University of Hertfordshire

Our laboratory combines the experimental analysis of behaviour and the effects of drugs on it in rodents with neurochemical techniques (High-Performance Liquid Chromatography) to assess both stable as well as dynamic correlates of neurotransmitter function.

Summary of work:

Project I: Behavioural Pharmacology of Cannabinoids

Our current research in this project is focusing on

(i.) The functions of (endogenous) cannabinoids and their receptors in mediating learning, memory, emotionality and reinforcement mechanisms and their neurochemical concomitants. For this purpose, we established and validated a variety of behavioural tests to investigate reward and addiction, learning/memory and emotionality. The behavioural tests include the drug sensitization paradigm, the elevated plus- and T-maze and the open field test for emotional reactivity to measure different types of anxiety as well as associative and non-associative learning and memory processes. Furthermore, to correlate the behavioural outcome to brain variables we established HPLC to measure monoamines and their metabolites as well as GABA and glutamate. Applying these techniques after the endocannabinoid tone has been blocked with selective cannabinoid antagonists, we found that endocannabinoids have a crucial role in the inhibitory control of associative processing, mediate anxiolysis and modulate forebrain monoamine activity, especially in reward-relevant brain structures, i.e. the ventral striatum comprising the nucleus accumbens.

(ii.) Behavioural and neurochemical phenotyping of mouse mutants, including mice deficient in the cannabinoid CB1 cannabinoid receptor. The key finding was that the genetic invalidation of CB1 receptors attenuates the psychomotor-stimulant and sensitizing effects of amphetamine, providing supportive evidence for the ‘gateway hypothesis’ of cannabinoids for addictive processes.

Project II: Neurochemical aspects of Functional Brain Ageing & Neurodegeneration

This is an example of pseudocolor-coded images of autoradiographs of coronal sections showing the regional and laminar distribution of different binding site (receptor) densities in the hippocampus of old rats. Variations in the density of the binding sites correlated with the quality of learning of a water maze task.

(i.) We investigated behavioural and neurobiological concomitants of aging, with the tactic to relate individual differences in learning and other tasks to biochemical, physiological and anatomical variation in the brain. Our recent work provides evidence that differences in extracellular space (ECS) diffusion parameters are related to the extent of cognitive impairment. We found that the degree of impaired maze performance of old rats correlates, for one, with the decrease in ECS volume and the loss of diffusion anisotropy in hippocampus and, secondly, with the reduction of hippocampal ECS matrix molecules chondroitin sulphate proteogycans and fibronectin. This is the first report indicating that diffusion in the extracellular space - the underlying mechanism of the extrasynaptic (volume, paracrine) transmission - could be functionally important in behavioural processes, learning and plasticity.

(ii.) In collaboration with Dr Lucy Annett, we investigate changes in monoaminergic parameters in the 6-OHDA rat model of Parkinson’s disease. The major focus is on how interventions like ‘enriched environment’ can facilitate post-lesion behavioural recovery and the concomitant changes in nigro-striatal monoamine functioning as measured with neurochemical and immunohistochemical methods.

Publications

[1] Thiemann G, Fletcher B, Ledent C, Molleman A, Hasenohrl RU. The genetic versus pharmacological invalidation of the cannabinoid CB1 receptor results in differential effects on ‘non-associative’ memory and forebrain monoamine concentrations in mice. Neurobiol Lern Mem (under review).

[2] Thiemann G, Ledent C, Molleman A, Hasenohrl RU. Differential modulation of anxiety by acute and chronic blockade of the CB1 cannabinoid receptor in mice together with biogenic amine changes in the forebrain. Neuropsychopharmacology (revised).

[3] Thiemann G, Di Marzo V, Molleman A, Hasenohrl RU. The cannabinoid CB1 receptor antagonist AM251 blocks amphetamine-induced behavioural sensitization while causing monoamine changes in nucleus accumbens and hippocampus. Behav Pharmacol (under review)

[4] Thiemann G, van der Stelt M, Petrosino S, Molleman A, Di Marzo V, Hasenohrl RU. The role of the CB1 cannabinoid receptor and its endogenous ligands, anandamide and 2-arachidonoylglycerol, in amphetamine-induced behavioural sensitization. Behav Brain Res (under review).

[5] De Souza Silva MA, Jezek K, Weth K, Muller HW, Huston JP, Brandao ML, Hasenohrl RU (2002) Facilitation of learning and modulation of frontal cortex acetylcholine by ventral pallidal injection of heparin glucosaminoglycan. Neuroscience, 113, 529-535.

[6] Topic B, Tani E, Tsiakitzis K, Kourounakis PN, Dere E, Hasenohrl RU, Hacker R, Mattern CM, Huston JP (2002) Enhanced maze performance and reduced oxidative stress by combined extracts of zingiber officinale and ginkgo biloba in the aged rat. Neurobiol Aging, 23, 135-143.

[7] Topic B, Willuhn I, Palomero-Gallagher N, Zilles K, Huston JP, Hasenohrl RU (2007) Impaired maze performance in aged rats is accompanied by increased density of NMDA, 5-HT1A and alpha-adrenoceptor binding in hippocampus. Hippocampus, 17, 68-77.

[8] Syková E, Mazel T, Hasenohrl RU, Harvey AR, Simonová Z, Mulders WHAM, Huston JP ( 2002) Learning deficits in aged rats related to decrease in extracellular volume and loss of diffusion anisotropy in hippocampus. Hippocampus, 12, 269-279.

Grants:

Supported by grants from the German Research Council (together with Dr J.P. Huston) and by a grant from the Parkinson’s Disease Society, UK. (together with Dr Lucy Annett).