P. Leon Brown

University of Maryland, Baltimore | UMB · Maryland Psychiatric Research Center (MPRC)

Introduction Clinically relevant sex differences have been noted in a number of affective, behavioral, cognitive, and neurological health disorders. Midbrain dopamine neurons are implicated in several of these same disorders and consequently are under investigation for their potential role in the manifestation of these sex differences. The lateral...

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input...

Background The volatile anesthetic isoflurane may exert a rapid and long-lasting antidepressant effect in patients with medication-resistant depression. The mechanism underlying the putative therapeutic actions of the anesthetic have been attributed to its ability to elicit cortical burst suppression, a distinct EEG pattern with features resembling...

Neurons in the lateral habenula (LHb) are transiently activated by aversive events and have been implicated in associative learning. Functional changes associated with tonic and phasic activation of the LHb are often attributed to a corresponding inhibition of midbrain dopamine (DA) neurons. Activation of GABAergic neurons in the rostromedial tegme...

Significance statement: Phasic changes in the activity of midbrain dopamine cells motivate and guide future behavior. Activation of the lateral habenula by aversive events transiently inhibits dopamine neurons, providing a neurobiological representation of learning models that incorporate negative reward prediction errors. Anatomical evidence sugg...

The Research Domain Criteria (RDoC) initiative was implemented to reorient the approach to mental health research from one focused on Diagnostic and Statistical Manual of Mental Disorders (DSM) nosology to one oriented to psychological constructs constrained by neurocircuitry and molecular entities. The initiative has generated significant discussi...

The lateral habenula, a phylogenetically conserved, epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the late...

Manganese-enhanced magnetic resonance imaging (MEMRI) is a powerful technique for assessing the functional connectivity of neurons within the central nervous system. Despite the widely held proposition that MEMRI signal is dependent on neuronal activity, few studies have directly tested this implicit hypothesis. In the present series of experiments...

Midbrain dopamine neurons are an essential part of the circuitry underlying motivation and reinforcement. They are activated by rewards or reward-predicting cues and inhibited by reward omission. The lateral habenula (lHb), an epithalamic structure that forms reciprocal connections with midbrain dopamine neurons, shows the opposite response being a...

Representative photomicrographs illustrating the effects of high-intensity footshock on the expression of cFos in the RMTg, Hb and PVTp in a sham operated rat. cFos expression within the RMTg (A,B), habenula (C,D) and PVTp (E,F). Boxes within the low-magnification micrographs (left) approximate the area of the high-magnification illustrations (righ...

Representative photomicrographs illustrating the effects of high-intensity footshock on the expression of cFos in the RMTg, habenula and PVTp in an fr lesioned rat. cFos expression within the RMTg (A,B), habenula (C,D) and PVTp (E,F). Boxes within the low-magnification micrographs (left) approximate the area of the high-magnification illustrations...

Representative photomicrographs illustrating the effects of fr lesion on the expression of TH in the Hb and PVTp. TH immunostaining (dark grey) in the Hb of a sham (A) and lesioned (B) rat Illustrates the significant decrease in habenular TH expression following fr lesion. TH immunostaining in the PVTp is unaffected by fr lesion, as illustrated by...

Representative photomicrographs illustrating the effects of low-intensity footshock on the expression of cFos in the RMTg, Hb and PVTp in a fr lesioned rat. cFos expression within the RMTg (A,B), habenula (C,D) and PVTp (E,F). Boxes within the low-magnification micrographs (left) approximate the area of the high-magnification illustrations (right),...

Adult rats exposed to the DNA-methylating agent methylazoxymethanol on embryonic day 17 show a pattern of neurobiological deficits that model some of the neuropathological and behavioral changes observed in schizophrenia. Although it is generally assumed that these changes reflect targeted disruption of embryonic neurogenesis, it is unknown whether...

Orbitofrontal cortex (OFC) is critical for reversal learning. Reversal deficits are typically demonstrated in complex settings that combine Pavlovian and instrumental learning. Yet recent work has implicated the OFC specifically in behaviors guided by cues and the features of the specific outcomes they predict. To test whether the OFC is important...

The ventral striatum (VS) is thought to serve as a gateway whereby associative information from the amygdala and prefrontal regions can influence motor output to guide behavior. If VS mediates this "limbic-motor" interface, then one might expect neural correlates in VS to reflect this information. Specifically, neural activity should reflect the in...

Intravenous (iv) cocaine mimics salient somato-sensory stimuli in their ability to induce rapid physiological effects, which appear to involve its action on peripherally located neural elements and fast neural transmission via somato-sensory pathways. To further clarify this mechanism, single-unit recording with fine glass electrodes was used in aw...

To clarify the role of brain temperature in permeability of the blood-brain barrier (BBB), rats were injected with methamphetamine (METH 9 mg/kg) at normal (23 degrees C) and warm (29 degrees C) environmental conditions and internal temperatures were monitored both centrally (nucleus accumbens, NAcc) and peripherally (skin and nonlocomotor muscle)....

Cocaine's (COC) direct interaction with the dopamine (DA) transporter is usually considered the most important action underlying the psychomotor stimulant and reinforcing effects of this drug. However, some physiological, behavioral and psycho-emotional effects of COC are very rapid and brief and they remain intact during DA receptor blockade, sugg...

Rectal probe thermometry is commonly used to measure body core temperature in rodents because of its ease of use. Although previous studies suggest that rectal measurement is stressful and results in long-lasting elevations in body temperatures, we evaluated how this procedure affects brain, muscle, skin, and core temperatures measured with chronic...

