solid basic science,
recognized by ECNP award in 2009.
Our team succeeded in
key receptors of addiction
compounds inhibiting these receptors
a therapeutic composition suitable for human
the concept on proper animal models
Kinnov Therapeutics’ proprietary pharmaceutical composition KT-110 is designed
to become a first-in-class therapy for addiction diseases, with the following assets:
High efficacy on different animal models of addiction
Easy transposition to human (drug repurposing)
According to the 2018 WHO Global Report, about 3.3 million deaths (5.3% of all deaths), were attributable to alcohol consumption in 2016. There are significant sex differences in the proportion of global deaths attributable to alcohol, 7.6% of deaths among males and 4.0% of deaths among females were attributable to alcohol. Overall, 133 million disability-adjusted life years, or 5.1% of the global burden of disease and injury, were attributable to alcohol consumption. There is also a wide geographical variation in the proportion of alcohol-attributable deaths, with the highest alcohol-attributable fractions reported in the WHO European Region. Evidence of a causal impact of average volume of alcohol consumption was found for the following major diseases: tuberculosis, cancer, diabetes mellitus, alcohol use disorders (AUDs), unipolar depressive disorders, epilepsy, hypertensive heart disease, ischemic heart disease, ischemic and haemorrhagic stroke, conduction disorders and other dysrhythmias, lower respiratory infections (pneumonia), cirrhosis of the liver, preterm birth complications and foetal alcohol syndrome .
Despite intensive research, the neurobiological substrates responsible for AUDs are still poorly understood.
Ethanol is a small amphiphilic molecule which can bind to numerous sites in the central nervous system, such as cell membranes and their receptors. For example, ethanol was shown to inhibit NMDA-mediated glutamatergic transmission and to potentiate GABAergic inhibitory currents. Ethanol was also shown to increase dopamine (DA) release in rat nucleus accumbens, a property which is shared by most drugs abused by humans, such as psychostimulants and opiates. Also like psychostimulants and opiates, ethanol can trigger in rodents a locomotor response that increases with repeated injections, especially in DBA/2J or Swiss (CD1) mice. This phenomenon, called behavioural sensitization, is thought to play a critical role in the development of drug-taking and drug-seeking behaviours.
The pharmacological treatment of alcohol dependence is a major challenge in public health. The exiting pharmacopoeia has therefore developed around substitution products, for which the main therapeutic objective is to limit the physical symptoms induced by withdrawal. However, there are few if any substances that aim to counteract the states of psychic dependence, i.e. the irrepressible need (or craving) for alcohol. This state of psychic dependence is much more robust and is generally the cause of relapses.
Several pharmacological treatments have been proposed for the treatment of alcohol dependence.
Naltrexone, an opiate antagonist, has been tested in clinical trials. Studies have shown that it reduces alcohol consumption, the relapse rate and the desire to drink, especially in the case of severe alcoholization. Unfortunately, its use is limited due to its gastrointestinal side effects (nausea, vomiting and loss of appetite).
Mention may also be made of the use of naltrindole, a δ-opiate receptor antagonist, which has shown some efficacy in animal models.
The use of acamprosate has also been considered. Although its mechanism of action has not been elucidated fully, there is good deal of evidence suggesting that acamprosate acts by modulation of glutamatergic transmission. The molecule would appear to be effective, at least in the treatment of withdrawal symptoms. Its efficacy with respect to craving for alcohol is still under discussion.
Serotonergic antidepressants have also been used. Therapeutic trials based on the serotonin reuptake inhibitors have given variable results, and clinical studies have not demonstrated any real efficacy.
Benzodiazepines are effective when used at the time of withdrawal. Long-term efficacy is controversial, especially as patients follow this type of treatment for long periods to combat symptoms of abstinence such as anxiety and insomnia. There is the question of the benefit/risk ratio of replacing one product of abuse with another, in a patient who is already susceptible to the phenomenon of dependence.
Last but not least, disulfiram is an aversion drug, used since 1940. When it is taken simultaneously with alcohol, this product triggers unpleasant effects such as nausea, vomiting, an increase in blood pressure and heart rate.
Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of DA in the ventral striatum. However, some experiments indicated an implication of α1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. DA release induced in the ventral striatum by morphine (20 mg/kg) was completely blocked by drug2 (1 mg/kg), an α1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the α1b-adrenergic receptor (α1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in α1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in α1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and α1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses, but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). Inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naive WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of α1b-adrenergic receptors, the existence of a functional link between these receptors could be postulated.
Kinnov-Therapeutics board is made of experts in addiction. They work on this subject for
more that 20 years and have written dozens of international publications.
Kinnov-Therapeutics board is made of experts of addiction. They works on this subject since more that 20 years and have written dozens of international publications.
- The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence. - Trovero F, David S, Bernard P, Puech A, Bizot JC, Tassin JP. PLoS One. 2016 Mar 11;11(3):e0151242. - Link
- D-amphetamine improves attention performance in adolescent Wistar, but not in SHR rats, in a two-choice visual discrimination task. - Bizot JC, Cogrel N, Massé F, Chauvin V, Brault L, David S, Trovero F. - Psychopharmacology (Berl). 2015 Sep;232(17):3269-86. doi: 10.1007/s00213-015-3974-2. Epub 2015 Jun 4. - Link
- Pleasure: Neurobiological conception and Freudian conception. - Chenu A, Tassin JP. - Encephale. 2014 Apr;40(2):100-7. doi: 10.1016/j.encep.2013.06.003. Epub 2013 Nov 1. Review. French. - Link
- Repeated exposure to MDMA triggers long-term plasticity of noradrenergic and serotonergic neurons. - Lanteri C, Doucet EL, Hernández Vallejo SJ, Godeheu G, Bobadilla AC, Salomon L, Lanfumey L, Tassin JP. - Mol Psychiatry. 2014 Jul;19(7):823-33. doi: 10.1038/mp.2013.97. Epub 2013 Aug 20. - Link
- Traumatic stress in rats induces noradrenergic-dependent long-term behavioral sensitization: role of individual differences and similarities with dependence on drugs of abuse. - Toledano D, Tassin JP, Gisquet-Verrier P. - Psychopharmacology (Berl). 2013 Dec;230(3):465-76. doi: 10.1007/s00213-013-3179-5. Epub 2013 Jun 29. - Link
- Sustained impairment of α2A-adrenergic autoreceptor signaling mediates neurochemical and behavioral sensitization to amphetamine. - Doucet EL, Bobadilla AC, Houades V, Lanteri C, Godeheu G, Lanfumey L, Sara SJ, Tassin JP. - Biol Psychiatry. 2013 Jul 15;74(2):90-8. doi: 10.1016/j.biopsych.2012.11.029. Epub 2013 Jan 17. - Link
- Chronic stress triggers social aversion via glucocorticoid receptor in dopaminoceptive neurons. - Barik J, Marti F, Morel C, Fernandez SP, Lanteri C, Godeheu G, Tassin JP, Mombereau C, Faure P, Tronche F. - Science. 2013 Jan 18;339(6117):332-5. doi: 10.1126/science.1226767. - Link
