Becky T. Davies

Caffeine exposure sensitizes rats to the reinforcing effects of cocaine

The present study examined the effect of pre-exposure to a moderate dose of caffeine (20 mg kg-1) on the acquisition of self-administration of cocaine (0.125 mg kg-1/infusion or 0.25 mg kg-1/infusion) in the rat. Rats pre-exposed to caffeine acquired self-administration more rapidly. Furthermore, sensitization to cocaines reinforcing effects was accompanied by an increase in the neurochemical response of the mesolimbic dopamine system to an acute injection of cocaine (10 mg kg-1, i.p.) as measured by in vivo microdialysis. Thus, the data suggest that exposure to caffeine can increase the reinforcing effects of cocaine, possibly via an enhanced response to the mesolimbic dopamine system.

Reversal of cirazoline- and phenylpropanolamine-induced anorexia by the α1-receptor antagonist prazosin

Phenylpropanolamine (PPA) is a phenethylamine anorectic drug that exerts direct agonist effects predominantly on alpha 1-adrenoceptors, with some alpha 2-adrenergic activity. Microinjections of PPA, as well as the alpha 1-adrenergic receptor agonists cirazoline, methoxamine, and 1-phenylephrine, into rat paraventricular nucleus (PVN) suppress feeding. The present study further evaluates the alpha 1-adrenergic basis of PPA-induced anorexia by examining the effects of systemic injections of the alpha 1-adrenergic antagonist prazosin (PRAZ, 2 and 5 mg/kg, IP) on the anorexia induced by systemic injections of PPA (5, 10, and 20 mg/kg, IP), as well as cirazoline (0.05, 0.1, and 0.2 mg/kg, IP). Although neither PRAZ dose alone altered food intake in the present study, 2 mg/kg PRAZ effectively reversed the feeding-suppressive effects of both PPA and cirazoline. These results strongly support the hypothesis that alpha 1-adrenoceptor stimulation mediates the anorexia induced by drugs such as PPA and cirazoline.

Reversal of phenylpropanolamine anorexia in rats by the alpha-1 receptor antagonist benoxathian.

Phenylpropanolamine (PPA) is a phenethylamine anorectic drug that exerts direct agonist effects predominantly on alpha-1 adrenergic receptors, with some alpha-2 adrenergic activity. Direct injections of PPA as well as the alpha-1 agonist 1-phenylephrine into rat paraventricular nucleus (PVN) suppress feeding. In the present study, we evaluate the hypothesis that systemic PPA acts within the PVN on an alpha-1 receptor population to suppress feeding. Accordingly, adult male rats were prepared with a unilateral guide cannula aimed at the PVN. Microinjection of the alpha-1 adrenergic receptor antagonist benoxathian (0, 2.5, 5.0 or 10.0 nmol) into the PVN was found to have no effect on baseline feeding behavior. Microinjection of 10.0 nmol benoxathian into the PVN completely reversed the anorexia induced by 2.5, 5.0 or 10.0 mg/kg PPA (IP), yet did not alter the hypodipsia produced by PPA. These data strongly suggest that PPA anorexia is mediated by an alpha-1 adrenergic satiety mechanism within the PVN.

Effects on ingestive behavior in rats of the α1-adrenoceptor agonist cirazoline

Abstract Microinjections of various α 1 -adrenoceptor agonists including phenylephrine and phenylpropanolamine into the paraventricular hypothalamic nucleus (PVN) suppress food intake in rats, suggesting that this receptor type might act in opposition to previously identified facilatory PVN α 2 -adrenoceptors in the modulation of feeding. In the present experiments, we examine the effects on food and water intake of intra-PVN as well as systemic injection of cirazoline, a highly potent α 1 -adrenoceptor agonist. In Experiment 1, intra-PVN microinjection of cirazoline (0, 3, 6, 12 and 24 nmol) suppressed food intake (ED 50 = 23.4 nmol) without significant effects on water intake. In Experiment 2, systemic injection of cirazoline (0, 0.05, 0.1, 0.2, 0.4 mg/kg) also markedly suppressed food intake (ED 50 = 0.05 mg/kg i.p.), with a less potent action on water intake (ED 50 = 0.22 mg/kg i.p.). The results of this study as well as our previous investigations strongly support the notion that α 1 -adrenoceptors within rat PVN act to reliably suppress food intake.

Effects of paraventricular hypothalamic microinjections of phenylpropanolamine and d-amphetamine on mash intake in rats ☆

The present experiment compared the effects of unilateral microinjections (40, 80 and 160 nmol/0.5 microliter) of phenylpropanolamine (PPA: d,l-norephedrine) and d-amphetamine sulfate within the paraventricular hypothalamus (PVN) on consumption of a palatable sweetened-mash diet in 15-hour food-deprived adult male rats. Intracranial microinjections were administered 5 minutes prior to each 30-minute feeding trial. PPA, at a dose of 160 nmol, suppressed feeding by 42%, whereas a similar dose of amphetamine suppressed feeding by 49%. Amphetamine or PPA doses of 40 and 80 nmol were without significant effect on feeding behavior. A relatively high dose of 160 nmol amphetamine was required to suppress feeding after injection into the PVN whereas much lower amphetamine concentrations are required to suppress feeding after injection into the perifornical hypothalamus. In contrast, PPA has some anorexic activity within the PVN but not within the perifornical hypothalamus.

Novel versus familiar ethanol: a comparison of aversive and rewarding properties.

