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The ventral tegmental area (VTA) is an important component of the mesolimbic dopamine circuit and processes reward and motivational behaviors. In response to drug exposure, synaptic connections of this circuit can be rewired via synaptic plasticity—a phenomenon thought be responsible for the pathology of addiction. While much is known about dopamine neuron plasticity, less is known regarding plasticity exhibited by VTA GABA cells, specifically inhibitory inputs from outside the VTA. Expanding on the work of Bocklisch et al. (2013), we investigated the plasticity of inhibitory inputs to VTA GABA neurons. Using whole cell electrophysiology in GAD67 GFP mice, we observed that these VTA GABA cells can experience either long-term potentiation (LTP) or long-term depression (LTD) in response to a 5 Hz stimulus. While neither the LTP nor LTD appear to be mediated by the cannabinoid-1 receptor (CB1), the nitric oxide synthase (NOS) pathway, or the dopamine-2 (D2) receptor, the LTP is blocked by APV, an NMDA receptor antagonist, and the LTD is blocked by CGP 54626, an antagonist of the GABAB receptor. Additionally, µ-opioid and adenosine-1 receptors modulated plasticity at this synapse, but chronic morphine administration (10mg/kg) did not block the observed LTP or LTD. Furthermore, we used an optogenetic approach in VGAT-Cre mice to target inhibitory inputs from the lateral hypothalamus (LH) to the VTA. An optical stimulus (5 Hz) caused these inputs to depress, which has not been previously described and may be behaviorally important in reward processing. These novel findings increase our understanding of VTA neural circuitry, ultimately increasing our capacity to better comprehend and treat the pathology of addiction. Additionally, changes in synaptic strength in hippocampal CA1 pyramidal cells are thought to be responsible for the acquisition and retention of short-term memory. Feedforward stratum radiatum interneurons of many subtypes experience LTD, short-term depression (STD), or lack of plasticity, but it is not known whether plasticity correlates with specific interneuron subtypes. Using whole cell electrophysiology and qPCR, we characterized the plasticity expressed by hippocampal interneurons in correlation with their mRNA expression patterns to determine cell subtype. We also assessed the expression of endocannabinoid (eCB) biosynthetic enzymes as well as metabotropic glutamate receptor subunits known to mediate plasticity. Cells exhibiting LTD tended to express mRNA for at least one of the eCB biosynthetic enzymes and the metabotropic glutamate receptor subunit mGluR5. mGluR5 was not expressed by cells exhibiting STD or no plasticity. Cells that exhibited short-term depression tended to express mRNA for at least one of the eCB biosynthetic enzymes, but not mGluR5. This suggests that stratum radiatum interneuron plasticity can be predicted based on mGluR expression, and that these different types of plasticity may have some importance in hippocampal function.

Major depression and suicide are associated with altered concentrations of specific noradrenergic proteins in the human locus coeruleus (LC). Based on experimental studies that can reproduce these LC abnormalities in laboratory animals, we hypothesized that noradrenergic pathobiology in depression is a result of overactivity of the LC. LC activity is under the control of both excitatory and inhibitory inputs. A major inhibitory input to the LC is GABAergic, arising from the nucleus prepositus hypoglossi. Numerous studies demonstrating low levels of GABA in the CSF and plasma of subjects with major depressive disorder (MDD) raise the possibility that LC overactivity in depression may be secondary to reduced GABAergic input to the LC. Here, GABAergic input to the LC in depression was evaluated by studying the binding of [ H]flunitrazepam to GABA receptors at three anatomically defined levels of the human postmortem LC. LC tissues were collected from subjects with MDD, subjects with depressive disorders including MDD that died as a result of suicide, and psychiatrically normal control subjects. A modest rostral-caudal gradient of GABA receptor binding density was observed among all subjects. No significant differences in the amount of binding to GABA receptors were observed between control subjects (n = 21) and MDD subjects (n = 9) or depressed suicide victims (n = 17). These results demonstrate that GABA receptor binding in the LC measured with [ H]flunitrazepam is not altered in subjects with depressive illnesses.

