Juan Agustin Escribano Rodriguez

Attenuation of cocaine-induced locomotor sensitization in rats sustaining genetic or pharmacologic antagonism of ghrelin receptors.

Systemic infusions of the orexigenic peptide ghrelin (GHR) increase dopamine levels within the nucleus accumbens and augment cocaine‐stimulated locomotion and conditioned place preference in rats; observations that suggest an important role for GHR and GHR receptors (GHR‐Rs) in drug reinforcement. In the present studies, we examined the development of cocaine locomotor sensitization in rats, sustaining either pharmacologic antagonism or genetic ablation of GHR‐Rs. In a pharmacologic study, adult male rats were injected (i.p.) with either 0, 3 or 6 mg/kg JMV 2959 (a GHR‐R1 receptor antagonist), and 20 minutes later, with either vehicle or 10 mg/kg cocaine HCl on each of 7 consecutive days. Rats pretreated with JMV 2959 showed significantly attenuated cocaine‐induced hyperlocomotion. In a second study, adult wild‐type (WT) or mutant rats sustaining ENU‐induced knockout of GHR‐R [GHR‐R (−/−)] received daily injections (i.p.) of vehicle (0.9% saline) or 10.0 mg/kg cocaine HCl for 14 successive days. GHR‐R null rats treated repeatedly with cocaine showed diminished development of cocaine locomotor sensitization relative to WT rats treated with cocaine. To verify the lack of GHR‐R function in the GHR‐R (−/−) rats, a separate feeding experiment was conducted in which WT rats, but not GHR‐R (−/−) rats, were noted to eat more after a systemic injection of 15 nmol GHR than after vehicle. These results suggest that GHR‐R activity is required for the induction of locomotor sensitization to cocaine and complement an emerging literature implicating central GHR systems in drug reward. GHR is an orexigenic gut peptide that is transported across the blood–brain barrier and interacts with GHR‐Rs located on ventral tegmental dopamine neurons.

Pharmacologic antagonism of ghrelin receptors attenuates development of nicotine induced locomotor sensitization in rats.

AIMS Ghrelin (GHR) is an orexigenic gut peptide that interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement circuits. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, whereas genetic or pharmacological ablation of GHR-Rs has been shown to attenuate the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and to blunt the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. A key issue is whether pharmacological antagonism of GHR-Rs would similarly attenuate nicotine-induced locomotor sensitization. METHOD To examine the role of GHR-Rs in the behavioral sensitizing effects of nicotine, adult male rats were injected with either 0, 3 or 6 mg/kg of the GHR-R receptor antagonist JMV 2959 (i.p.) and 20 min later with either vehicle or 0.4 mg/kg nicotine hydrogen tartrate (s.c.) on each of 7 consecutive days. RESULTS Rats treated with nicotine alone showed robust locomotor sensitization, whereas rats pretreated with JMV 2959 showed significantly attenuated nicotine-induced hyperlocomotion. CONCLUSIONS These results suggest that GHR-R activity is required for the induction of locomotor sensitization to nicotine and complement an emerging literature implicating central GHR systems in drug reward/reinforcement.

Brain reinforcement system function is ghrelin dependent: studies in the rat using pharmacological fMRI and intracranial self-stimulation.

Ghrelin (GHR) is an orexigenic gut peptide that interacts with brain ghrelin receptors (GHR‐Rs) to promote food intake. Recent research suggests that GHR acts as a modulator of motivated behavior, suggesting a direct influence of GHR on brain reinforcement circuits. In the present studies, we investigated the role of GHR and GHR‐Rs in brain reinforcement function. Pharmacological magnetic resonance imaging was used to spatially resolve the functional activation produced by systemic administration of an orexigenic GHR dose. The imaging data revealed a focal activation of a network of subcortical structures that comprise brain reinforcement circuits—ventral tegmental area, lateral hypothalamus and nucleus accumbens. We next analyzed whether brain reinforcement circuits require functional GHR‐Rs. To this purpose, wild‐type (WT) or mutant rats sustaining N‐ethyl‐N‐nitrosourea‐induced knockout of GHR‐Rs (GHR‐R null rats) were implanted with stimulating electrodes aimed at the lateral hypothalamus, shaped to respond for intracranial self‐stimulation (ICSS) and then tested using a rate‐frequency procedure to examine ICSS response patterns. WT rats were readily shaped using stimulation intensities of 75 µA, whereas GHR‐R null rats required 300 µA for ICSS shaping. No differences in rate‐frequency curves were noted for WT rats at 75 µA and GHR‐R null rats at 300 µA. When current intensity was lowered to 100 µA, GHR‐R null rats did not respond for ICSS. Taken collectively, these data suggest that systemic GHR can activate mesolimbic dopaminergic areas, and highlight a facilitative role of GHR‐Rs on the activity of brain reinforcement systems.

