Development Of Behavioral Sensitization Research Articles

Repeated amphetamine administration induces a prolonged augmentation of phosphorylated cyclase response element-binding protein and Fos-related antigen immunoreactivity in rat striatum

Semi-quantitative immunocytochemistry was used to investigate the levels of cyclase response element-binding protein, phosphorylated cyclase response element-binding protein, Fos and Fos-related antigen immunoreactivity in the striatum of rats after acute or repeated amphetamine administration. Rats were perfused 20 min (phosphorylated cyclase response element-binding protein) or 2 h (cyclase response element-binding protein, phosphorylated cyclase response element-binding protein, Fos, Fos-related antigen) after a single injection (5 mg/kg, i.p.) or five daily injections of amphetamine. The latency to onset of stereotypical behaviors was significantly reduced in rats exposed to repeated amphetamine as compared to acute amphetamine, indicating development of behavioral sensitization. Cyclase response element-binding protein immunoreactivity was not altered in the dorsal or ventral striatum following acute or repeated amphetamine. Phosphorylated cyclase response element-binding protein immunoreactivity was significantly induced 20 min, but not 2 h, following acute amphetamine, whereas a significant induction of phosphorylated cyclase response element-binding protein immunoreactivity was found 20 min and 2 h after repeated amphetamine in the dorsal striatum only. Fos immunoreactivity was significantly induced in the dorsal striatum following acute and repeated amphetamine. Fos immunoreactivity in the core of the nucleus accumbens was significantly increased following repeated amphetamine only. Acute amphetamine induced, and repeated amphetamine further augmented, Fos-related antigen immunoreactivity in the dorsal striatum, while not affecting Fos-related antigen immunoreactivity in the nucleus accumbens. These data demonstrate that repeated amphetamine administration results in a prolonged induction of phosphorylated cyclase response element-binding protein and Fos-related antigen immunoreactivity in the dorsal striatum, indicating that alterations in striatal gene expression associated with the development of behavioral sensitization may be mediated, in part, by these transcription factors.

A glutamatergic hypothesis of drug dependence

This article explores some of the data available on processes underlying dependence and withdrawal following chronic treatment with substances acting at GABA(A) receptors. It is argued that adaptations arising from chronic treatment with benzodiazepines (BZs) and ethanol, on the one hand, and inverse agonists at BZ receptors, on the other, cannot be explained by changes primarily in GABAergic systems, and that compensatory changes in glutamatergic transmission account at least partially for tolerance to, and dependence on, BZs and ethanol. The literature on ethanol dependence also points to sensitisation following repeated withdrawals (i.e. increasing intensity of certain withdrawal symptoms and signs) as a potentially important factor in ethanol dependence. It is predicted that a similar sensitisation may also result from repeated BZ withdrawal. In the case of ethanol, this kindling-like process is also dependent on glutamatergic neurotransmission. Parallels are drawn between changes underlying the increase in sensitivity to repeated withdrawal and kindling to BZ receptor inverse agonists. The involvement of glutamatergic mechanisms in the development of tolerance to and dependence on other abused drugs is also explored. The role of glutamate in the development of behavioural sensitisation to psychomotor stimulants and other abused drugs is addressed, and the possibility raised that similar processes may be involved in both behavioural sensitisation and withdrawal sensitisation.

Scopolamine prevents the development of sensitization to methamphetamine.

The cholinergic neurotransmission has been implicated in various forms of neural plasticity such as kindling and learning. The present study examined the effects of scopolamine, a muscarinic cholinergic antagonist, on the development of behavioral sensitization to methamphetamine (MA). Rats treated with MA (1 mg/kg, sc) for 10 days indicated significantly enhanced motor activity when tested with MA (0.5 mg/kg) after a 7-8 day withdrawal, indicating the development of behavioral sensitization. Pretreatment with scopolamine (3 mg/kg) prior to MA administration prevented the development of the phenomenon. Rats treated with scopolamine alone showed no difference in the motor activity compared to those treated with saline. These results suggest that stimulation of muscarinic cholinergic receptors plays a role in the development of behavioral sensitization.