Immunological analogues of band 3, the anion transporter of the human erythrocyte, have been identified in all cells, including both isolated neurons and neurons of the central nervous system. We hypothesized that the anion channel is altered in neurological disease associated with choreiform movements because γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in mammalian brain, binds to its receptor and opens an integral membrane chloride channel. In order to examine this hypothesis, we studied a family with a serious, progressive, genetic neurologic disorder with acanthocytosis (choreoacanthocytosis) that resembles Huntington's chorea. We selected choreoacanthocytosis because erythrocytes, which are readily obtained, are affected in this disease as well as the central nervous system. Biochemical studies of erythrocytes from the proposita, mother, and brother revealed that sulfate transport Vmax was increased, and glucose efflux was decreased. Erythrocytes exhibited immunological changes indicative of cellular aging/transporter damage. In addition, transporter reactive antibodies were present. This is the first evidence for abnormalities of membrane transport in this neurologic disorder.

The present study explored the antinociceptive effects of H3 (R-alpha-methylhistamine) and GABAB (baclofen) receptor ligands in an orofacial model of pain in rats. Orofacial pain was induced by subcutaneous injection of formalin (50 μl, 5 %) in the upper lip region, and the number of jumps and time spent face rubbing was recorded for 40 min. Formalin produced a marked biphasic pain response; first phase, 0-10 min (jumps), and second phase, 15-40 min, (rubbing). Baclofen (50 μg) injected into the rat wiskerpad 5 min before formalin administration suppressed both phases of pain whereas R-alpha-methylhistamine (12.5 μg) abolished the first phase only. Brains were taken immediately after behavioral testing was completed. HPLC/ED analysis showed that 5-hydroxytryptamine (5-HT) turnover was increased in hippocampus, thalamus, and brain stem of all formalin groups, excepting the baclofen group in which the balance of 5-HT metabolism was restored to control values. These findings demonstrate that GABAB receptors represent peripheral targets for analgesia. Consequently, locally administered baclofen may be a useful approach in treating inflammatory trigeminal pain.

Despite the consensus that glutamatergic and GABAergic imbalance is likely to be involved in anesthesia or coma, there is little known about molecular mechanisms of action of gaseous anesthetics. The target article by Smythies (1999) is engagingly analytical and insightful, proposing novel and testable hypotheses for the molecular mechanisms of action of anesthetics as well as for processes that may be involved in coma. The most creative and convincing of his hypotheses concerns the crucial role of iron in maintaining neural respiration and energy production as well as its involvement in synaptic plasticity. Smythies' paper is certain to stimulate new ideas and experiments on the molecular mechanisms of anesthesia and coma.

The present study explored the antinociceptive effects of H3 (R-alpha-methylhistamine) and GABAB (baclofen) receptor ligands in an orofacial model of pain in rats. Orofacial pain was induced by subcutaneous injection of formalin (50 μl, 5 %) in the upper lip region, and the number of jumps and time spent face rubbing was recorded for 40 min. Formalin produced a marked biphasic pain response; first phase, 0-10 min (jumps), and second phase, 15-40 min, (rubbing). Baclofen (50 μg) injected into the rat wiskerpad 5 min before formalin administration suppressed both phases of pain whereas R-alpha-methylhistamine (12.5 μg) abolished the first phase only. Brains were taken immediately after behavioral testing was completed. HPLC/ED analysis showed that 5-hydroxytryptamine (5-HT) turnover was increased in hippocampus, thalamus, and brain stem of all formalin groups, excepting the baclofen group in which the balance of 5-HT metabolism was restored to control values. These findings demonstrate that GABAB receptors represent peripheral targets for analgesia. Consequently, locally administered baclofen may be a useful approach in treating inflammatory trigeminal pain.

