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Neuregulin-1 (NRG-1) is genetically linked with schizophrenia, a neurodevelopmental cognitive disorder characterized by imbalances in glutamatergic and dopaminergic function. NRG-1 regulates numerous neurodevelopmental processes and, in the adult, suppresses or reverses long-term potentiation (LTP) at hippocampal glutamatergic synapses. Here we show that NRG-1 stimulates dopamine release in the hippocampus and reverses early-phase LTP via activation of D4 dopamine receptors (D4R). NRG-1 fails to depotentiate LTP in hippocampal slices treated with the antipsychotic clozapine and other more selective D4R antagonists. Moreover, LTP is not depotentiated in D4R null mice by either NRG-1 or theta-pulse stimuli. Conversely, direct D4R activation mimics NRG-1 and reduces AMPA receptor currents and surface expression. These findings demonstrate that NRG-1 mediates its unique role in counteracting LTP via dopamine signaling and opens future directions to study new aspects of NRG function. The novel functional link between NRG-1, dopamine, and glutamate has important implications for understanding how imbalances in Neuregulin-ErbB signaling can impinge on dopaminergic and glutamatergic function, neurotransmitter pathways associated with schizophrenia.depotentiation ͉ ErbB receptor ͉ plasticity ͉ schizophrenia ͉ clozapine T he trophic and differentiation factor NRG-1 and its receptors (ErbB2-4) are expressed in the developing nervous system and adult brain, including the hippocampus. NRG-1 is translated as a transmembrane protein and released in an activity-dependent manner (1). Initially, long-term NRG-1 signaling was shown to regulate neuronal expression of neurotransmitter receptor genes for glutamate, acetylcholine, and GABA (2-5). More recently, the tight association of the NRG-1 receptor ErbB4 with glutamate receptors at postsynaptic densities suggested that NRG-1 signaling could regulate synaptic function in a more acute fashion (6, 7). Consistent with this idea, we and others have shown that NRG-1␤ rapidly regulates glutamatergic (7-11) and cholinergic (12) synaptic function in the hippocampus and prefrontal cortex (PFC).Long term potentiation (LTP) and long term depression (LTD) at Schaeffer collateral-to-CA1 hippocampal synapses (SC-CA1) are believed to underlie complex cognitive processes such as learning and memory. At this synapse, postsynaptic NMDAR activation and increases in AMPAR excitatory postsynaptic currents (EPSCs) are necessary for LTP induction and expression, respectively. An additional mechanism that contributes to synaptic homeostasis at adult glutamatergic synapses is depotentiation (13,14). In acute hippocampal slices and in freely moving animals, LTP is reversed (depotentiated) by brief, subthreshold theta pulse stimulation (TPS) if delivered during a labile period shortly after LTP induction (14). In the amygdala, depotentiation correlates with fear extinction and requires AMPAR internalization (15). We recently reported that NRG-1␤ depotentiates early-phase LTP at hippocampal SC-CA1 synapses,...

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Rats learned to self-administer d-amphetamine (10 micrograms/microliter) through a cannula implanted in the nucleus accumbens. They responded more frequently for 65 +/- 15 nl of amphetamine than for equal amounts of saline. When presented with two levers (one amphetamine, one blank) they responded more on the correct lever for amphetamine. They would also switch levers, when necessary, to maintain access to the drug. When half the usual drug intake was given automatically, animals reduced their response rate by half, thus self-regulating the total amount of amphetamine they received. In tests for leakage into the ventricles, eight rats that self-injected with an accumbens cannula showed response extinction when switched to a ventricular cannula. We conclude that amphetamine self-injected into the accumbens is a positive reinforcer. This localization of 'amphetamine reward' suggests that the nucleus accumbens contains a synaptic mechanism underlying amphetamine abuse and, perhaps, also natural reinforcement of behavior.

Metformin did not prevent olanzapine-induced BWG. While some lipid parameters worsened during placebo, the HOMA-IR improved in both the placebo and the metformin groups. Carbohydrate metabolism impairment was not systematically observed during short-term olanzapine administration.

This minireview deals with the possible roles of monoamines in feeding and feeding disorders. The introduction sketches the results of earlier studies with local drug injections and selective neurotoxins which provided pharmacological evidence that monoamines can influence food intake and body weight. A table summarizing this evidence is used to list monoamine changes that could underlie anorexia or hyperphagia. It is apparent that abnormalities in the monoamines, along with their cotransmitters, could cause many forms of feeding disorder. It is proposed as a working hypothesis that several varieties of hyperphagia leading to obesity have a common element. This common factor is a change in excitability of a lateral hypothalamic reinforcement system as manifested in self-stimulation at a stimulation-bound feeding site. Understanding this feeding reward-aversion system helps us understand hyperphagia and anorexia. The neurochemistry of reward and aversion involves the monoamines. This paper focuses on dopamine and serotonin. The data support the hypothesis that dopamine systems projecting to the nucleus accumbens and other forebrain areas from the mid-brain ventral tegmental area (VTA) are important for approach and positive reinforcement in ingestive behavior and self-stimulation. Serotonin is hypothesized to facilitate satiety and inhibition of feeding reward in the hypothalamus. The next section abstracts our recent experiments that measured pharmacological and physiological release of the monoamines in the hypothalamus and nucleus accumbens during ingestive behavior and self-stimulation. In vivo microdialysis in freely moving rats suggested the following: (1) Norepinephrine was released in the paraventricular nucleus during the active, feeding period of the circadian cycle. (2) The serotonin metabolite 5-HIAA also increased in the PVN at the same time if there was food to eat. (3) Amphetamine infused into the lateral hypothalamus (LH) by reverse dialysis increased synaptic dopamine, norepinephrine, and serotonin. (4) The anorectic drug d-fenfluramine increased synaptic serotonin in the LH and also increased the dopamine metabolite DOPAC, suggesting that serotonin and dopamine in the LH might contribute to fenfluramine-induced satiety. Local d-fenfluramine injection into the LH or local infusion by reverse dialysis again increased serotonin and decreased 5-HIAA and interfered with local dopamine metabolism as reflected in decreased DOPAC and HVA. (5) Tryptophan, a serotonin precursor, given systemically at an anorectic dose, increased extracellular serotonin in the LH, but this effect was only detectable in food-deprived rats. This was seemingly pH independent (between 5.8 and 8). The passage other cations through CFo is strictly suppressed (even at pH 8 and with 300 mM NaCl in the medium).(ABSTRACT TRUNCATED AT 400 WORDS)

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