Decreased brain reward produced by ethanol withdrawal.

Abstract

Abstinence (CNS) hyperexcitability that can result, in varying degrees of severity, in profound physiological disturbances such as tremors, hyperthermia, seizures, rigidity, hyperreflexia, and hallucinations and delirium (1-3). This constellation of withdrawal signs is largely unique to the sedative-hypnotics, and withdrawal from this class of drugs can be life-threatening. Other classes of drugs, such as opiates and psychostimulants, are associated with different withdrawal syndromes. The opiate withdrawal syndrome, which has been described as an intense "flu-like state," includes symptoms such as lacrimation, rhinorrhea, sweating, dilated pupils, gooseflesh, intestinal spasm, diarrhea, hyperthermia, anorexia/weight loss, and muscle spasms (2, 4). Withdrawal from chronic abuse of psychostimulants such as cocaine and amphetamines is associated with relatively minor somatic disturbances, including fatigue and suppressed heart rate, and is primarily characterized by more affective or emotional signs such as depression, dysphoria, and anxiety (2, 5). These differences in withdrawal symptomatology are not unexpected given the vastly different pharmacodynamic mechanisms of action of sedative/hypnotic, opiate, and psychomotor stimulant drugs and the unique neuroanatomical localization of receptors with which theseThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact. different drugs interact. However, there is some clinical evidence that chronic dependence and withdrawal from all three of these classes of abused drugs may share common symptomatology in the form of affective or emotional disturbances, such as irritability, restlessness, anxiety, and mood disturbances such as dysphoria, depression, and anhedonia (1, 2, 4-12). It has been shown in studies with rodents that ethanol, opiate, and psychostimulant withdrawal appear to produce a similar anxiety-like state (13).Furthermore, despite their distinct pharmacodynamic profiles, ethanol, opiates, and psychostimulants all share reinforcing or rewarding properties upon acute administration, which appear to involve activation of common reward circuits in the brain, including most notably the nucleus accumbens in the basal forebrain and its afferent connections from ventral midbrain (i.e., the ventral tegmental area) and limbic portions of the CNS (14-16).The symptoms of drug dependence have long been considered from the perspective of neuroadaptation theories. One such theory postulates that all positive reinforcers, including drugs of abuse, produce positive affective responses in the CNS that are opposed by negative affective responses as a natural consequence of an organism's propensity to maintain affective homeostasis (17-19). These negative affective consequences, which are hypothesized to be the consequence of neuroadaptations within the brain reward circuitry (17, 18), may upon termination of drug ad...

Withdrawal from Chronic Phencyclidine Treatment Induces Long-Lasting Depression in Brain Reward Function

“…We observed an overall longer-lasting elevation in brain reward threshold in animals withdrawn from either 15 or 20 mg/kg/day PCP compared to rats treated with 10 mg/ kg/day PCP or saline that was indicative of an enduring depression in brain reward function. This 1-month duration is unusual compared to the 1-to 7-day effect seen in rats withdrawn from chronic amphetamine (eg Leith and Barrett, 1976;Kokkinidis and Zacharko, 1980;Kokkinidis et al, 1986;Lin et al, 1999;Paterson et al, 2000), cocaine Koob, 1991, 1992a;Baldo et al, 1999), opiates (Schulteis et al, 1994), ethanol (Schulteis et al, 1995), and nicotine (Epping-Jordan et al, 1998;Harrison et al, 2001). Further, attempts to increase the duration of the effect of amphetamine and nicotine withdrawal on reward threshold using repeated withdrawal from continuous administration of these drugs were not successful (Paterson et al, 2000;Skjei and Markou, 2003).…”

“…An operational measure of this deficit in animals is the elevation in brain reward threshold observed during drug withdrawal that reflects diminished interest of the subjects in the rewarding electrical stimuli (Geyer and Markou, 1995). A deficit in brain reward function has been reported during withdrawal from amphetamine (eg Leith and Barrett, 1976;Kokkinidis and Zacharko, 1980;Kokkinidis et al, 1986;Lin et al, 1999;Paterson et al, 2000), cocaine Koob, 1991, 1992a;Baldo et al, 1999), opiates (Schulteis et al, 1994), ethanol (Schulteis et al, 1995), and nicotine (Epping-Jordan et al, 1998;Harrison et al, 2001). The aim of the present study was to characterize in rats the effects on brain stimulation reward of withdrawal from different PCP treatments.…”

Effects of NPY and the specific Y1 receptor agonist [d-His26]-NPY on the deficit in brain reward function and somatic signs associated with nicotine withdrawal in rats

“…Elevations in brain reward thresholds are mediated by a decrease in the positive reinforcing properties of pleasurable electrical stimuli and have been suggested to reflect an anhedonic-state . Elevations in brain reward thresholds have also been observed after the discontinuation of the administration of drugs of abuse such as amphetamine, fentanyl, and alcohol (Bruijnzeel et al, 2006;Schulteis et al, 1995;Wise and Munn, 1995). Antidepressant treatments, such as co-administration of the selective serotonin reuptake inhibitor fluoxetine and the serotonin-1A receptor antagonist p-MPPI ([4-(2'-methoxy-phenyl)-1-[2'-(n-(2"-pyridinyl)-p-iodobenzamido]-ethyl-piperazine]), partly prevent the elevations in brain reward thresholds associated with spontaneous nicotine withdrawal (Harrison et al, 2001).…”

“…The state of the brain reward system was investigated using a discrete-trial intracranial self-stimulation procedure. This procedure was used as it provides a quantitative measure of the emotional aspects of drug withdrawal (Bruijnzeel et al, 2006;Schulteis et al, 1995;Wise and Munn, 1995). The effect of [D-His 26 ]-NPY on nicotine withdrawal was investigated as this compound, in contrast to NPY, has a low affinity for the Y5 receptor (NPY, Ki of 0.28 nM for Y1, Ki of 1.5 nM for Y5; ]-NPY, Ki of 2.0 nM for Y1, Ki of 34.6 nM for Y5) (Mullins et al, 2001).…”

Fluoxetine Combined with a Serotonin-1A Receptor Antagonist Reversed Reward Deficits Observed during Nicotine and Amphetamine Withdrawal in Rats

“…Brain reward threshold elevation is an operational measure of this symptom because it reflects diminished sensitivity to rewarding electrical stimuli. In rats, withdrawal from drugs of abuse belonging to diverse pharmacological classes, such as nicotine (Epping-Jordan et al 1998;Watkins et al 2000b), amphetamine Zacharko 1980a, 1980b;Kokkinidis et al 1980Kokkinidis et al , 1986Barrett 1976, 1980;Lin et al 1999Lin et al , 2000Paterson et al 2000;Wise and Munn 1995), cocaine (Baldo et al 1999; Kokkinidis and McCarter 1990;Koob 1991, 1992a;Markou et al 1992) morphine (Schulteis et al 1994) and ethanol (Schulteis et al 1995) elevated brain stimulation reward thresholds.…”