The amygdala, experimental anxiety and alcohol consumption : an integrative study in the rat

University dissertation from Stockholm : Karolinska Institutet, Department of Clinical Neuroscience, Occupational Therapy and Elderly Care Research (NEUROTEC)

Abstract: The amygdala integrates emotionally relevant stimuli. Here, the aversive value of stimuli and memories is extracted and transduced into a behavioral response. This rapid processing leads to a coordinated activation of autonomic, endocrine, behavioral and emotional functions that together comprise the fear reaction. Anxiety is a psychopathological state in which subjective feelings of fear and a coordinated fear response is present in the absence of a relevant external threat. An activation of the amygdala thus participates in a state of negative affect which may be either physiological (fear) or pathological (anxiety, depression). In this capacity, the amygdala is involved in negative reinforcement, and in the complex motivational mechanisms underlying alcohol dependence. We have examined the functional role of amygdala activation in experimental anxiety using a validated animal model, the Vogel conflict test. Expression of the immediate-early-gene c-fos, a neuronal activity marker, was induced within the amygdala by the conflict procedure. Injection of c-fos antisense in the amygdala blocked this expression, and had behavioral effects similar to those of established anti-anxiety compounds. These findings support the notion that neuronal activation and c-fos induction in the amygdala may be important for mechanisms underlying fear and anxiety (paper 1). Further, the possibility that mechanisms underlying experimental anxiety might be related to regulation of voluntary ethanol intake was examined. Rats were bilaterally lesioned in central amygdala, resulting in a release of punished responding in the conflict test, and an attenuated response to restraint stress, effects typical of anxiety reducing drugs. Ethanol intake was markedly decreased in the lesioned. animals. Thus, our results support a relation between experimental anxiety and voluntary ethanol consumption in genetically heterogenous animals (paper 2). Ethanol dependence is a heterogenous disorder, with different relationships between anxiety and alcohol reinforcement in different subtypes of alcoholism. The AA line of alcohol preferring rats was studied as a model of genetic alcoholism. Experimental anxiety was examined in the conflict test and in the elevated plusmaze. AA animals displayed a markedly disinhibited behavior in the conflict test and also showed low levels of experimental anxiety on the plusmaze. The disinhibited behavior and spontaneous ethanol preference displays similarities to genetically transmitted type 11 alcoholism according to Cloninger's nomenclature (paper 3). The neuropeptide galanin is present in brain areas important for emotionality. Using the conflict test, we examined whether galanin may be involved in mechanisms of anxiety. Following intracerebroventricular administration of the peptide, an anxiolytic-like effect was obtained in the conflict test (paper 4). We also examined the effects of administration of the peptide directly into the amygdala. Using this mode of administration, punished responding was dose dependently suppressed, suggesting that pre- and postsynaptic galanin receptors may be differentially activated following the two modes of administration, accounting for the differential effects observed (paper 5). Intracerebroventricular administration of another neuropeptide, glucagon-like peptide-1 (GLP-1), induces expression of c-fos in the central nucleus of the amygdala. We examined experimental anxiety in rats following this route of administration of GLP-1 and found a robust proconflict / anxiogenic-like effect in the conflict test during the light, inactive phase of the circadian rhytm, but not during the dark and active phase (paper 6). This result further supports that an activation of the amygdala is involved in a fear / anxiety response.

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