Biomedical subjects

David A Gutman

Publications and source records attributed to David A Gutman.

6 recordsLinked to original sources

PubMed2006

Serotonin and norepinephrine transporter binding profile of SSRIs.

Even today, pharmacotherapy for mood disorders is based almost entirely on the observation in the 1950s and 1960s that agents that enhance monoamine transmitter activity are effective antidepressants. Preclinical studies have shown that long-term administration of nearly all effective antidepressants increases the efficiency of postsynaptic serotonin transmission; many also modify central noradrenergic activity. For the majority of antidepressants, these changes are the result of their ability to block serotonin and/or norepinephrine activity at their "presynaptic uptake sites" (i.e., at the serotonin transporter [SERT] or the norepinephrine transporter [NET]). Drugs that are highly selective for one transporter over another have been demonstrated to be effective and tolerable, whereas agents that act on multiple transporters may not necessarily achieve better efficacy and may result in additional adverse events. The rationale for the use of drugs that affect multiple transports is based on the suggestion that antidepressants that block both the SERT and the NET may provide better efficacy. This can only be determined through empirical studies.

Animals↗

PubMed2005

Doxapram-induced panic attacks and cortisol elevation.

Numerous agents with differing biological properties and central nervous system (CNS) effects can induce panic attacks in predisposed individuals. A potential explanation of this finding is that panic disorder patients are more likely to panic than normal control subjects when given a panicogen due to an excessive fear response to somatic arousal. We test this hypothesis by using doxapram, a panicogen with minimal CNS effects, to induce panic in patients and control subjects. Doxapram was given to six subjects with panic disorder with or without agoraphobia and four healthy volunteers. Measures comprised the Acute Panic Inventory, the Borg Exertion scale, the 10-point Anxiety Scale, the 10-point Apprehension Scale, cortisol, prolactin, and MHPG, all obtained at baseline and multiple time points after the doxapram infusion. All panic disorder patients panicked with doxapram, whereas no control subjects had a panic attack. Panic patients had similar levels of breathlessness with doxapram compared with control subjects. Although panic patients had higher levels of anxiety and apprehension, these did not change significantly with doxapram compared with control levels. Doxapram led to similar increases in cortisol and prolactin in both groups, and MHPG was consistently elevated in panic patients, but unaffected by doxapram. These results show that doxapram is a useful panicogen in the study of panic disorder. Since the panic patients and control subjects had similar levels of physiological and psychological arousal, but the panic patients were more likely to have a panic attack, this lends support to the concept of a sensitized fear network in panic disorder patients.

Adult↗

PubMed2003

Persistent central nervous system effects of an adverse early environment: clinical and preclinical studies.

In the search for the underlying biological causes of psychiatric disorders, primary roles for both genetics and environment have been clearly established. A family history of mood or anxiety disorders, representing the genetic component, clearly increases the risk for developing these illnesses in adulthood. The pivotal role of early environmental influences in the pathogenesis of these disorders is also supported by an abundance of both clinical and preclinical data. This review will highlight some of the preclinical and clinical literature that suggests early adverse experience may sensitize corticotropin-releasing factor (CRF) circuitry. The neurobiology of depression highlighting the pathophysiological role of CRF is reviewed. Next, some of the preclinical models of early life stress are discussed; along with a review of the relevant clinical literature that suggests that the functional dysregulation of CRF circuitry in response to early life trauma may contribute to adulthood depression. The discussion will be framed in regards to a stress-diathesis model in which early adverse events result in a sensitized stress axis that predisposes individuals to develop mood disorders.

Animals↗

PubMed2003

Cellular and behavioral effects of D2 dopamine receptor hydrophobic eigenmode-targeted peptide ligands.

Patterns in G-protein-coupled receptors' hydrophobically transformed amino-acid sequences can be computationally characterized as hierarchies of autocorrelation waves, "hydrophobic eigenmodes", using autocovariance matrix decomposition and all poles power spectral and wavelet transformations. L- or D-amino acid (retro-inverso) 12-18 residue peptides targeting these modes can be designed using eigenvector templates derived from these computations. In all, 12 human long-form D(2) dopamine receptor eigenmode-targeted 15 mer peptides were designed, synthesized, and shown to modulate and/or indirectly activate the extracellular acidification response, EAR, in stably receptor-transfected CHO and LtK cells, with an 83% hit rate. Representative L- and D-amino-acid retro-inverso peptides injected bilaterally in the nucleus accumbens demonstrated changes in rat exploratory behavior and prepulse inhibition similar to those observed following parenteral amphetamine. In contrast with geometric models used for ligand design, such as pharmacophores, the hydrophobic eigenmode approach to lead modulatory peptide design targets hydrophobic eigenmode-bearing subsequences, including those not visible from X-ray and NMR studies such as extracellular segments and loops.

Amino Acid Sequence↗

PubMed2003

The corticotropin-releasing factor1 receptor antagonist R121919 attenuates the behavioral and endocrine responses to stress.

Corticotropin-releasing factor (CRF) is the major physiological regulator of the hypothalamic-pituitary-adrenal (HPA) axis and serves to coordinate the mammalian endocrine, autonomic, and behavioral responses to stress. Considerable literature from clinical and preclinical data suggests that hypersecretion of hypothalamic and/or extrahypothalamic CRF systems is a major factor in the pathogenesis of affective and anxiety disorders. Based on this premise, a CRF(1) receptor antagonist has been hypothesized to possess anxiolytic and/or antidepressant properties. In this study, an acute dose of the lipophilic CRF(1) receptor antagonist 3-[6-(dimethylamino)-4-methyl-pyrid-3-yl]-2,5-dimethyl-N,N-dipropyl-pyrazolo[2,3-a]pyrimidin-7-amine (R121919), administered i.v. to rats with surgically implanted jugular cannula 60 min before a 5-min restraint stress, dose dependently attenuated peak plasma adrenocorticopin hormone (ACTH) and corticosterone concentrations by 91 and 75%, respectively. In a second study, acute administration of R121919 reduced measures of anxiety in a rodent defensive withdrawal paradigm. R121919 dose dependently decreased latency to exit the tube, and total time spent in the tube 60 min after a single subcutaneous administration. In addition, the ACTH and corticosterone response to novelty was decreased by 82 and 97%, respectively, at the 10-mg/kg dose of R121919. In another study, this dose was associated with approximately an 85% occupancy of the CRF(1) receptor in the cortex measured 75-min postsubcutaneous injection. These data confirm that R121919 acts as a CRF(1) receptor antagonist in vivo, attenuates HPA axis responsivity, and possesses anxiolytic properties.

Adrenocorticotropic Hormone↗

PubMed2002

Neurobiology of early life stress: rodent studies.

It is now clear that early experience influences the long-term development of behavioral, neuroendocrine, and cognitive systems in a number of animal species. This article examines the effects of early life stress on the development of the rodent. Postnatal maternal separation is often used as a potent early life stressor, and some of the major findings from these studies are discussed. A majority of these studies have shown that early life stress can lead to a heightened stress response when maternally deprived rodents are tested as adults. The effects of early life stress on the development of brain structures involved in regulating the stress response as adults are also discussed. Finally the influence of both genetics and maternal style are mentioned in relation to their ability to alter the effects of early life stress.

Adrenocorticotropic Hormone↗