- Effects of atomoxetine, desipramine, d-amphetamine and methylphenidate on impulsivity in juvenile rats, measured in a T-maze procedure. - Bizot JC, David S, Trovero F. - Neurosci Lett. 2011 Feb 1;489(1):20-4. doi: 10.1016/j.neulet.2010.11.058. Epub 2010 Dec 1. - Link
- α7 and β2 nicotinic receptors control monoamine-mediated locomotor response. - Villégier AS, Salomon L, Granon S, Champtiaux N, Changeux JP, Tassin JP. - Neuroreport. 2010 Dec 8;21(17):1085-9. doi: 10.1097/WNR.0b013e328340536a. - Link
- Inhibition of monoamine oxidases desensitizes 5-HT1A autoreceptors and allows nicotine to induce a neurochemical and behavioral sensitization. - Lanteri C, Hernández Vallejo SJ, Salomon L, Doucet EL, Godeheu G, Torrens Y, Houades V, Tassin JP. - J Neurosci. 2009 Jan 28;29(4):987-97. doi: 10.1523/JNEUROSCI.3315-08.2009. - Link
- Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism. - Lanteri C, Salomon L, Torrens Y, Glowinski J, Tassin JP. - Neuropsychopharmacology. 2008 Jun;33(7):1724-34. Epub 2007 Sep 5. - Link
- Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse. - Tassin JP. - Biochem Pharmacol. 2008 Jan 1;75(1):85-97. Epub 2007 Jun 30. Review. - Link
- Paradoxical constitutive behavioral sensitization to amphetamine in mice lacking 5-HT2A receptors. - Salomon L, Lanteri C, Godeheu G, Blanc G, Gingrich J, Tassin JP. - Psychopharmacology (Berl). 2007 Sep;194(1):11-20. Epub 2007 May 19. - Link
- Elevated dopamine D2High receptors in alpha-1b-adrenoceptor knockout supersensitive mice. - Tassin JP, Torrens Y, Salomon L, Lanteri C, Seeman P. - Synapse. 2007 Jul;61(7):569-72. - Link
- Methylphenidate reduces impulsive behaviour in juvenile Wistar rats, but not in adult Wistar, SHR and WKY rats. - Bizot JC, Chenault N, Houzé B, Herpin A, David S, Pothion S, Trovero F. - Psychopharmacology (Berl). 2007 Aug;193(2):215-23. Epub 2007 Apr 4. - Link
- [Uncoupling between noradrenergic and serotonergic neurons: As a mechanism for drug addiction]. - Tassin JP, Lanteri C, Salomon L. - Med Sci (Paris). 2006 Oct;22(10):798-800. French. No abstract available. - Link
- Irreversible blockade of monoamine oxidases reveals the critical role of 5-HT transmission in locomotor response induced by nicotine in mice. - Villégier AS, Salomon L, Blanc G, Godeheu G, Glowinski J, Tassin JP. - Eur J Neurosci. 2006 Sep;24(5):1359-65. Epub 2006 Sep 8. - Link
- [Neurobiology in the neuropharmacology of antipsychotic drugs]. - Tassin JP. - Encephale. 2006 Jan;32 Pt 2:S6-7. French. No abstract available. - Link
- Behavioral sensitization to amphetamine results from an uncoupling between noradrenergic and serotonergic neurons. - Salomon L, Lanteri C, Glowinski J, Tassin JP. - Proc Natl Acad Sci U S A. 2006 May 9;103(19):7476-81. Epub 2006 Apr 28. - Link
- Monoamine oxidase inhibitors allow locomotor and rewarding responses to nicotine. - Villégier AS, Salomon L, Granon S, Changeux JP, Belluzzi JD, Leslie FM, Tassin JP. - Neuropsychopharmacology. 2006 Aug;31(8):1704-13. Epub 2005 Dec 14. - Link
- cAMP and extracellular signal-regulated kinase signaling in response to d-amphetamine and methylphenidate in the prefrontal cortex in vivo: role of beta 1-adrenoceptors. - Pascoli V, Valjent E, Corbillé AG, Corvol JC, Tassin JP, Girault JA, Hervé D. - Mol Pharmacol. 2005 Aug;68(2):421-9. Epub 2005 May 12. - Link
