Assessment of the impact of pattern of cocaine dosing schedule during conditioning and reconditioning on magnitude of cocaine CPP, extinction, and reinstatement.

RATIONALE AND OBJECTIVE: We sought to examine the impact of differing cocaine administration schedules and dosing on the magnitude of cocaine conditioned place preference (CPP), extinction, and stress- and cocaine-induced reinstatement of CPP. METHODS: First, in C57Bl/6J mice, we investigated whether total cocaine administration or pattern of drug exposure could influence the magnitude of cocaine CPP by conditioning mice with a fixed-low dose (FL; 7.5 mg/kg; total of 30 mg/kg), a fixed-high dose (FH; 16 mg/kg; total of 64 mg/kg), or an ascending dosing schedule (Asc; 2, 4, 8, and 16 mg/kg; total of 30 mg/kg). Next, we investigated if cocaine or saline is more effective at extinguishing preference by reconditioning mice with either a descending dosing schedule (Desc; 8, 4, 2, and 1 mg/kg) or saline. Finally, we examined if prior conditioning and reconditioning history alters stress (~2-3-min forced swim test) or cocaine-induced (3.5 mg/kg) reinstatement. RESULTS: We replicated and extended findings by Itzhak and Anderson (Addict. Biol. 17(4): 706-16, 2011) demonstrating that Asc conditioning produces a greater CPP than either the FL or FH conditioning schedules. The magnitude of extinction expressed was similar in the Desc reconditioned and saline groups. Moreover, only the saline, and not the Desc reconditioned mice, showed stress and cocaine-induced reinstatement of CPP. CONCLUSIONS: Our results suggest that the schedule of cocaine administration during conditioning and reconditioning can have a significant influence on the magnitude of CPP and extinction of preference and the ability of cocaine or a stressor to reinstate CPP.

Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis.

In vulnerable individuals, exposure to stressors can result in chronic disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). The extended amygdala is critically implicated in mediating acute and chronic stress responsivity and anxiety-like behaviors. The bed nucleus of the stria terminalis (BNST), a subregion of the extended amygdala, serves as a relay of corticolimbic information to the paraventricular nucleus of the hypothalamus (PVN) to directly influence the stress response. To investigate the influence of the corticosteroid milieu and housing conditions on BNST function, adult C57Bl/6J were either acutely or chronically administered corticosterone (CORT, 25mg/kg in sesame oil) or vehicle (sesame oil) or were group housed or socially isolated for 1 day (acute) or 6-8 weeks (chronic). To ascertain whether these stressors could influence anxiety-like behavior, studies were performed using the novel open-field (NOF) and the elevated zero maze (EZM) tests. To investigate potential associated changes in plasticity, alterations in BNST function were assessed using ex vivo extracellular field potential recordings in the (dorsal-lateral) dlBNST and a high frequency stimulus protocol to induce long-term potentiation (LTP). Our results suggest that chronic CORT injections and chronic social isolation housing conditions lead to an increase in anxiety-like behavior on the EZM and NOF. Chronically stressed mice also displayed a parallel blunting of LTP in the dlBNST. Conversely, acute social isolation housing had no effect on anxiety-like behavior but still resulted in a blunting of LTP in the dlBNST. Collectively, our results suggest acute and chronic stressors can have a distinct profile on plasticity in the BNST that is not uniformly associated with an increase in anxiety-like behavior.

Tachycardia, reduced vagal capacity, and age-dependent ventricular dysfunction arising from diminished expression of the presynaptic choline transporter.

Healthy cardiovascular function relies on a balanced and responsive integration of noradrenergic and cholinergic innervation of the heart. High-affinity choline uptake by cholinergic terminals is pivotal for efficient ACh production and release. To date, the cardiovascular impact of diminished choline transporter (CHT) expression has not been directly examined, largely due to the transporter's inaccessibility in vivo. Here, we describe findings from cardiovascular experiments using transgenic mice that bear a CHT genetic deficiency. Whereas CHT knockout (CHT(-/-)) mice exhibit early postnatal lethality, CHT heterozygous (CHT(+/-)) mice survive, grow, and reproduce normally and exhibit normal spontaneous behaviors. However, the CHT(+/-) mouse heart displays significantly reduced levels of high-affinity choline uptake accompanied by significantly reduced levels of ACh. Telemeterized recordings of cardiovascular function in these mice revealed tachycardia and hypertension at rest. After treadmill exercise, CHT(+/-) mice exhibited slower heart rate recovery, consistent with a diminished cholinergic reserve, a contention validated through direct vagal nerve stimulation. Echocardiographic and histological experiments revealed an age-dependent decrease in fractional shortening, increased left ventricular dimensions, and increased ventricular fibrosis, consistent with ventricular dysfunction. These cardiovascular phenotypes of CHT(+/-) mice encourage an evaluation of humans bearing reduced CHT expression for their resiliency in maintaining proper heart function as well as risk for cardiovascular disease.

Subbarrel patterns of thalamocortical innervation in rat somatosensory cortical barrels: Organization and postnatal development.

Barrel hollows in the posteromedial barrel subfield of adult rat somatosensory cortex typically encompass two or three metabolically and structurally distinct regions, termed subbarrels. We used immunohistochemical staining for vesicular glutamate transporter 2 and the neuronal serotonin transporter, in conjunction with cytochrome oxidase (CO) histochemistry, to investigate the distribution of thalamocortical (TC) axon terminals in relation to subbarrel domains. We found, first, that CO-dark subbarrels are more intensely immunoreactive for thalamocortical terminals than the CO-light clefts that separate them. Second, during the first postnatal week, immunoreactivity for markers of TC terminals is relatively homogeneous throughout the barrel hollow; subbarrel patterns of distribution only become recognizable between P-8 and P-10. These observations extend previous findings that subbarrels denote barrel regions enriched in synaptic contacts. The data also indicate that allocation of TC terminals into subbarrel domains does not occur immediately upon thalamic axon ingrowth. Instead, refinement of TC arbors into subbarrels is a gradual process, the outcome of which is not manifest until the second week of postnatal life.