Up to a third of North Americans report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human consumption are critical to study the impact of cannabis on brain and behaviour. Most animal studies to date utilize injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics. The current study directly examined if administration route (injection versus inhalation) alters metabolism and central accumulation of THC and metabolites over time. Adult male and female Sprague–Dawley rats received either an intraperitoneal injection or a 15-min session of inhaled exposure to THC. Blood and brains were collected at 15, 30, 60, 90 and 240-min post-exposure for analysis of THC and metabolites. Despite achieving comparable peak blood THC concentrations in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentration, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence of different pharmacokinetic profiles following inhalation versus injection. Accordingly, administration route should be considered during data interpretation, and translational animal work should strongly consider using inhalation models.
Oxytocin is a potent anorexigen and is believed to have a role in satiety signaling. We developed rat models to study the activity of oxytocin neurons in response to voluntary consumption or oral gavage of foods using c-Fos immunohistochemistry and in vivo electrophysiology. Using c-Fos expression as an indirect marker of neural activation, we showed that the percentage of magnocellular oxytocin neurons expressing c-Fos increased with voluntary consumption of sweetened condensed milk (SCM). To model the effect of food in the stomach, we gavaged anesthetized rats with SCM. The percentage of supraoptic nucleus and paraventricular nucleus magnocellular oxytocin-immunoreactive neurons expressing c-Fos increased with SCM gavage but not with gastric distention. To further examine the activity of the supraoptic nucleus, we made in vivo electrophysiological recordings from SON neurons, where anesthetized rats were gavaged with SCM or single cream. Pharmacologically identified oxytocin neurons responded to SCM gavage with a linear, proportional, and sustained increase in firing rate, but cream gavage resulted in a transient reduction in firing rate. Blood glucose increased after SCM gavage but not cream gavage. Plasma osmolarity and plasma sodium were unchanged throughout. We show that in response to high-sugar, but not high-fat, food in the stomach, there is an increase in the activity of oxytocin neurons. This does not appear to be a consequence of stomach distention or changes in osmotic pressure. Our data suggest that the presence of specific foods with different macronutrient profiles in the stomach differentially regulates the activity of oxytocin neurons.
Cannabis use during pregnancy has increased over the past few decades, with recent data indicating that, in youth and young adults especially, up to 22% of people report using cannabis during pregnancy. Animal models provide the ability to study prenatal cannabis exposure (PCE) with control over timing and dosage; however, these studies utilize both injection and inhalation approaches. While it is known that Δ9‐tetrahydrocannabinol (THC; primary psychoactive component of cannabis) can cross the placenta, examination of the transmission and concentration of THC and its metabolites from maternal blood into the placenta and fetal brain remains relatively unknown, and the influence of route of administration has never been examined. Pregnant female rats were exposed to either vaporized THC‐dominant cannabis extract for pulmonary consumption or subcutaneous injection of THC repeatedly during the gestational period. Maternal blood, placenta, and fetal brains were collected following the final administration of THC for analysis of THC and its metabolites, as well as endocannabinoid concentrations, through mass spectrometry. Both routes of administration resulted in the transmission of THC and its metabolites in placenta and fetal brain. Repeated exposure to inhaled THC vapor resulted in fetal brain THC concentrations that were about 30% of those seen in maternal blood, whereas repeated injections resulted in roughly equivalent concentrations of THC in maternal blood and fetal brain. Neither inhalation nor injection of THC during pregnancy altered fetal brain endocannabinoid concentrations. Our data provide the first characterization of maternal‐fetal transmission of THC and its metabolites following both vaporized delivery and injection routes of administration. These data are important to establish the maternal‐fetal transmission in preclinical injection and inhalation models of PCE and may provide insight into predicting fetal exposure in human studies.