NMDA antagonist effects on the development of L-dopa behavioral sensitization in rats.

This study, which used an animal model of Parkinsonism, evaluated whether the NMDA antagonist MK-801 can prevent the development of L-3-4-dihydroxyphenylalanine (L-DOPA) sensitization. In separate groups, rats with unilateral 6-hydroxydopamine (6-OHDA) lesions were treated with saline, 25 mg/kg L-DOPA methyl ester, 0.1 mg/kg MK-801, or MK-801 plus L-DOPA once per day for 13 days beginning 18 to 20 hr postoperatively, well before the onset of denervation supersensitivity. Following 14 days of withdrawal, all treatment groups were given a saline test and on the next day, an L-DOPA challenge test. Contralateral rotation, the behavioral index of denervation supersensitivity, emerged on Day 7 in both L-DOPA groups. However, on the L-DOPA challenge test, only the L-DOPA group showed enhanced contralateral rotations compared with a drug-naive group. In contrast, the MK-801 and MK-801/L-DOPA groups were indistinguishable from the drug-naive L-DOPA-treated rats. These findings indicate that although MK-801 treatment did not prevent the development of behavioral sensitization to the L-DOPA treatment, it did prevent its persistence following drug withdrawal.

Sensitization to cocaine's motor activating properties produced by electrical kindling of the medial prefrontal cortex but not of the hippocampus

A substantial body of evidence has accumulated that implicates NMDA systems in the neural changes that are associated with the development of both electrical kindling of limbic sites and sensitization to the behavioral effects of repeated stimulant exposure. This study sought to establish whether electrical kindling of the brain was a sufficient condition for inducing sensitization to cocaine's motor activating effects and, if so, whether the cross sensitization was a result of kindling of a specific locus. Rats received daily electrical stimulation of either the medial prefrontal cortex or the hippocampus. Other rats received the electrode implants and were handled daily but received no electrical stimulation. Stage 5 seizures developed in response to the stimulation in 32–35 days. Once this criterion of kindling was established and following a 14 day waiting period the effectiveness of cocaine (0.0, 5.0 or 10.0 mg/kg) in elevating horizontal motor activity was determined. For all 3 groups (sham controls, prefrontal cortical and hippocampal stimulated rats) cocaine produced a dose-dependent increase in horizontal activity. The slam controls and hippocampal rats did not differ in the magnitude of the cocaine-produced effect. However, rats that had received stimulation of the prefrontal cortex showed heightened levels of cocaine-induced activity that were particularly apparent in response to 10.0 mg/kg cocaine. These data suggest that kindling of the prefrontal cortex had sensitized rats to the behavioral effects of cocaine. Since the NMDA system has been implicated in both electrical kindling and sensitization produced by repeated stimulant exposures it is possible that the development of behavioral sensitization is a result of increased sensitivity of specific glutamatergic inputs that arise from a prefrontal cortical substrate and project to cocaine-sensitive sites.

Dynamics of behavioral sensitization induced by the dopamine agonist quinpirole and a proposed central energy control mechanism

The study characterizes the process of sensitization induced by intermittent administrations of quinpirole (0.5 mg/kg) in rats in a large open field. Sensitization was found to be self-limiting, with all measures of behavior reaching a plateau after the tenth twice-weekly injection. Kinetics of sensitization were a simple hyperbolic function of the number of drug injections for some measures (speed of locomotion, length of locomotor bouts) but showed positive co-operativity for others (distance travelled, duration of locomotion, frequency of stops, route stereotypy), suggesting potentiation of the effect by preceding injections. The pace of sensitization varied for different behaviors: locomotor speed changed fastest in the early portion of chronic treatment; stereotypy of route changed primarily during the late phase; mouthing did not sensitize. Sensitization evolved by a cascade of changes that included: advancing the onset of locomotor activation; prolonging the duration of locomotion; establishing new maxima of observable responses; altering the mode of locomotion; raising speed, rate and length of locomotor bouts; and increasing stereotypy of travel. These observations do not substantiate the prediction that development of behavioral sensitization is associated with emergence of disorganized activity and/or fractionation of response chains. Instead, it is proposed that development of sensitization may represent a build-up and strengthening of performance, reflecting enhanced central control of energy expenditure stimulated by repeated injections of quinpirole. Furthermore, it is suggested that for at least one response, the maximum observable amount of locomotion, development of sensitization requires only D2 stimulation, independent of D1 tone.