- 5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants. - Auclair A, Drouin C, Cotecchia S, Glowinski J, Tassin JP. - Eur J Neurosci. 2004 Dec;20(11):3073-84. - Link
- Role of serotonin 2A receptors in the D-amphetamine-induced release of dopamine: comparison with previous data on alpha1b-adrenergic receptors. - Auclair A, Blanc G, Glowinski J, Tassin JP. - J Neurochem. 2004 Oct;91(2):318-26. - Link
- Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors. - Villégier AS, Blanc G, Glowinski J, Tassin JP. - Pharmacol Biochem Behav. 2003 Sep;76(2):267-74. - Link
- Stimulation of postsynaptic alpha1b- and alpha2-adrenergic receptors amplifies dopamine-mediated locomotor activity in both rats and mice. - Villégier AS, Drouin C, Bizot JC, Marien M, Glowinski J, Colpaërt F, Tassin JP. - Synapse. 2003 Dec 15;50(4):277-84. - Link
- D-amphetamine fails to increase extracellular dopamine levels in mice lacking alpha 1b-adrenergic receptors: relationship between functional and nonfunctional dopamine release. - Auclair A, Cotecchia S, Glowinski J, Tassin JP. - J Neurosci. 2002 Nov 1;22(21):9150-4. - Link
- Amisulpride does not prevent relapse in primary alcohol dependence: results of a pilot randomized, placebo-controlled trial. - Marra D, Warot D, Berlin I, Hispard E, Notides C, Tilikete S, Payan C, Lépine JP, Dally S, Aubin HJ. - Alcohol Clin Exp Res. 2002 Oct;26(10):1545-52. - Link
- [Role of dopamine in drug dependence processes]. - Tassin JP. - Bull Acad Natl Med. 2002;186(2):295-304; discussion 304-5. Review. French. - Link
- Alpha1b-adrenergic receptors control locomotor and rewarding effects of psychostimulants and opiates. - Drouin C, Darracq L, Trovero F, Blanc G, Glowinski J, Cotecchia S, Tassin JP. - J Neurosci. 2002 Apr 1;22(7):2873-84. - Link
- Critical role of alpha1-adrenergic receptors in acute and sensitized locomotor effects of D-amphetamine, cocaine, and GBR 12783: influence of preexposure conditions and pharmacological characteristics. - Drouin C, Blanc G, Villégier AS, Glowinski J, Tassin JP. - Synapse. 2002 Jan;43(1):51-61. - Link
- Cortical alpha 1-adrenergic regulation of acute and sensitized morphine locomotor effects. - Drouin C, Blanc G, Trovero F, Glowinski J, Tassin JP. - Neuroreport. 2001 Nov 16;12(16):3483-6. - Link
- Stimulation of metabotropic but not ionotropic glutamatergic receptors in the nucleus accumbens is required for the D-amphetamine-induced release of functional dopamine. - Darracq L, Drouin C, Blanc G, Glowinski J, Tassin JP. - Neuroscience. 2001;103(2):395-403. - Link
- Sequential improvement of anxiety, depression and anhedonia with sertraline treatment in patients with major depression. - Boyer P, Tassin JP, Falissart B, Troy S. - J Clin Pharm Ther. 2000 Oct;25(5):363-71. - Link
- Integrity of the mesocortical dopaminergic system is necessary for complete expression of in vivo hippocampal-prefrontal cortex long-term potentiation. - Gurden H, Tassin JP, Jay TM. - Neuroscience. 1999;94(4):1019-27. - Link
- Ginkgo biloba extract EGb761 reduces the development of amphetamine-induced behavioral sensitization: effects on hippocampal type II corticosteroid receptors. - Trovero F, Brochet D, Tassin JP, Drieu K. - Brain Res. 1999 Feb 6;818(1):135-9. - Link
