The selective norepinephrine (NE)

Studies in several species of rodents show that arginine vasopressin (AVP) acting through a V 1A receptor facilitates offensive aggression, i.e., the initiation of attacks and bites, whereas serotonin (5-HT) acting through a 5-HT 1B receptor inhibits aggressive responding. One area of the CNS that seems critical for the organization of aggressive behavior is the basolateral hypothalamus, particularly the anterior hypothalamic region. The present studies examine the neuroanatomical and neurochemical interaction between AVP and 5-HT at the level of the anterior hypothalamus (AH) in the control of offensive aggression in Syrian golden hamsters. First, specific V 1A and 5-HT 1B binding sites in the AH are shown by in vitro receptor autoradiography. The binding for each neurotransmitter colocalizes with a dense field of immunoreactive AVP and 5-HT fibers and putative terminals. Putative 5-HT synapses on AVP neurons in the area of the AH are identified by double-staining immunocytochemistry and laser scanning confocal microscopy. These morphological data predispose a functional interaction between AVP and 5-HT at the level of the AH. When tested for offensive aggression in a resident /intruder paradigm, resident hamsters treated with fluoxetine, a selective 5-HT reuptake inhibitor, have significantly longer latencies to bite and bite fewer times than vehicle-treated controls. Conversely, AVP microinjections into the AH significantly shorten the latency to bite and increase biting attacks. The action of microinjected AVP to increase offensive aggression is blocked by the pretreatment of hamsters with fluoxetine. These data suggest that 5-HT inhibits fighting, in part, by antagonizing the aggressionpromoting action of the AVP system. Two neurotransmitter systems implicated in the control of aggressive behavior are arginine vasopressin (AVP) and serotonin (5-HT). AVP is a neurochemical signal affecting numerous brain functions (DeWied, 1971;Cooper et al., 1979;Pittman et al., 1982;Fehm-Wolfsdorf et al., 1988;Dantzer and Bluthe, 1992), including aggression (Ferris and Potegal, 1988, Koolhaas et al., 1990Potegal and Ferris, 1990;Winslow et al., 1993; Delville et al., 1996a,b). For example, microinjection of AVP V 1A -receptor antagonist into the anterior hypothalamus (AH) of a hamster causes a dose-dependent inhibition of offensive aggression, i.e., initiated attacks and bites toward a conspecific placed into their home cage (Ferris and Potegal, 1988). Similarly, AVP receptor blockade in the AH significantly reduces aggression between hamsters paired together in a neutral arena .Although AVP facilitates offensive aggression, 5-HT is reported to have the opposite effect and diminishes aggressive behavior (for review, see Olivier and Mos, 1990). For example, rats show an increase in offensive aggression after treatment with neurotoxins that deplete 5-HT levels in the hypothalamus (Vergnes et al., 1988). Conversely, rats treated with eltoprazine, a 5-HT 1 receptor agonist, show a dose-dependent decrease in offensive aggressi...

In the early 1970s, evidence of the role of serotonin (5-hydroxytryptamine or 5-HT) in depression began to emerge and the hypothesis that enhancing 5-HT neurotransmission would be a viable mechanism to mediate antidepressant response was put forward. On the basis of this hypothesis, efforts to develop agents that inhibit the uptake of 5-HT from the synaptic cleft were initiated. These studies led to the discovery and development of the selective serotonin-reuptake inhibitor fluoxetine hydrochloride (Prozac; Eli Lilly), which was approved for the treatment of depression by the US FDA in 1987. Here, we summarize this research and discuss the many challenges that we encountered during the development of fluoxetine hydrochloride, which has now been widely acknowledged as a breakthrough drug for depression.

1 In order to explore potential therapeutic implications of cannabinoid antagonists, the eects of the prototypical cannabinoid antagonist SR141716A on monoamine eux from the medial prefrontal cortex and the nucleus accumbens of the rat were investigated by in vivo microdialysis. 2 SR141716A moderately increased serotonin eux and concentrations of its metabolite 5-HIAA, both in the medial prefrontal cortex and the nucleus accumbens, and increased norepinephrine, dopamine and their metabolites in the medial prefrontal cortex. In contrast, it had no eect on norepinephrine, dopamine and their metabolites in the nucleus accumbens. 3 At the same doses, SR141716A increased acetylcholine eux in the medial prefrontal cortex, in agreement with previous studies; contrary to the eects in cortex, SR141716A had no eect on acetylcholine eux in the nucleus accumbens. 4 The ecacy of SR141716A in the psychostimulant-induced hyperlocomotion and the forced swimming paradigms was also explored in mice. SR141716A attenuated phenylcyclidine-and damphetamine-induced hyperlocomotion, without aecting locomotor activity when administered alone, and decreased immobility in the forced swimming test. 5 These results suggest that the cortical selectivity in the release of catecholamines, dopamine in particular, induced by the cannabinoid antagonist SR141716A, its procholinergic properties, together with its mild stimulatory eects on serotonin and norepinephrine eux make similar compounds unique candidates for the treatment of psychosis, aective and cognitive disorders.

Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.