Dale M. Atrens

Metabolic effects of neuropeptide Y injections into the paraventricular nucleus of the hypothalamus

The metabolic effects of single injections of neuropeptide Y (NPY) into the paraventricular hypothalamus were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. Over the dose range of 10-156 pmol NPY had large effects on respiratory quotient (RQ) while having no effect on energy expenditure or locomotor activity. The effects of NPY on RQ were unusual both in respect to their dose-response and time-dose-response characteristics. The lowest dose (10 pmol) produced a very low latency reduction in RQ which indicates a decreased utilization of carbohydrates as an energy substrate. The next higher dose (20 pmol) had no effect, whereas the next three doses (39, 78 and 156 pmol) produced increases in RQ which indicate an increased utilization of carbohydrates as an energy substrate. Surprisingly, the latencies of the increased RQs were dose-dependent over the range of 30 min to 20 h with the highest dose producing the longest latency effect. The finding of a positive relation of dose to response latency over a time range of from a few minutes to 20 h is unprecedented and appears to represent a neuromodulatory effect of NPY that acts in concert with its neurotransmitter effects. These data highlight the central role of NPY in modulating energy substrate utilization and indicate the importance of elucidating time-dose-response relationships when investigating the effects of NPY.

Insulin and the paraventricular hypothalamus: modulation of energy balance

The effects of insulin injections (0.1, 1, 10 and 40 mU) into the paraventricular hypothalamus (PVN) were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. The 0.1 and 1 mU doses had no effects on either respiratory quotient or energy expenditure. The 10 mU dose increased respiratory quotient which indicates increased dependency on carbohydrates as an energy substrate. The same dose had no effects on thermogenesis. In contrast, the 40 mU dose decreased respiratory quotient which indicates increased dependency on fats as an energy substrate. The higher dose also increased thermogenesis. Since neither dose significantly affected locomotor activity, the metabolic data are not confounded with activity effects. These data indicate that insulin in the PVN produces a primary modulation of the metabolic parameters central to maintaining energy balance. In separate experiments, the 4 doses of insulin reduced food intake and body weight over a 24 h period. They also produced a dose-related increase in blood glucose concentration over a one hour period. Taken together, these findings are interpreted in a model in which insulin in the PVN acts as a signal indicating increased body fat. This increases thermogenesis, fat utilization and glycemic levels, and inhibits feeding. The net effect of this integrated metabolic-behavioural response is a regulatory reduction in body fat.

α-Noradrenergic modulation of hypothalamic self-stimulation: Studies employing clonidine, 1-phenylephrine and α-methyl-p-tyrosine

Abstract An α-noradrenergic substrate of rewarding intracranial stimulation (ICS) has been hypothesized based on the observation that the α-antagonist phentolamine produced an inhibition of self-stimulation. The present experiment investigated the effects on hypothalamic self-stimulation of the alpha agonist clonidine in normal and in catecholamine-depleted rats. Using a shuttle-box technique that provides a rate-independent index of the rewarding and aversive components of ICS, it was demonstrated that clonidine produces a dose-dependent inhibition of reward that is clearly dissociable from any non-specific effects of the drug. The ineffectiveness of the peripheral α-agonist 1-phenylephrine indicates that the inhibition of reward produced by clonidine is mediated centrally. Clonidine and the catecholamine synthesis inhibitor α-methyl-p-tyrosine act together in a synergistic manner to greatly increase the magnitude and prolong the duration of the inhibition of reward while leaving the aversive component unaffected. These data are interpreted as supporting an α-noradrenergic basis of ICS reward while indicating that the aversive component of ICS is essentially independent of noradrenergic transmission.

Metabolic effects of galanin injections into the paraventricular nucleus of the hypothalamus

The metabolic effects of single injections of galanin into the paraventricular nucleus of the hypothalamus (PVN) were investigated in an open-circuit calorimeter. Wistar rats were tested, with no food available during the tests. In the dose range of 0.03-0.3 nmol, galanin produced a very short-latency (approximately 2 minutes) and short-lasting (approximately 15 minutes) reduction in energy expenditure. Since the same doses had no effect on respiratory quotient or locomotor activity, the metabolic effect is not secondary to changes in energy substrate utilization or locomotor activity. This antithermogenic effect complements the eating stimulatory action of PVN galanin, and together these phenomena suggest a role for galanin as an anabolic neuropeptide. The similarity of galanins effects to those of norepinephrine, with which it coexists in PVN nerve endings, further suggests the involvement of this amine and the PVN alpha2-noradrenergic system in galanins mechanism of action.

5-hydroxytryptamine depletion with para-chlorophenylalanine: effects on eating, drinking, irritability, muricide, and copulation.

Forty-four male rats were tested for eating, drinking, irritability, and copulation before and after intraperitonial para-chlorophenylalanine (PCPA) or control injections. Eleven of these rats were tested for muricide before and after PCPA injections (Group 1), while 18 others were tested only after PCPA injections (Groups 2). Group 1 rats received four 350 mg/kg PCPA injections spaced 6 days apart and showed hyperdipsia, weight loss, and a 24% increase in muricide. Group 2 rats received five daily 100 mg/kg PCPA injections repeated 11 days later and showed hyperdipsia and weight loss; in addition, 78% of them killed mice. Neither group showed significant changes in copulation. At the end of the experiment, t6 rats from Group 2 that were irritable and killed mice were injected intraperitonially with 5-hydroxytryptophan (80 mg/kg). Five of these rats lost their irritability and four stopped killing. The various behavioral changes were not corrleated significantly either with each other or with the degree of 5-hydroxytryptamine depletion. This tentatively suggests that PCPA may produce its effects on behavior by other means in addition to 5-hydroxytryptamine depletion.

