Professor of Pharmacology
Faculty Background and Research Interests
Ph.D., Pharmacology and Toxicology, and Neuroscience, 1984
Post-doc, Medical College of Virginia, 1984-1986
Department of Pharmacology
University of New England
11 Hills Beach Rd.
Biddeford ME 04005
Phone: (207) 602-2210
Current Research: Our laboratory has been investigation how the 5-hydroxytryptamine (5-HT, serotonin) and dopamine neurotransmitter systems of the brain work. We use the technique of in vivo microdialysis to observe the changes in extracellular 5-HT and dopamine in the brain of the rat following stimulation of the brain or administration of drugs. In vivo microdialysis is a method of monitoring the extracellular concentration of neurotransmitters in the brain of the conscious rat. Using microdialysis we can determine how drugs affect the release of these neurotransmitters in the conscious brain. We can also watch the animal’s behavior and correlate the changes in neurotransmitter release with the behavior. Current projects include 1) the actions of hallucinogens on serotonin release in different brain areas; 2) the neurotoxic effects of 3,4 - methylenedioxymethamphetamine (MDMA, ecstasy); and 3) the changes in dopamine and serotonin after chronic use of morphine. We are also investigating the physiology of the serotonin system and how the serotonin (raphé) nuclei interact. We have also begun to investigate the adolescent brain and how it may differ from the adult brain. Link to laboratory webpage
Dr. Mokler is also a Research Associate Professor at the Center for Behavioral Development and Mental Retardation in the Department of Psychiatry at the Boston University School of Medicine. He is a co-investigator on a program project grant to study the effects of prenatal protein malnutrition on the brain. He works on this project with Dr. Peter Morgane, who also shares appointments at UNE and BUSM. Link to BU CBDMR
The limbic brain: continuing resolution.
Morgane PJ, Mokler DJ.
Neuroscience and Biobehavioral Review 2006;30(2):119-25. Epub 2005 Aug 22.
This paper presents an overview of the limbic brain and its distributed sub-systems. The extent of the limbic system has expanded in recent years. Among the brain areas that we now argue should be included in the extended limbic system are the medial prefrontal cortex, the insular cortex as well as the lower brainstem and spinal cord. In addition the limbic forebrain and limbic midbrain may be divided into medial and lateral divisions both anatomically and physiologically. This serves as an introduction to the papers that follow.
A review of systems and networks of the limbic forebrain/limbic midbrain.
Morgane PJ, Galler JR, Mokler DJ.
Progress in Neurobiology 2005 Feb;75(2):143-60
Evolutionarily older brain systems, such as the limbic system, appear to serve fundamental aspects of emotional processing and provide relevant and motivational information for phylogenetically more recent brain systems to regulate complex behaviors. Overall, overt behavior is, in part, determined by the interactions of multiple learning and memory systems, some seemingly complementary and some actually competitive. An understanding of limbic system function in emotion and motivation requires that these subsystems be recognized and characterized as extended components of a distributed limbic network. Behavioral neuroscientists face the challenge of teasing apart the contributions of multiple overlapping neuronal systems in order to begin to elucidate the neural mechanisms of the limbic system and their contributions to behavior. One major consideration is to bring together conceptually the functions of individual components of the limbic forebrain and the related limbic midbrain systems. For example, in the rat the heterogeneous regions of the prefrontal cortex (e.g., prelimbic, anterior cingulate, subgenual cortices and orbito-frontal areas) make distinct contributions to emotional and motivational influences on behavior and each needs consideration in its own right. Major interacting structures of the limbic system include the prefrontal cortex, cingulate cortex, amygdaloid nuclear complex, limbic thalamus, hippocampal formation, nucleus accumbens (limbic striatum), anterior hypothalamus, ventral tegmental area and midbrain raphe nuclei; the latter comprising largely serotonergic components of the limbic midbrain system projecting to the forebrain. The posterior limbic midbrain complex comprising the stria medullaris, central gray and dorsal and ventral nuclei of Gudden are also key elements in the limbic midbrain. Some of these formations will be discussed in terms of the neurochemical connectivity between them. We put forward a systems approach in order to build a network model of the limbic forebrain/limbic midbrain system, and the interactions of its major components. In this regard, it is important to keep in mind that the limbic system is both an anatomical entity as well as a physiological concept. We have considered this issue in detail in the introduction to this review. The components of these systems have usually been considered as functional units or 'centers' rather than being components of a larger, interacting, and distributed functional system. In that context, we are oriented toward considerations of distributed neural systems themselves as functional entities in the brain.
Calcium influx through presynaptic 5-HT3 receptors facilitates GABA release in
the hippocampus: in vitro slice and synaptosome studies.
Turner TJ, Mokler DJ, Luebke JI.