- Alpha1-adrenergic, D1, and D2 receptors interactions in the prefrontal cortex: implications for the modality of action of different types of neuroleptics. - Gioanni Y, Thierry AM, Glowinski J, Tassin JP. - Synapse. 1998 Dec;30(4):362-70. - Link
- A functional model of some Parkinson's disease symptoms using a Guided Propagation Network. - Toffano-Nioche C, Beroule D, Tassin JP. - Artif Intell Med. 1998 Nov;14(3):237-58. - Link
- Antimalarial and cytotoxic potential of four quassinoids from Hannoa chlorantha and Hannoa klaineana, and their structure-activity relationships. - François G, Diakanamwa C, Timperman G, Bringmann G, Steenackers T, Atassi G, Van Looveren M, Holenz J, Tassin JP, Assi LA, Vanhaelen-Fastre R, Vanhaelen M. - Int J Parasitol. 1998 Apr;28(4):635-40. - Link
- Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of D-amphetamine. - Darracq L, Blanc G, Glowinski J, Tassin JP. - J Neurosci. 1998 Apr 1;18(7):2729-39. - Link
- Norepinephrine-dopamine interactions in the prefrontal cortex and the ventral tegmental area: relevance to mental diseases. - Tassin JP. - Adv Pharmacol. 1998;42:712-6. No abstract available. - Link
- Sensitivity and specificity to amphetamine of a French version of the 49-item form of the addiction research center inventory. - Warot D, Danjou P, Payan C, Puech AJ. - Drug Alcohol Depend. 1997 May 2;45(3):177-83. - Link
- Simultaneous determination of cytotoxic (adriamycin, vincristine) and modulator of resistance (verapamil, S 9788) drugs in human cells by high-performance liquid chromatography and ultraviolet detection. - Tassin JP, Dubois J, Atassi G, Hanocq M. - J Chromatogr B Biomed Sci Appl. 1997 Apr 11;691(2):449-56. - Link
- [Schizophrenia and neural transmission: an excess of analogical treatment?]. - Tassin JP. - Encephale. 1996 Oct;22 Spec No 3:91-8. Review. French. No abstract available. - Link
- [Deficit schizophrenia: from pharmacology to clinical practice]. - Tassin JP. - Encephale. 1996 Jun;22 Spec No 2:9-12. Review. French. - Link
- A reversible monoamine oxidase A inhibitor (moclobemide) facilitates smoking cessation and abstinence in heavy, dependent smokers. - Berlin I, Saïd S, Spreux-Varoquaux O, Launay JM, Olivares R, Millet V, Lecrubier Y, Puech AJ. - Clin Pharmacol Ther. 1995 Oct;58(4):444-52. - Link
- HPLC determination of a new multidrug resistance modulator (S9788) extracted from cancer cells in vitro. - Tassin JP, Dubois J, Hanocq M, Atassi G. - Talanta. 1995 May;42(5):747-53. - Link
- [Interrelations between neuromediators implicated in depression and antidepressive drugs]. - Tassin JP. - Encephale. 1994 Dec;20 Spec No 4:623-8. Review. French. - Link
- Accelerated resensitization of the D1 dopamine receptor-mediated response in cultured cortical and striatal neurons from the rat: respective role of alpha 1-adrenergic and N-methyl-D-aspartate receptors. - Trovero F, Marin P, Tassin JP, Premont J, Glowinski J. - J Neurosci. 1994 Oct;14(10):6280-8. - Link
- Le clonage des gènes codant pour les récepteurs opiacés permet-il une meilleure compréhension de la toxicomanie? - Trovero F. - Neuro-psy, 1994, 9, 227-233.
