast, no differences were found in the density of D2 binding sites. These findings suggest a pervasive effect of cocaine on the regulation of D2 receptors in the striatum. The lack of change within the ventral midbrain, however, suggests a differential regulation of D2 receptors in the striatum and ventral midbrain. This study confirms and extends our knowledge of the neurobiological changes in the mesolimbic dopamine system that result from chronic exposure to cocaine.

Angiotensin-(1-7) immunoreactivity in the hypothalamus of the (mRen-2d)27 transgenic rat.

The distribution of angiotensin-(1-7) immunoreactive neurons was compared to those of vasopressin-(VP) and oxytocin-(OT) immunoreactive (IR) neurons in the hypothalamus of adult (mRen-2d)27 transgenic hypertensive and Sprague-Dawley rats. In both strains, angiotensin (Ang)-(1-7)-IR cells were found in the supraoptic nucleus (SON), and in the anterior (ap-), medial (mp-), and lateral (lp-) parvocellular, and posterior magnocellular (pm-) subdivisions of the paraventricular (PVN) nucleus. Three-dimensional reconstructions showed that cells immunoreactive to Ang-(1-7) and VP were specifically co-distributed in the SON and in the pmPVN. Double-labeling neurons for both peptides revealed that both Ang-(1-7) and VP were colocalized in a subpopulation of neurons in the pmPVN and SON. In combination with previous studies, our results suggest that Ang-(1-7) and VP are colocalized, co-released and may have a combined action at a common target. In addition, the introduction of the mouse submandibular renin (mRen-2d) transgene into Sprague-Dawley rats does not appear to have altered the fundamental organization of hypothalamic peptide systems involved in fluid homeostasis.