Serotonin 5-hydroxytryptamine type 3 receptors (5HT3R) are Ca2+-permeant, non-selective cation channels that have been localized to presynaptic terminals and demonstrated to modulate neurotransmitter release. In the present study the effect of 5-HT on GABA release in the hippocampus was characterized using both electrophysiological and biochemical techniques. 5-HT elicited a burst-like, 6-to 10-fold increase in the frequency of GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) measured with whole-cell voltage-clamp recordings of CA1 neurons in hippocampal slices. When tetrodotoxin was used to block action potential propagation, the 5-HT-induced burst of IPSCs was still observed. Stimulation of hippocampal synaptosomes with 5-HT resulted in a significant increase in the amount of [3H]GABA released by hyperosmotic saline. In both preparations, the 5-HT effect was shown to be mediated by 5HT3Rs, as it was mimicked by the selective 5HT3R agonist m-chlorophenyl biguanide and blocked by the selective 5HT3R antagonist 3-tropanylindole-3-carboxylate hydrochloride. The 5HT3R-mediated increase in GABA release was blocked by 100 microM cadmium or by omitting Ca2+ in external solutions, indicating the Ca2+-dependence of the effect. The high voltage-activated Ca2+ channel blockers omega-conotoxin GVIA and omega-conotoxin MVIIC and 10 microM cadmium had no significant effect on the 5-HT3R-mediated enhancement of GABA release, indicating that Ca2+ influx through the 5-HT3R facilitates GABA release. Taken together, these data provide direct evidence that Ca2+ entry via presynaptic 5HT3Rs facilitates the release of GABA from hippocampal interneurons.
Modulation of 5-HT release in the hippocampus of 30-day-old rats exposed in utero to protein malnutrition.
Mokler DJ, Galler JR, Morgane PJ.
Developmental Brain Research 2003 May 14;142(2):203-8.
Previous in vivo microdialysis studies have shown increased spontaneous release of 5-HT in the hippocampus of adult behaving rats exposed to prenatal protein malnutrition. Furthermore, behavioral studies have shown that adolescent rats (PD30) that have been prenatally protein malnourished demonstrate an increased sensitivity to the benzodiazepine chlordiazepoxide (CDP). Given this altered sensitivity to benzodiazepines in adolescent malnourished rats, the present study was designed to test the hypothesis that the increased release of 5-HT in the hippocampus is present in adolescent rats and that this release is modulated by CDP. An altered release of 5-HT at PD30 would suggest an early developmental change associated with prenatal malnutrition. PD30 rats were implanted with microdialysis probes into the dorsal hippocampus and 5-HT release was monitored before and after administration of CDP. As previously reported in adult rats, release of 5-HT was significantly elevated in the dorsal hippocampus of PD30 rats as compared to well-nourished 30-day-old controls. Administration of CDP did not affect the release of 5-HT from the hippocampal formation of well-nourished rats but significantly decreased the elevated release of 5-HT in the malnourished rats. Following CDP, 5-HT release in the malnourished rats was at the same levels as release in well-nourished animals. Benzodiazepines have been reported to decrease extracellular 5-HT in stressed rats but not in unstressed rats. Thus, the elevated 5-HT release in the hippocampus in rats exposed to prenatal protein malnutrition may be associated with an increased response to stress. These data support other data that prenatal protein malnutrition alters the response to stressful stimuli possibly through changes in the GABAergic and/or serotonergic systems.
Effects of prenatal protein malnutrition on the hippocampal formation.
Morgane, P.J., Mokler, D.J. and Galler, J.R.
Neuroscience and Biobehavioral Reviews 26 (4):471-484, 2002.
In this review we have assessed the effects of prenatal protein malnutrition on the hippocampal formation of the developing brain. In investigating this insult in the hippocampal neuronal model we have concentrated on aspects of enhanced inhibition we have shown in our previous studies. Since this involves particular attention to the GABAergic interneurons we have examined the complex interneuronal networks of the hippocampal formation and their neurotransmitter afferent inputs, particularly the serotonergic system from the midbrain raphé nuclei. A variety of combinations of specialized interneurons are discussed in terms of how malnutrition insults perturb function in these inhibitory and disinhibitory networks. Pathological enhancement of inhibition manifests itself by diminished plasticity, alterations in theta activity and deficits in long-term learning behaviors. Long-term inhibition in select GABA interneuron systems may form a major derangement seen following prenatal protein malnutrition. The focus of this study is to relate enhanced inhibition to the several forms of inhibitory systems present in the hippocampal formation and develop hypotheses as to the primary derangements that may account for pathological inhibition in prenatal malnutrition.
Development and modulation of GABAA receptor-mediated neurotransmission in the CA1 region of prenatally protein malnourished rats.
