Dissociation in control of physiological and behavioral responses to emotional stress by cholinergic neurotransmission in the bed nucleus of the stria terminalis in rats.

The bed nucleus of the stria terminalis (BNST) is a forebrain structure implicated in physiological and behavioral responses to emotional stress. However, the local neurochemical mechanisms mediating the BNST control of stress responses are not fully known. Here, we investigated the involvement of BNST cholinergic neurotransmission, acting via muscarinic receptors, in cardiovascular (increase in blood pressure and heart rate and fall in tail skin temperature) and neuroendocrine (increase in plasma corticosterone) responses and behavioral consequences (anxiogenic-like effect in the elevated plus-maze) evoked by acute restraint stress in rats. Bilateral microinjection into the BNST of either the choline uptake inhibitor hemicholinium-3 (3 nmol/100 nl) or the muscarinic receptor antagonist methylatropine (3 nmol/100 nl) enhanced the heart rate increase and inhibited the anxiogenic-like effect observed in the elevated plus-maze evoked by restraint. However, neither hemicholinium-3 nor methylatropine affected the increase in blood pressure and plasma corticosterone levels and the fall in tail skin temperature. Facilitation of local cholinergic signaling by microinjection of the acetylcholinesterase inhibitor neostigmine (0.1 nmol/100 nl) into the BNST reduced restraint-evoked pressor and tachycardiac responses and the fall in tail cutaneous temperature, without affecting the increase in plasma corticosterone. All effects of neostigmine were completely abolished by local BNST pretreatment with methylatropine. These findings indicate an opposite role of BNST cholinergic neurotransmission, acting via local muscarinic receptor, in control of cardiovascular responses (inhibitory influence) and emotional consequences (facilitatory influence) evoked by restraint stress. Furthermore, present findings provide evidence that BNST control of neuroendocrine responses to stress is mediated by mechanisms others than local cholinergic signaling.

Prevention of social stress-escalated cocaine self-administration by CRF-R1 antagonist in the rat VTA.

RATIONALE: Intermittent exposure to social defeat stress can induce long-term neural plasticity that may influence escalated cocaine-taking behavior. Stressful encounters can lead to activation of dopamine neurons in the ventral tegmental area (VTA), which are modulated by corticotropin releasing factor (CRF) neurons. OBJECTIVE: The study aims to prevent the effects of intermittently scheduled, brief social defeat stress on subsequent intravenous (IV) cocaine self-administration by pretreatment with a CRF receptor subtype 1 (CRF-R1) antagonist. MATERIALS AND METHODS: Long-Evans rats were submitted to four intermittent social defeat experiences separated by 72 h over 10 days. Two experiments examined systemic or intra-VTA antagonism of CRF-R1 subtype during stress on the later expression of locomotor sensitization and cocaine self-administration during fixed (0.75 mg/kg/infusion) and progressive ratio schedules of reinforcement (0.3 mg/kg/infusion), including a continuous 24-h "binge" (0.3 mg/kg/infusion). RESULTS: Pretreatment with a CRF-R1 antagonist, CP 154,526, (20 mg/kg i.p.) prior to each social defeat episode prevented the development of stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h "binge". In addition, pretreatment with a CRF-R1 antagonist (0.3 µg/0.5 µl/side) into the VTA prior to each social defeat episode prevented stress-induced locomotor sensitization to a cocaine challenge and prevented escalated cocaine self-administration during a 24-h "binge". CONCLUSIONS: The current results suggest that CRF-R1 subtype in the VTA is critically involved in the development of stress-induced locomotor sensitization which may contribute to escalated cocaine self-administration during continuous access in a 24-h "binge".