Rats were given a series of the conditioning trials during which sucrose solution was paired with ethanol which had previously been experienced on 0, 3, or 9 occasions. On each conditioning trial, the rats received a Taste Reactivity Trial, a Taste Avoidance Trial, and a Place-Conditioning Trial. After the rats had received 4 conditioning trials, they were given a Conditioned Place Preference Test, a Taste Reactivity (TR) Test, and a Conditioned Aversion Extinction Test. Only the group conditioned with novel ethanol demonstrated aversive TR responses, although all CS + groups eventually demonstrated suppressed ingestive TR responses and enhanced neutral TR responses. Familiarization attenuated, but did not eliminate, ethanol-induced CTAs. There was no evidence of place conditioning.

An assessment of the involvement of paraventricular hypothalamic α2-adrenoceptors in phenylpropanolamine anorexia

Systemic injection of phenylpropanolamine (PPA), an alpha 1-adrenergic receptor agonist with some activity at alpha 2-adrenergic receptors, suppresses food intake in rats. However, only limited information is available as to the effect of intracranial PPA injections on food and water intake. In Experiment 1, microinjection of PPA (80-240 nM) into the hypothalamic paraventricular nucleus (PVN) induced a dose-dependent suppression of feeding (ED50 = 181 nM) but was without significant effect on water intake. Experiment 2 evaluated the effect of systemic PPA on paraventricular hypothalamic norepinephrine (NE) levels. Rats were treated with either vehicle or 20 mg/kg (IP) PPA prior to a 100-min period in which extracellular NE within the PVN was monitored via an indwelling microdialysis probe. Systemic injection of PPA suppressed extracellular NE level within PVN by approximately 70%, an action consistent with stimulation by PPA of a presynaptic alpha 2-adrenergic autoreceptor. Experiment 3 evaluated whether the alpha 2-adrenergic activity of PPA contributes to its feeding-suppressive action. Unlike prior results using the alpha 1-antagonist benoxathian, PVN microinjection of the alpha 2-antagonist rauwolscine in Experiment 3 of the present study failed to block systemically induced PPA anorexia. These results further support the contention that PVN alpha 1-adrenergic receptors suppress feeding and suggest that PPAs alpha 2-adrenergic effects do not modulate the anorexic action of PPA.

Microinjection of the α1-agonist methoxamine into the paraventricular hypothalamus induces anorexia in rats

Adrenergic receptors within the paraventricular hypothalamus (PVN) play a prominent role in the control of food intake: stimulation of alpha 2-adrenoceptors induces food intake whereas stimulation of alpha 1-adrenoceptors suppresses food intake. This study further examines the role of PVN alpha 1-adrenoceptors by examining the effects on food and water intake of the alpha 1-adrenergic agonist methoxamine (100, 200, 400 nMol) microinjected into the rat paraventricular hypothalamus. Methoxamine suppressed food intake but not water intake. Doses of 100, 200, and 400 nMol methoxamine suppressed food intake by 47%, 64%, and 96%, respectively. These results further confirm the hypothesis that administration of alpha 1-agonists into the PVN acts to significantly suppress food intake; an action that is in opposition to the facilitory effects of alpha 2-adrenergic agonists on food intake.

Conditioned taste reactivity in rats after phenylpropanolamine, d-amphetamine or lithium chloride

That an aversive property of phenylpropanolamine (PPA) in part contributes to its anorexic capacity is suggested by the demonstration of conditioned taste avoidance to PPA doses ranging from 10-40 mg/kg. In order to further evaluate the putative aversive property of PPA, the present experiment compared the effects of PPA on multiple measures of aversion (chin rubs, gaping) in the taste reactivity (TRT) paradigm with those produced by the classic agent lithium chloride and by amphetamine. Male rats were infused via an intraoral cannula with 0.5 M sucrose followed by injection with either vehicle, 127 mg/kg lithium chloride (LiCl), 1.5 or 3.0 mg/kg amphetamine or by 10, 20 or 40 mg/kg PPA. LiCl and 40 mg/kg PPA induced significant chin rub responses during conditioning but only the aversive response induced by 40 mg/kg PPA persisted during extinction trials. In contrast, lower doses of PPA (10 mg/kg, 20 mg/kg) were not aversive in the TRT paradigm. These results suggest that an aversive component is not contributing to anorexia induced by PPA within the dose range of 10-20 mg/kg, but that higher doses may further suppress appetite via an aversive action.

Effects of the α1-adrenergic agonist cirazoline on locomotion and brown adipose tissue thermogenesis in the rat

Anorexia is induced by injection of alpha 1-adrenergic receptor agonists into the hypothalamic paraventricular nucleus (PVN) in rats. Of the agonists tested to date, cirazoline is the most potent when administered either into the PVN or systemically. The present experiments assess the effects of systemically administered cirazoline, at doses that suppress food intake, on dopamine and norepinephrine systems as evident in locomotion and stereotypy and in the induction of brown adipose tissue (BAT) thermogenesis. In Experiment 1, adult male rats were treated with either vehicle (0) or 0.05, 0.1, 0.2 or 0.4 mg/kg cirazoline (IP) prior to 30 minutes assessment of horizontal and vertical locomotion and stereotypy in Omnitech activity chambers. Horizontal activity and stereotypy were significantly suppressed at 0.05 mg/kg cirazoline but these effects waned at higher cirazoline doses. In Experiment 2, interscapular BAT temperature in adult male rats was monitored for 30 minutes after injection (IP) of either vehicle or 0.4 mg/kg cirazoline. Cirazoline, at 0.4 mg/kg did not influence BAT temperature whereas a positive control treatment (phenylpropanolamine: 40 mg/kg) rapidly increased BAT temperature during a 15 minute period after injection. These results suggest that cirazoline-induced anorexia is not the result of competing motor responses and that this drug, at a dose that produces maximal suppression of feeding, does not alter BAT thermogenesis.