Mokler, D.J., Galler, J.R. and Luebke, J.I.
Nutritional Neuroscience 4:109-119, 2001.
Previous work has shown a derangement in the raphé-hippocampal 5-HT system and the hippocampal GABA system of rats exposed to prenatal protein malnutrition. Specifically, there is a diminution in innervation and an increase in basal release of 5-HT in the hippocampus, and a decreased sensitivity to the GABA modulator chlordiazepoxide and an increase in GABAA-mediated miniature post synaptic currents (mIPSCs) in the CA1 region of the hippocampus. Using whole-cell patch clamping we investigated the development of mIPSCs and the effects of 5-HT and zolpidem on CA1 pyramidal cells in the hippocampus. Hippocampal slices were prepared from 21 day-old male Sprague-Dawley rats whose dams were fed either a normal (25% casein) or low (6%) protein diet during pregnancy. Pyramidal cells displayed mIPSCs at a holding potential of 80 mV in the presence of TTX, CNQX and APV. At postnatal days 7 (p7), p14, p21 and adult ages, there were no differences between malnourished and well-nourished rats in terms of the characteristics of mIPSCs. Zolpidem increased the mean decay time of mIPSCs in both groups of animals at all ages. 5-HT (100 mM) produced a burst of mIPSCs that resulted in an increase in the frequency of mIPSCs. There were no differences between nutritional groups in the effect of 5-HT on mIPSCs. These data suggest that prenatal protein malnutrition does not alter the development of GABAA-mediated mIPSCs in the CA1 region of the hippocampus, the effect of the GABA modulator zolpidem, or the effect of 5-HT on the release of GABA.
Decreased accumbens dopamine release after cocaine challenge in behaviorally sensitized female rats.
Johnson, D.W., Eodice, P. , Winterbottom, H. , and Mokler, D.J.
Pharmacology Biochemistry Behavior 65 (4):659-664, 2000.
The effects of the competitive NMDA receptor antagonist CPP on the initiation of behavioral sensitization to acute cocaine and basal and acute cocaine-induced dopamine (DA) release in the nucleus accumbens (NAC) were assessed in female Sprague-Dawley rats. Cocaine pretreated rats (30 mg/kg IP, once daily for 7 days) challenged with cocaine (10 mg/kg) on day 8 displayed increased motor activity relative to controls challenged with cocaine on day 8. This effect was blocked in rats receiving CPP (2 mg/kg) 15 min prior to all cocaine pretreatments. Basal DA levels in the NAC of both cocaine-pretreated and CPP plus cocaine-pretreated rats were higher on day 8 compared to controls. Acute cocaine challenge on day 8 resulted in increased extracellular DA concentrations in the NAC in control rats, no increase in rats pretreated with CPP plus cocaine, and a decrease in rats pretreated with cocaine only. These data demonstrate that development of behavioral sensitization to cocaine in female Sprague-Dawley rats can be completely blocked by a peripherally administered competitive NMDA receptor antagonist and that an increase in DA release in the NAC after a cocaine challenge is not an absolute requirement for expression of motor sensitization to cocaine in female rats.
Effects of median raphé electrical stimulation on serotonin release in the dorsal hippocampal formation of prenatally malnourished rats.
Mokler, D.J., Bronzino, J.D., Galler, J.R., and Morgane, P.J.
Brain Research 838 (12): 95-103, 1999.
Our previous work had shown an enhanced inhibition in the hippocampal formation or prenatally protein malnourished rats. We have also found a diminishment in 5-HT fibers in the hippocampal formation of malnourished rats. The purpose of the present study was to determine 5-hydroxytryptamine (5-HT) release in the dorsal hippocampal formation following electrical stimulation of the median raphé nucleus in unanesthetized prenatally malnourished rats. Stimulation of this nucleus at 20 Hz in malnourished rats resulted in a significantly diminished release of 5-HT compared to well-nourished rats. The latter group showed a lesser, though still significant, decrease in 5-HT release following raphé stimulation. Basal release of 5-HT prior to stimulation was significantly higher in malnourished rats as compared to well-nourished controls. This may be the result of a decreased density of 5-HT neurons and a diminished control of release. Stimulation of the median raphé nucleus in behaving malnourished animals may markedly affect the recurrent negative feedback collaterals onto somatodendritic 5-HT1A and 5-HT1D autoreceptors thus enhancing the inhibitory effects of stimulation of the median raphé on 5-HT release. Studies are underway to examine the sensitivity of both the somatodendritic and terminal 5-HT autoreceptors in malnourished animals, in order to understand possible mechanisms for our findings.