It is well known that the dopamine (DA) system plays an essential role in the organization and regulation of brain activational processes. Various environmental stimuli that induce locomotor activation also increase DA transmission, while DA antagonists decrease spontaneous locomotion. Our previous work supports close relationships between locomoto...

While cocaine's interaction with the dopamine (DA) transporter and subsequent increase in DA transmission are usually considered key factors responsible for its locomotor stimulatory and reinforcing properties, many centrally mediated physiological and psychoemotional effects of cocaine are resistant to DA receptor blockade, suggesting the importan...

While alterations in dopamine (DA) uptake appear to be a critical mechanism underlying locomotor and reinforcing effects of cocaine (COC), many centrally mediated physiological and affective effects of this drug are resistant to DA receptor blockade and are expressed more quickly following an intravenous (i.v.) injection than expected based on the...

Speed of intravenous (i.v.) injection presumably affects the rewarding effects of cocaine in humans. Work with animals has shown alterations in the behavioral and neurochemical effects of cocaine based on delivery speed. We studied the effects of cocaine (1 mg/kg) as both a single i.v. injection and a series of five repeated injections (8-min inter...

Brain temperature fluctuates biphasically in response to repeated, intravenous (i.v.) cocaine injections, perhaps reflecting cocaine's inhibiting effect on both dopamine (DA) transporters and Na+ channels. By using a DA receptor blockade, one could separate these actions and determine the role of DA-dependent and DA-independent mechanisms in mediat...

High-speed, multi-site thermorecording offers the ability to follow the dynamics of heat production and flow in an organism. This approach was used to study brain-body temperature homeostasis during the development of general anesthesia induced by sodium pentobarbital (50 mg/kg, ip) in rats. Animals were chronically implanted with thermocouple prob...

To study the role of ambient temperature and brain blood outflow in modulating physiological brain hyperthermia, temperatures in two brain structures (nucleus accumbens or NAcc and hippocampus or Hippo) and a non-locomotor head muscle (musculus temporalis) were monitored in rats exposed to three arousing stimuli (placement in the cage or environmen...

Drugs of abuse, such as 3,4-methylenedioxymethamphetamine (MDMA), often have more powerful effects during states of increased activation and under specific environmental conditions. Because hyperthermia is a major complication of MDMA use and a factor potentiating neurotoxicity, we examined the effects of this drug (9 mg/kg, sc; approximately one-f...

While it is generally assumed that cocaine self-administration (SA) is determined and maintained by the pharmacological actions of cocaine in the brain, it is also a drug-motivated and drug-reinforced goal-directed behavior, which is determined by concurrent learning and behavioral performance. To dissociate the contributions of pharmacological and...

Hyperthermia is a symptom of methamphetamine (METH) intoxication and a factor implicated in neurotoxicity during chronic METH use. To characterize the thermic response to METH, it was injected once daily into rats at increasing doses (0, 1, 3, and 9 mg/kg, s.c.) while brain [nucleus accumbens (NAcc), hippocampus] and body (deep temporal muscle) tem...

Hyperthermia is a symptom of methamphetamine (METH) intoxication and a factor implicated in neurotoxicity during chronic METH use. To characterize the thermic response to METH, it was injected once daily into rats at increasing doses (0, 1, 3, and 9 mg/kg, s.c.) while brain [nucleus accumbens (NAcc), hippocampus] and body (deep temporal muscle) tem...

While dopamine mechanisms play a crucial role in cocaine-taking behavior, the contribution of endogenous opioid systems is less clear. We assessed the effects of opioid receptor blockade by naloxone (1 mg/kg, s.c.) on the daily performance and subsequent initiation of cocaine self-administration in trained rats. Naloxone decreased self-administrati...

Since metabolic neural activity is accompanied by heat release, measurement of local brain temperature offers a method for assessing alterations in neural activity. This approach, continuous monitoring of local brain (ventral tegmental area, ventral striatum, and hippocampus) and body (temporal muscle) temperature, was used to study intravenous coc...

Although it is known that relatively large increases in local brain temperature can occur during behaviour and in response to various novel, stressful and emotionally arousing environmental stimuli, the source of this heat is not clearly established. To clarify this issue, we monitored the temperature in three brain structures (dorsal and ventral s...

Previous animal stress studies have illustrated the marked impact of coping on subsequent behavior and physiology by using shock as the stressor. The current study evaluates the generality of shock stress controllability effects in a new swim stress paradigm on several dependent measures: behavioral despair, analgesia, shuttlebox escape, and alcoho...

The purpose of this study was to examine whether acute stress exposure would alter the ataxic properties of midazolam or ethanol in rats. Rats were administered either vehicle or FG 7142 (10 mg/kg) and placed back in their home cages, or placed in restraining tubes for 90 min. Three and one-half or 24 h following injection all subjects were then ad...

The medicinal leech possesses FMRFamide-like immunoreactivity in neural processes and somata associated with the pharynx and pharyngeal ganglia. The pharynx possessed about 25 immunoreactive somata; about half of the approximately 20 neurons of the pharyngeal ganglia were immunoreactive. We provide brief descriptions of several neurons located in t...

The medicinal leech possesses FMRFamide-like immunoreactivity in neural processes and somata associated with the pharynx and pharyngeal ganglia. The pharynx possessed about 25 immunoreactive somata; about half of the approximately 20 neurons of the pharyngeal ganglia were immunoreactive. We provide brief descriptions of several neurons located in t...