The circulating orexigenic hormone ghrelin targets many brain areas involved in feeding control and signals via a dedicated receptor, the growth hormone secretagogue receptor 1A. One unexplored target area for ghrelin is the supramammillary nucleus (SuM), a hypothalamic area involved in motivation and reinforcement and also recently linked to metabolic control. Given that ghrelin binds to the SuM, we explored whether SuM cells respond to ghrelin and/or are activated when endogenous ghrelin levels are elevated. We found that peripheral ghrelin injection activates SuM cells in rats, reflected by an increase in the number of cells expressing c‐Fos protein in this area, as welll as by the predominantly excitatory response of single SuM cells recorded in in vivo electrophysiological studies. Further c‐Fos mapping studies reveal that this area is also activated in rats in situations when circulating ghrelin levels are known to be elevated: in food‐restricted rats anticipating the consumption of food and in fed rats anticipating the consumption of an energy‐dense food. We also show that intra‐SuM injection of ghrelin induces a feeding response in rats suggesting that, if peripheral ghrelin is able to access the SuM, it may have direct effects on this brain region. Collectively, our data demonstrate that the SuM is activated when peripheral ghrelin levels are high, further supporting the emerging role for this brain area in metabolic and feeding control.
The supramammillary nucleus (SuM) has an emerging role in appetite control. We have shown that the rat SuM is activated during hunger or food anticipation, or by ghrelin administration. In the present study, we characterised the connectivity between the SuM and key appetite‐ and motivation‐related nuclei in the rat. In adult wild‐type rats, or rats expressing Cre recombinase under the control of the tyrosine hydroxylase (TH) promoter (TH‐Cre rats), we used c‐Fos immunohistochemistry to visualise and correlate the activation of medial SuM (SuMM) with activation in the lateral hypothalamic area (LH), the dorsomedial hypothalamus (DMH) or the ventral tegmental area (VTA) after voluntary consumption of a high‐sugar, high‐fat food. To determine neuroanatomical connectivity, we used retrograde and anterograde tracing methods to specifically investigate the neuronal inputs and outputs of the SuMM. After consumption of the food there were positive correlations between c‐Fos expression in the SuMM and the LH, DMH and VTA (P = 0.0001, 0.01 and 0.004). Using Fluoro‐Ruby as a retrograde tracer, we demonstrate the existence of inputs from the LH, DMH, VTA and ventromedial hypothalamus (VMH) to the SuMM. The SuMM showed reciprocal inputs to the LH and DMH, and we identified a TH‐positive output from SuMM to DMH. We co‐labelled retrogradely‐labelled sections for TH in the VMH, or for TH, orexin and melanin‐concentrating hormone in the LH and DMH. However, we did not observe any colocalisation of immunoreactivity with any retrogradely‐labelled cells. Viral mapping in TH‐Cre rats confirms the existence of a reciprocal SuMM‐DMH connection and shows that TH‐positive cells project from the SuMM and VTA to the lateral septal area and cingulate cortex, respectively. These data provide evidence for the connectivity of the SuMM to brain regions involved in appetite control, and form the foundation for functional and behavioural studies aiming to further characterise the brain circuitry controlling eating behaviours.
Up to a third of North Americans over 16 years old report using cannabis in the prior month, most commonly through inhalation. Animal models that reflect human cannabis consumption are critical to study its impacts on brain and behaviour. Nevertheless, most animal studies to date examine effects of cannabis through injection of delta-9-tetrahydrocannabinol (THC; primary psychoactive component of cannabis). THC injections produce markedly different physiological and behavioural effects than inhalation, likely due to distinctive pharmacokinetics of each administration route. The current study directly examined if administration route (injection versus inhalation), with dosing being matched on peak THC blood levels, alters the metabolism of THC, and the central accumulation of THC and its metabolites over time. Adult male and female Sprague-Dawley rats received either a single intraperitoneal injection of THC (2.5 mg/kg) or a single (15 min) session of inhaled exposure to THC distillate (100 mg/mL) vapour. Blood and brains were collected at 15, 30, 60, 90 and 240 minutes post-exposure for analysis of THC and metabolites through mass spectrometry-liquid chromatography. Inhalation results in immediate hypothermia, whereas injection results in delayed hypothermia. Despite achieving comparable peak concentrations of blood THC in both groups, our results indicate higher initial brain THC concentration following inhalation, whereas injection resulted in dramatically higher 11-OH-THC concentrations, a potent THC metabolite, in blood and brain that increased over time. Our results provide evidence that THC and its metabolites exhibit different pharmacokinetic profiles following inhalation versus injection, which could have significant impacts for data interpretation and generalizability. Accordingly, we suggest that translational work in the realm of THC and cannabis strongly consider using inhalation models over those that employ injection.