Ghrelin and ghrelin receptor modulation of psychostimulant action

Ghrelin (GHR) is an orexigenic gut peptide that modulates multiple homeostatic functions including gastric emptying, anxiety, stress, memory, feeding, and reinforcement. GHR is known to bind and activate growth-hormone secretagogue receptors (termed GHR-Rs). Of interest to our laboratory has been the assessment of the impact of GHR modulation of the locomotor activation and reward/reinforcement properties of psychostimulants such as cocaine and nicotine. Systemic GHR infusions augment cocaine stimulated locomotion and conditioned place preference (CPP) in rats, as does food restriction (FR) which elevates plasma ghrelin levels. Ghrelin enhancement of psychostimulant function may occur owing to a direct action on mesolimbic dopamine function or may reflect an indirect action of ghrelin on glucocorticoid pathways. Genomic or pharmacological ablation of GHR-Rs attenuates the acute locomotor-enhancing effects of nicotine, cocaine, amphetamine and alcohol and blunts the CPP induced by food, alcohol, amphetamine and cocaine in mice. The stimulant nicotine can induce CPP and like amphetamine and cocaine, repeated administration of nicotine induces locomotor sensitization in rats. Inactivation of ghrelin circuit function in rats by injection of a ghrelin receptor antagonist (e.g., JMV 2959) diminishes the development of nicotine-induced locomotor sensitization. These results suggest a key permissive role for GHR-R activity for the induction of locomotor sensitization to nicotine. Our finding that GHR-R null rats exhibit diminished patterns of responding for intracranial self-stimulation complements an emerging literature implicating central GHR circuits in drug reward/reinforcement. Finally, antagonism of GHR-Rs may represent a smoking cessation modality that not only blocks nicotine-induced reward but that also may limit weight gain after smoking cessation.

The GHR-R antagonist JMV 2959 neither induces malaise nor alters the malaise property of LiCl in the adult male rat

The orexigenic peptide ghrelin (GHR) interacts with ghrelin receptors (GHR-Rs) to modulate brain reinforcement and feeding circuits. Pharmacological inactivation of GHR-Rs via administration of the drug JMV 2959 attenuates the rewarding/reinforcing effects of several drugs of abuse including alcohol, morphine, amphetamine and nicotine. One view of these results is that inactivation of GHR-Rs taps into brain reinforcement/feeding circuits acted upon by drugs of abuse. An alternate explanation is that JMV 2959 may induce malaise, which in turn may limit reinforcement as well as food ingestion. This is a variable of interest given that nicotine alone can induce malaise which may be enhanced by JMV 2959. In the present study, we assessed the capacity of JMV 2959 to produce malaise using a conditioned taste aversion (CTA) task. Adult male rats were allowed to consume a 0.1% sodium saccharin solution and then injected IP with either vehicle, 0.4mg/kg nicotine, 3mg/kg JMV 2959, a combination of 0.4mg/kg nicotine and 3mg/kg JMV 2959, or 32mg/kg lithium chloride (a positive control known to support induction of CTA). Lithium chloride produced a robust avoidance of the saccharin solution in subsequent 2 bottle (water and saccharin) tests, whereas JMV 2959 alone did not induce CTA. The combination of JMV 2959 and nicotine induced a moderate degree of CTA that was similar to that produced by nicotine alone. These results suggest that JMV 2959 is unlikely to limit either reinforcement or food ingestion via induction of malaise.