Scientific Achievements and Research Leadership

Major Scientific Discoveries:

  • Sex steroids control of central serotonergic mechanisms. We elucidated the mechanism by which estradiol selectively induces the central gene expression and function of the serotonin 2A receptor and the serotonin transporter. This is relevant for understanding gender differences and sex hormone influences on cognition, mood and mental state in normal subjects and in people with schizophrenia, bipolar disorder and major depression. The brain serotonin 2A receptor is the molecular site of action of hallucinogens such as LSD and a target also for atypical (or second generation) antipsychotic drugs such as clozapine and risperidone. The serotonin transporter is the target of the selective serotonin reuptake inhibitors such as fluoxetine (“Prozac”), which are anti-depressants. Our findings therefore have relevance for clinical studies as well as our fundamental knowledge of sex steroid control of brain neurochemistry. Studies are currently in progress to assess whether and how sex steroids might potentiate the action of antipsychotic and antidepressant drug action.
  • Elucidation of the central control of ovulation. We discovered that the spontaneous ovulatory gonadotropin surge is triggered by estrogen-induced positive feedback stimulation of the surge release of the decapeptide gonadotropin releasing hormone (GnRH) into hypophysial portal blood and the concomitant 20- to 50- fold increase in pituitary responsiveness to GnRH. The spontaneous GnRH surge is relatively small, and without the gain provided by this massive increase in pituitary responsiveness the ovulatory surge of gonadotropin would not occur.
  • Discovery of the Priming effect of GnRH whereby the decapeptide increases pituitary responsiveness to itself and thereby synchronizes the estrogen-triggered spontaneous GnRH surge and increase in pituitary responsiveness to ensure coincidence and the consequent ovulatory gonadotropin surge. The priming effect of GnRH is essential for spontaneous ovulation in humans as well as other mammals. The discovery of the priming effect of GnRH provided the basis for the rational clinical therapeutic use of GnRH analogs in the human for the treatment of clinical conditions such as precocious puberty, infertility and hormone dependent cancers.
  • Elucidation of the central neuroendocrine stress response mechanisms, including:  (i) the first direct demonstration that a corticotropin releasing factor (CRF) is released from the hypothalamus into hypophysial portal blood; (ii) direct demonstration that the effects of CRF on pituitary adrencorticotropin (ACTH) release…a pivotal event in the stress response… are enhanced by the synergistic action of arginine vasopressin (AVP) ; (iii) that AVP and CRF release into hypophysial portal blood are inhibited by glucocorticoids; (iv) the CRF-induced release of ACTH is blocked by glucocorticoid action on the anterior pituitary gland. Glucocorticoid inhibition of AVP and CRF release and CRF-induced ACTH release are pivotal mechanisms in the negative feedback control within the hypothalamic-pituitary-adrenal (HPA) axis.
  • Feedback mechanisms in neuroendocrine control: how gonadal and adrenal steroids regulate pituitary hormone secretion by way of feedback and servo mechanisms that affect hypothalamic neurohormones and pituitary responsiveness to neurohormones.
  • How gonadal and adrenal steroids affect brain differentiation, plasticity and neurochemistry.
  • Neurohormone release into hypophysial portal vessel blood. With Curtis Worthington Jr, I developed a transpharyngeal method for collecting blood from the hypophysial portal vessels that was pivotal for direct proof of the neurohumoral hypothesis of anterior pituitary control. The method was also used to identify hypothalamic neurohormones (mainly neuropeptides) and to characterize neurohormone release and posttranslational processing of neuropeptide precursors. The Fink -Worthington method was subsequently adapted for neurohormonal studies in larger species such as the sheep and rhesus monkey.
  • Mutant Neuroendocrine Animal models. With BM Cattanach and HM Charlton we discovered and characterized the hypogonadal (hpg) mouse (which was used to elucidate several key mechanisms in reproductive behaviour (e.g. social memory) physiology and pathology.

Research Leadership:

Under my Directorship the MRC Brain Metabolism Unit (Edinburgh University 1980-1999) became renowned for its molecular neuroendocrinology, neuropharmacology, and psychopharmacology and for the fact that it was first in the UK to establish a modern neuroimaging (SPECT and MRI) facility dedicated to Psychiatry. Our single photon emission computerized tomography (SPECT) studies were the first to demonstrate the use of modern neuroimaging for the diagnosis of Creutzfeldt –Jakob Disease and Alzheimer’s Disease.

I have supervised more than 45 graduate students and postdoctoral scientists. Of these 20 have attained senior (full professor/head of department level) academic, research or industrial positions.

Clinical Experience and Clinical Trials:

Direction of clinical neuropsychiatry and psychoneuroendocrinology in the MRC Brain Metabolism Unit (Edinburgh, Scotland) and the Mental Health Research Institute (Melbourne, Australia) provided experience in the diagnosis and treatment of patients with schizophrenia, manic-depressive disorder, major depression and dementia, and the use and adverse effects of psychoactive drugs. My time at Pharmos Corp added to my experience in traumatic brain injury, stroke, neuropathic pain and neurodegenerative disorders.

I was involved in the design and running of several clinical trials in the Brain Metabolism Unit and at the Mental Health Research Institute. Much of our work at the Brain Metabolism Unit involved neuroendocrine and pharmacological studies of mainly drug free patients with psychosis or dementia. These studies provided novel insights into glucocorticoid and pituitary hormone secretion as biomarkers of mental disorders.