Cross-Sensitization to Morphine in Cocaine-Sensitized Rats: Behavioral Assessments Correlate with Enhanced Responding of Ventral Pallidal Neurons to Morphine and Glutamate, with Diminished Effects of GABA

Abstract

Common neurobiological substrates contribute to the progressively increased behavioral effects (i.e., sensitization) that occur with repeated intermittent treatments of cocaine and morphine. Consequently, repeated exposure to cocaine can augment responding to morphine (termed cross-sensitization). Drug-induced sensitization in rats may model aspects of the dysfunction in motivation that are imposed by addiction. The ventral pallidum (VP) is involved in motivated behaviors and its function is altered by acute administration of cocaine and morphine, but the effects of repeated drug exposure remain unknown. Targeting this paucity, the present study evaluated electrophysiological changes in the VP of rats exposed to five once-daily cocaine treatments (15 mg/kg i.p.). This regimen also induced behavioral-sensitization that was expressed 3 days later when the rats received either an acute injection of cocaine (15 mg/kg i.p.) or morphine (10 mg/kg i.p.). VP neurons recorded in vivo 3 days after the repeated cocaine treatment regimen demonstrated increased excitatory responding to microiontophoretic applications of morphine and glutamate. The maximal effect (E max ) was increased without altering potency, suggesting a change in the functional efficacy of the respective receptor systems. This did not represent a potentiation in transmission in general, for the effects of GABA were diminished. The results provide the first evidence for cellular adaptation in the VP after a sensitizing drug treatment paradigm and reveal that crosssensitization of drug-induced behaviors temporally correlates with changes in VP neuronal responding. These findings advance an emerging theme that alterations in the VP may contribute to the increased motivation for drug seeking that occurs in drug-withdrawn addicts.

Clonidine attenuates morphine withdrawal and subsequent drug sensitization in rhesus monkeys

“…During the 21 d withdrawal period, a significant difference in heart rate (F [2,11] =4.722, P<0.05; Figure 1C) was observed in the 3 groups. Clonidine was found to increase the monkeys' heart rate in the first withdrawal week.…”

“…An injection of 5 mg/kg cocaine increased all the observed behaviors in the Mor-Sal group ( Figure 4B): locomotor activity (F [2,11] =8.941, P<0.01), vocalization (F [2,11] =7.364, P<0.01), grooming (F [2,11] =5.535, P<0.05), and irritability (F [2,11] =5.914, P<0.05). The monkeys that received clonidine treatment during the first week of morphine withdrawal showed significantly decreased vocalization compared with no clonidine treatment after morphine withdrawal (P<0.05, Mor-Clo vs Mor-Sal), and enhanced grooming performance compared with saline control (P<0.05, Sal-Clo vs Sal-Sal).…”

“…An injection of 5 mg/kg morphine caused a significant increase in locomotor activity (F [2,11] =29.9, P<0.01) and irritability (F [2,11] =24.8, P<0.01), but not in vocalization (F [2,11] = 1.445, P>0.05) and grooming (F [2,11] =1.445, P>0.05; Figure 4A). The monkeys naive to morphine (Sal-Sal) showed deceased locomotor activity and irritability, which may reflect the sedative effects of morphine [33][34][35] .…”

“…Effects of clonidine on morphine withdrawal signs During the 21 d withdrawal period, different weight loss trends was observed in the 3 groups (F [2,11] =3.341 P=0.074; Figure 1A). Most withdrawal signs were observed in the first week after cessation of morphine treatment; thus, the effects of clonidine on body weight were analyzed in the first, second, and third week separately.…”

“…Indeed, it has been shown that repeated morphine administration produces hypersensitivity to subsequent doses of morphine ("behavioral sensitization") and to other drugs of abuse ("cross-sensitization"). Sensitization and cross-sensitization have been extensively studied in rodents [9][10][11] , but there is little evidence for such phenomenon in primates. Since drug priming effectively reinstates extinguished drug self-administration behavior in animals [12][13][14] , it is likely that enhanced reactivity to the effects of drug of abuse may facilitate relapse in drug addicts.…”