ObjectiveEnergy intake is regulated by overlapping homeostatic and hedonic systems. Consumption of palatable foods has been implicated in weight gain, but this assumes that homeostatic control systems do not accurately detect this hedonically driven energy intake. This study tested this assumption, hypothesizing that satiated rats would reduce their voluntary food intake and maintain a stable body weight after consuming a palatable food.MethodsLean rats or rats previously exposed to an obesogenic diet were schedule‐fed with fixed or varying amounts of palatable sweetened condensed milk (SCM) daily, and their voluntary energy intake and body weight were monitored.ResultsDuring scheduled feeding of SCM, rats voluntarily reduced bland food consumption and maintained a stable body weight. This behavior was also seen in rats with access to an obesogenic diet and was independent of the predictability of SCM access. However, lean rats offered large amounts of SCM showed an increase in total energy intake. To test whether a nutrient deficiency drove this under‐compensatory behavior, SCM was enriched with protein. However, no effect was seen on voluntary energy intake.ConclusionsIn schedule‐fed rats, compensatory reductions in voluntary energy intake were seen, but under‐compensation was observed if large amounts of SCM were consumed.
| INTRODUC TI ONIn all animals, the transition between night and day engages a host of physiological and behavioural rhythms. A subset of retinal ganglion cells (RGCs) that express melanopsin detect the ambient light level, and they project to the suprachiasmatic nucleus (SCN) of the hypothalamus to entrain circadian rhythms that are generated within the SCN. [1][2][3][4] We have recently shown that a subpopulation of these RGCs express the neuropeptide vasopressin (VP-RGCs). The electrical activity of VP-RGCs is stimulated by light, and vasopressin concentrations in the SCN, measured by microdialysis in vivo, increase following light exposure. 5Vasopressin is also expressed in many neurones of the dorsomedial SCN shell and these have a critical role in maintaining circadian rhythms. 6 SCN vasopressin concentrations and the expression of vasopressin V1A receptors in the SCN are under circadian control 7,8 and transgenic mice deficient in vasopressin V1A receptors show dampened circadian rhythms in the absence of light cues. 8 Additionally, infusion of vasopressin V1 antagonists into the SCN speeds up re-entrainment of mice to a new light/dark cycle when the light phase is shifted experimentally. 9 The vasopressin cells in the SCN shell are not direct recipients of signals from the VP-RGCs; the projections from the retina innervate just the ventrolateral 'core' of the SCN, which contains neurones Abstract Physiological circadian rhythms are orchestrated by the hypothalamic suprachiasmatic nucleus (SCN). The activity of SCN cells is synchronised by environmental signals, including light information from retinal ganglion cells (RGCs). We recently described a population of vasopressin-expressing RGCs (VP-RGC) that send axonal projections to the SCN. To determine how these VP-RGCs influence the activity of cells in the SCN, we used optogenetic tools to specifically activate their axon terminals within the SCN. Rats were intravitreally injected with a recombinant adenoassociated virus to express the channelrhodopsin-2 and the red fluorescent protein mCherry under the vasopressin promoter (VP-ChR2mCherry). In vitro recordings in acute brain slices showed that approximately 30% of ventrolateral SCN cells responded to optogenetic stimulation with an increase in firing rate that progressively increased during the first 200 seconds of stimulation and which persisted after the end of stimulation. Finally, application of a vasopressin V1A receptor antagonist dampened the response to optogenetic stimulation. Our data suggest that optogenetic stimulation of VP-RGC axons within the SCN influences the activity of SCN cells in a vasopressin-dependent manner. K E Y W O R D S channelrhodopsin, optogenetics, retina, SCN, vasopressin
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