5-Hydroxytryptamine Neuronal Release From Dorsal Hippocampus Following Electrical Stimulation Of The Dorsal And Median Raphé Nuclei In The Conscious Rat
Mokler, D.J., Larevierre, D., Johnson, D.W., Theriault, N.L., Dixon, M., and Morgane, P.J.
Hippocampus 8: 262-273 1998.
We have studied 5-hydroxytryptamine (5-HT) release in the hippocampal formation following electrical stimulation of the dorsal and median raphé nuclei in the behaving rat. The primary finding in this study is a decrease in neuronal release of serotonin in the dorsal hippocampal formation following electrical stimulation of either the dorsal or median raphé nucleus in conscious rats. The amount of 5-HT released was found to be frequency dependent with higher frequencies (20 Hz) producing larger decreases in release of 5-HT. However, the pattern of release differs between the two raphé nuclei. Extracellular levels of 5-HT decrease during stimulation of the dorsal raphé, whereas levels decrease only after stimulation of the median raphé nucleus. This may relate to the patterns of innervation of the dorsal hippocampal formation by these two midbrain raphé nuclei and may reflect an inhibition of median raphé cell firing during stimulation of the dorsal raphé. Strong reciprocal connections between these raphé nuclei make this a distinct possibility. In contrast, electrical stimulation of the dorsal raphé in anesthetized animals resulted in an enhanced release of 5-HT. The suppression of 5-HT release in the dorsal hippocampal formation in behaving animals was long-lasting, continuing for at least two hours following the cessation of stimulation, suggesting that the control mechanisms that regulate 5-HT release operate over a long time-course. This difference in release between non-anesthetized, behaving animals and anesthetized animals may relate to anesthesia blocking long- and/or short-loop serotonin recurrent axonal collaterals negatively feeding back onto 5-HT1A and, possibly, 5-HT1D somatodendritic autoreceptors on raphé neurons. Further, the anesthetized animal has diminished monoaminergic 'gating' influences on the hippocampal formation, whereas the behaving animal is more complex with behavioral (vigilance) states associated with different patterns of gating of information flow through the hippocampal formation. Studies in progress involve measures of serotonin release in the hippocampal formation in specific vigilance states defined more precisely by EEG measures. In this regard, it is important to note that at no time did electrical stimulation of either raphé nucleus result in behavioral changes. Additionally, autoreceptor regulation of raphé activity involves numerous types of 5-HT and GABA receptors playing major roles in raphé cell firing and 5-HT release in the hippocampal formation. Pharmacological manipulation of these specific receptors in association with electrical stimulation studies and measures of 5-HT release in the behaving animal are essential for unraveling the complex functions of the raphé-hippocampal system.
Effects Of Ketanserin On The Discrimination Of Electrical Stimulation Of The Dorsal Raphé Nucleus In Rats
David J. Mokler, Sal Abbruzzese, Valerie Trumble and Barbra Whitten
Neuropharmacology 36(4-5): 631-636, 1997
The electrical stimulation of the dorsal raphé nucleus was used as a training cue in a discrimination paradigm. Sprague-Dawley rats were trained to discriminate between electrical stimulation (ES; 200 µA) of the dorsal raphé nucleus (DRN) and non-stimulation. This was accomplished by associating ES with intraperitoneal (ip) injection of lithium chloride (LiCl) following the session with electrical stimulation. Following training, rats decreased saccharin consumption in sessions with ES. This made the drinking of saccharin during ES aversive by conditioned taste aversion. Following training, rats decreased saccharin consumption in ES sessions. This discrimination was learned within three pairings of the ES with LiCl. Lowering the ES current to 50-100 µA resulted in levels of saccharin consumption similar to non-stimulation levels, whereas 150 µA showed a response intermediate between the stimulation response at 200 µA and non-stimulation. The discrimination of ES of the DRN (200µA) was not affected by prior administration of the 5-HT2 antagonist ketanserin (1 or 2 mg/kg, i.p.), suggesting that activation of 5-HT2 receptors is not the primary discriminative cue generated by ES. However, the 5-HT2A/2C agonist DOI (0.25 - 0.5 mg/kg, i.p.) substituted for ES of the DRN, i.e. animals reduced saccharin consumption following DOI administration. This substitution of DOI for ES was antagonized by the administration of ketanserin (1 mg/kg, i.p.). These results suggest that ES of the DRN has properties that are similar to the activation of 5-HT2A/2C receptors by DOI. However, other stimuli such as activation of other 5-HT receptors are also involved, given that the discriminative cues of ES are not blocked by the 5-HT2A/2C antagonist ketanserin. Key words: 5-hydroxytryptamine, serotonin, 5-HT2 receptors, hallucinogens, behavior
prepared by Denis Letellier and updated by David Mokler on August 10, 2006