- Blockade of prefronto-cortical alpha 1-adrenergic receptors prevents locomotor hyperactivity induced by subcortical D-amphetamine injection. - Blanc G, Trovero F, Vezina P, Hervé D, Godeheu AM, Glowinski J, Tassin JP. - Eur J Neurosci. 1994 Mar 1;6(3):293-8. - Link
- Injections of 6-hydroxydopamine into the ventral tegmental area destroy mesolimbic dopamine neurons but spare the locomotor activating effects of nicotine in the rat. - Vezina P, Hervé D, Glowinski J, Tassin JP. - Neurosci Lett. 1994 Feb 28;168(1-2):111-4. - Link
- Blockade of D-1 dopamine receptors in the medial prefrontal cortex produces delayed effects on pre- and postsynaptic indices of dopamine function in the nucleus accumbens. - Vezina P, Blanc G, Glowinski J, Tassin JP. - Synapse. 1994 Feb;16(2):104-12. - Link
- G(olf) and Gs in rat basal ganglia: possible involvement of G(olf) in the coupling of dopamine D1 receptor with adenylyl cyclase. - Hervé D, Lévi-Strauss M, Marey-Semper I, Verney C, Tassin JP, Glowinski J, Girault JA. - J Neurosci. 1993 May;13(5):2237-48. - Link
- Potentiation by low doses of selected neuroleptics of food-induced conditioned place preference in rats. - Guyon A, Assouly-Besse F, Biala G, Puech AJ, Thiébot MH. - Psychopharmacology (Berl). 1993;110(4):460-6. - Link
- Drug interaction involving P-glycoprotein in relation to multidrug resistance. - Atassi G, Tassin JP. - Int J Clin Pharmacol Ther Toxicol. 1992 Nov;30(11):526-7. Review. No abstract available. - Link
- Inhibitory effects of ventral tegmental area stimulation on the activity of prefrontal cortical neurons: evidence for the involvement of both dopaminergic and GABAergic components. - Pirot S, Godbout R, Mantz J, Tassin JP, Glowinski J, Thierry AM. - Neuroscience. 1992 Aug;49(4):857-65. - Link
- In vivo partial inactivation of dopamine D1 receptors induces hypersensitivity of cortical dopamine-sensitive adenylate cyclase: permissive role of alpha 1-adrenergic receptors. - Trovero F, Hervé D, Blanc G, Glowinski J, Tassin JP. - J Neurochem. 1992 Jul;59(1):331-7. - Link
- Cortico-subcortical interactions in behavioral sensitization: differential effects of daily nicotine and morphine. - Tassin JP, Vezina P, Trovero F, Blanc G, Hervé D, Glowinski J. - Ann N Y Acad Sci. 1992 Jun 28;654:101-16. Review. No abstract available. - Link
- Nicotine and morphine differentially activate brain dopamine in prefrontocortical and subcortical terminal fields: effects of acute and repeated injections. - Vezina P, Blanc G, Glowinski J, Tassin JP. - J Pharmacol Exp Ther. 1992 May;261(2):484-90. - Link
- Biochemical and behavioural consequences of interactions between dopaminergic and noradrenergic systems in rat prefrontal cortex. - Tassin JP, Trovero F, Hervé D, Blanc G, Glowinski J. - Neurochem Int. 1992 Mar;20 Suppl:225S-230S. Review. No abstract available. - Link
- Contribution of an alpha 1-adrenergic receptor subtype to the expression of the "ventral tegmental area syndrome". - Trovero F, Blanc G, Hervé D, Vézina P, Glowinski J, Tassin JP. - Neuroscience. 1992;47(1):69-76. - Link
- Mesocortical dopamine-neurotensin neurons. Possible opposite role of noradrenergic pathways on heteroregulations of dopamine (D1) and neurotensin postsynaptic receptors in the rat prefrontal cortex. - Tassin JP, Trovero F, Hervé D, Blanc G, Glowinski J. - Ann N Y Acad Sci. 1992;668:205-16. Review. No abstract available. - Link
- NE/DA interactions in prefrontal cortex and their possible roles as neuromodulators in schizophrenia. - Tassin JP. - J Neural Transm Suppl. 1992;36:135-62. Review. - Link
- Autoradiographic identification of D1 dopamine receptors labelled with [3H]dopamine: distribution, regulation and relationship to coupling. - Hervé D, Trovero F, Blanc G, Glowinski J, Tassin JP. - Neuroscience. 1992;46(3):687-700. - Link
- Dopaminergic hetero-regulation of striatal mu-opiate receptors: further evidence for their postsynaptic location. In "Presynaptic Receptors and Neuronal Transmission". - Trovero F., Hervé D., Desban M., Glowinski J. and Tassin J.P - Pergamon Press, Oxford. 1991.
- Evidence for phosphatidylinositol anchorage of opioid binding proteins in rat brain. - Trovero F, Glowinski J, Lévy M. - Brain Res. 1990 Dec 24;537(1-2):381-5. - Link
- Striatal opiate mu-receptors are not located on dopamine nerve endings in the rat. - Trovero F, Herve D, Desban M, Glowinski J, Tassin JP. - Neuroscience. 1990;39(2):313-21. - Link