Modulation of reward and aversion processes in the rat diencephalon by neuroleptics: Differential effects of clozapine and haloperidol

The effects of clozapine and haloperidol on self-stimulation in rats were investigated in a shuttle-box that provides concurrent rate-independent indexes of the rewarding and aversive components of intracranial stimulation. The use of two concurrent measures of performance permits the differentiation of specific reward modulation effects from the variety of nonspecific performance decrements that these drugs may produce. Clozapine produced a dose-dependent reduction in reward that could be clearly dissociated from its nonspecific effects. In contrast, the apparent reduction in reward produced by haloperidol could not be dissociated from a nonspecific performance decrement. Consequently, the attenuation of self-stimulation produced by haloperidol does not indicate a direct role for dopamine in modulating reward. It is suggested that the attenuation of reward produced by neuroleptics reflects a reduction in noradrenergic transmission, whereas their nonspecific effects reflect their blockade of dopamine receptors.

The motivational properties of electrical stimulation of the medial and paraventricular hypothalamic nuclei

Abstract Rats with chronic electrodes implanted in various medial hypothalamic nuclei were tested for self-stimulation in a situation providing concurrent measures of reward and aversion. The subjects were also tested for stimulus-bound behaviors, rebound behavior and inhibition of deprivation-produced feeding. Stimulation at all sites produced both reward and aversion effects with the only notable anatomical specificity being that posterior paraventricular stimulation was highly rewarding and had the weakest aversion component yet found in the limbic system. These data suggest that the medial hypothalamus can no longer be considered to have a particularly important role in the neurological representation of aversion. The low probability of obtaining inhibition of feeding or rebound behaviors at any of the medial locations indicates that this zone of the hypothalamus is not a center for either satiety or behavior inhibition. Since stimulation was rewarding irrespective of whether a particular site produced elicitation or inhibition of feeding, feeding and reward must have different neurological substrates.

Effects of norepinephrine infused in the paraventricular hypothalamus on energy expenditure in the rat

The metabolic effects of norepinephrine (NE), when infused into the paraventricular nucleus of the hypothalamus (PVN), were examined using indirect calorimetry. In two separate experiments, it was found that NE infused into the PVN reduced energy expenditure in freely moving rats. While NE also reduced motor activity, these reductions were not statistically significant. Reductions in voluntary motor activity were not necessary for a reduction in energy expenditure, as NE still reduced energy expenditure in rats that were lightly sedated. Clonidine, but not L-phenylephrine, mimicked the hypometabolic effect of NE, suggesting an action at alpha 2 receptors. Infusions of NE were also found to increase blood glucose shortly after infusion, although the specificity of this effect is questionable. Taken together, these data suggest that activation of noradrenergic neurons within the PVN results in a metabolic shift towards energy conservation.

Metabolic effects of neuropeptide Y injected into the sulcal prefrontal cortex

The metabolic effects of 10, 39 and 156 pmol doses of neuropeptide Y (NPY) injected into the sulcal prefrontal cortex (SPC) were investigated in an open-circuit calorimeter. The 39 pmol dose produced a large and long lasting increase in respiratory quotient indicating both increased utilization of carbohydrate as an energy substrate and the synthesis of fat from carbohydrate. The 10 and 39 pmol doses produced an inhibition of energy expenditure that was still evident 24 hours following the 10, but not the 39 pmol, dose. These energy expenditure effects appeared to reflect an inhibition of thermogenesis as they were not systematically related to changes in locomotor activity. In separate tests, 39 pmol NPY reliably enhanced food intake. This combination of effects, namely increased carbohydrate utilization, fat synthesis and food intake with reduced energy expenditure, shows NPY to be a potent anabolic force. In addition, these results indicate both the functional significance of NPY at a cortical level and the important role of the SPC in the control of energy balance.

Serotonergic modulation of 3,4-methylenedioxymethamphetamine (MDMA)-elicited reduction of response rate but not rewarding threshold in accumbal self-stimulation

In a fixed interval 5-s rate-frequency function paradigm with rats, 3,4-methylenedioxymethamphetamine (MDMA; 0.5, 2 and 4 mg/kg) dose-dependently decreased response rate for nucleus accumbens self-stimulation while both D-amphetamine (0.3 and 1 mg/kg) and cocaine (5 and 15 mg /kg) increased response rates. The highest doses of MDMA caused a cessation of responding in many of the rats tested, but in those rats that continued to respond a significant reduction in frequency threshold for self-stimulation was seen. Cocaine and amphetamine dose-dependently reduced frequency threshold in all rats tested. The non-specific serotonin antagonist, methysergide (5 mg/kg), reversed the inhibitory effects of MDMA on response rates and caused all rats to respond following MDMA (4 mg/kg). Methysergide did not affect MDMAs threshold-lowering properties and when administered alone methysergide had not effect on self-stimulation. These results suggest serotonergic involvement in the performance but not reinforcement-modulating effect of MDMA in the self-stimulation paradigm.