Effects of Short-Term Abstinence from Escalating Doses of D-Amphetamine on Drug and Sucrose-Evoked Dopamine Efflux in the Rat Nucleus Accumbens

Abstract

Abstinence from high doses of psychostimulant drugs, in both humans and rodents, is linked to adverse psychological effects including anhedonia, a core symptom of major depression, manifested behaviorally as decreased responding for rewarding stimuli. The present study used brain microdialysis in freely moving rats to examine the effect of D-amphetamine (D-amph) withdrawal on changes in extracellular dopamine (DA) levels in the nucleus accumbens (NAc) evoked by D-amph or behavior related to sucrose consumption. D-amph was administered intraperitoneally (i.p.) according to an escalating dose (ED) schedule (from 1 to 10 mg/kg, 3 doses/day). We first confirmed the development of tolerance by monitoring DA efflux in the NAc in response to 5 and 10 mg/kg doses of D-amph administered during the ED schedule of drug administration and again in response to the 5 mg/kg dose of D-amph 72 h following the last 10 mg/kg D-amph injection. In a separate study, DA efflux in the NAc was first shown to be increased significantly during both preparatory and consummatory phases of responding for a 4% sucrose solution. Withdrawal from the ED schedule of D-amph caused a selective attenuation of DA efflux only during the preparatory phase of the sucrose test. These results provided convincing evidence of neurochemical adaptation within the mesocorticolimbic DA pathway during and following the administration of an ED schedule of D-amph as well as suppressed neurochemical responses to a psychostimulant drug and cues associated with a natural reward after withdrawal from drug treatment. Accordingly, these findings support the hypothesis that downregulation of mesocorticolimbic DA function maintained during D-amph withdrawal may account for the selective disruption of motivated behavior reported in studies employing psychostimulant drug withdrawal as a model of depression in rodents. Neuropsychopharmacology (2007) 32, 932-939.

Human Methamphetamine Pharmacokinetics Simulated in the Rat: Behavioral and Neurochemical Effects of a 72-h Binge

“…This diminished locomotor responsivity may be analogous to the psychostimulant withdrawal syndrome, or “crash,” following cessation of drug intake in humans ( Gawin and Kleber, 1986 ; Srisurapanont et al, 1999 ; Kampman et al, 2000 ). Anhedonia is a symptom frequently linked to stimulant withdrawal ( Gawin and Kleber, 1986 ), and preclinical studies suggest that stimulant withdrawal is associated with an attenuated mesoaccumbens dopamine response to both amphetamine and sucrose reward ( Vacca et al, 2007 ). The decreased locomotor response we observed to the METH challenge during withdrawal following the binge may similarly be mediated by diminished accumbens dopamine responsivity.…”

Prior Exposure to Salient Win-Paired Cues in a Rat Gambling Task Increases Sensitivity to Cocaine Self-Administration and Suppresses Dopamine Efflux in Nucleus Accumbens: Support for the Reward Deficiency Hypothesis of Addiction

“…Twenty-eight animals underwent aseptic stereotaxic surgery. As per previous work (Vacca et al, 2007), animals were bilaterally implanted with 15 mm 19 gauge nitric acid passivated stainless-steel guide cannulae above the NAc (from bregma 1.7 mm anterior and Ϯ1.1 mm lateral; from dura Ϫ1.0 mm ventral) (Paxinos and Watson, 1998), secured via skull screws and dental cement. Stainless-steel obdurators (15 mm) maintained patency of the guides until probe implantation.…”

The α2 adrenergic receptor antagonist idazoxan, but not the serotonin-2A receptor antagonist M100907, partially attenuated reward deficits associated with nicotine, but not amphetamine, withdrawal in rats

“…Psychostimulant, including nicotine, withdrawal has been associated with decreases in dopaminergic and serotonergic neurotransmission in the nucleus accumbens (Parsons et al, 1991b; a; Parsons et al, 1995; Fung et al, 1996; Parsons et al, 1996; Hildebrand et al, 1998; Hildebrand et al, 1999; Nomikos et al, 1999; Carboni et al, 2000; Hildebrand and Svensson, 2000; Rada et al, 2001; Rahman et al, 2004; Vacca et al, 2007). The partial effectiveness of idazoxan in attenuating nicotine withdrawal may be attributed to idazoxan-induced increase in dopamine (Hertel et al, 1999b) and serotonin (Garratt et al, 1991; Matsumoto et al, 1998) release in the medial prefrontal cortex, but not in the nucleus accumbens (Hertel et al, 1999b).…”