Cognitive symptoms, considered in conjunction both with their regional brain and biomarkers as well as affective, attributional and neurode-velopmental components, demonstate ever-increasing complexity to facilitate conceptualization yet, unavoidably, bedevil diagnosis in neuropsychiatry even before considerations of the enigmatic processes in memory, such as executive function and working memory, are drawn into the myriads of equations that await remedial interpretations. Prefrontal and limbic regions of the brain are involved in a diversity of expressions of cognition, normal or dysfunctional, at synaptic, intracellular and molecular levels that mobilize a concatenation of signaling entities. Serotoninergic neurotransission at prefrontal regions directs cogntive-affective entities that mediate decision-making and goal-directed behaviour. Clinical, non-clinical and basic studies challenge attempts to consolidate the multitude of evidence in order to obtain therapeutic notions to alleviate the disordered status of the diagnosed and yet-to-be diagnosed individuals. Locus of control, a concept of some utility in health-seeking procedures, is examined in three self-report studies from the perspective of a cognitive-emotional situation through observations of ordinary, 'healthy' young and middle-aged individuals, to assess the predictors of internal and external locus of control. A notion based on high level executive functioning in the dorsolateral prefrontal cortex (DLPFC) in individuals characterised by internal locus of control is contrasted with a hypofunctional executive DLPFC, characterising individuals that express an external locus of control, is discussed.

Substance abuse is a frequent comorbid condition with other psychiatric disorders including schizophrenia and depression. These disorders may share a common substrate at the neurotransmitter or neurocircuit level. One candidate is hypofunction of the glutamate system. Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptors may hypofunction in schizophrenia. Thus, NMDA receptor antagonists are schizophrenogenic; postmortem and imaging results point to reduced NMDA receptor function in schizophrenic brains; a number of genes that have been linked to schizophrenia code for proteins that influence NMDA function; and there is preliminary evidence that pro-NMDA drugs may be therapeutic in the treatment of schizophrenia. One of the most effective therapeutics for the treatment of substance abuse in schizophrenic people is clozapine, and clozapine may act at the glycine modulatory site to enhance NMDA receptor function. This preliminary line of evidence may link schizophrenia and drug abuse to a common neurochemical base, subnormal NMDA receptor function. People with schizophrenia and drug abusers similarly show deficits in tasks known to be sensitive to ventromedial prefrontal cortical damage, and both groups show decreased activation in the ventral striatum during reward anticipation in functional magnetic resonance imaging studies. These observations implicate common prefrontal cortical-striatal circuits and their modulation by hippocampal projections in schizophrenia and substance abuse. Withdrawal from substance abuse and depression both have been linked to changes in the function of several neurotransmitters including serotonin, dopamine and glutamate. These findings suggest possible common substrates and novel therapeutic approaches. Further studies are needed to fully characterize the neurocircuits and transmitters involved in various psychiatric disorders and their possible common elements in comorbid drug abuse.

Genetic studies have sought to identify subtypes or endophenotypes of schizophrenia in an effort to improve the reliability of findings. A number of chromosomal regions or genes have now been shown to have had replicated linkage to schizophrenia susceptibility. Molecules involved in neurodevelopment or neurotransmitter function are coded by many of the genes that have been implicated in schizophrenia. Studies of neurotransmitter function have identified, among others, a possible role for GABA, glutamate and dopamine in animal models of schizophrenia. GABA neurons that co-express the calcium binding protein parvalbumin have been implicated as have glutamatergic metabotropic receptors and dopamine D3 receptors. Stress influences glutamate and dopamine providing another environmental factor that may interact with the influence of genes on neurotransmitter function. Neurotransmitter interactions include influences on signaling molecules and these too have been implicated in forms of learning thought to be affected in schizophrenia. Results continue to unravel the interplay of genes and environment in the etiology of schizophrenia and other psychotic disorders.