Time course of extracellular dopamine and behavioral sensitization to cocaine. I. Dopamine axon terminals

Repeated administration of cocaine to rodents produces a progressive augmentation in motor activity known as behavioral sensitization. By using microdialysis in the ventral striatum, some studies have found that the development of behavioral sensitization is associated with a similar augmentation in dopamine release, while others have not. It was postulated that differences in doses and withdrawal periods may account for the discrepancies between studies. Rats were behaviorally sensitized to daily peripheral injections using two cocaine treatment regimens (15 mg/kg, i.p. x 5 d or 30 mg/kg, i.p. x 5 d). Using in vivo microdialysis in the ventral striatum, the effect of acute cocaine (15 mg/kg, i.p.) on extracellular dopamine content and motor behavior was examined at various times after discontinuing daily treatments. Twenty-four hours after discontinuing the low dose of daily cocaine, the increase in motor activity and extracellular dopamine elicited by an acute cocaine challenge was significantly elevated. In contrast, following the higher daily treatment regimen there was a significant augmentation in motor activity, but the increase in extracellular dopamine produced by cocaine was significantly reduced. When rats were challenged 10-14 d after discontinuing either dosage regimen of daily cocaine, the increase in both motor activity and extracellular dopamine was augmented. In general, the increase in extracellular dopamine by an acute cocaine challenge increased over time when rats were challenged between 1 and 22 d after discontinuing daily cocaine. Basal concentrations of extracellular dopamine were determined by measuring the in vivo flux of dopamine across the dialysis membrane, and there was no significant difference at 24 hr or 2 weeks following the last daily injection of saline or cocaine. It is concluded that behavioral sensitization to cocaine is generally associated with an augmentation in extracellular dopamine in the ventral striatum, but that high doses of daily cocaine produce apparent tolerance to the augmentation in extracellular dopamine during the early withdrawal period.

Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding.

Repeated cocaine intoxication can result in the development of behavioral sensitization in animals and psychosis in humans, phenomena that have been associated with alterations in dopamine (DA) function. Using electrophysiologic and autoradiographic techniques, modifications of central serotonin (5-hydroxytryptamine; 5-HT) systems were investigated in rats treated with a regimen of cocaine administration that produced behavioral sensitization. The inhibitory response of single 5-HT neurons in the dorsal raphe (DR) to (-)-cocaine, the 5-HT uptake inhibitor fluoxetine or the 5-HT1A agonist 8-hydroxy-2-[di-N-propylamino]tetralin (8-OHDPAT) was significantly enhanced in cocaine-treated rats. Furthermore, several brain areas that contain either cell bodies (DR) or terminals for 5-HT (medial and sulcal prefrontal cortex, frontal cortex) showed cocaine-induced elevations in [3H]imipramine-labeled 5-HT uptake sites, while [3H]-8-OHDPAT-labeled 5-HT1A receptors were decreased only in the central medial amygdala. These results suggest that modifications of autoregulatory mechanisms secondary to alterations of 5-HT uptake processes may contribute to the development of cocaine sensitization.

Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey

In order to determine if repeated injections of cocaine produced long-lasting alterations in catecholaminergic binding sites, rhesus monkeys were treated with saline (1.0 ml/15 kg) or cocaine (3.0–4.0 mg/kg) four times daily for 14 consecutive days and sacrified two weeks after the last injection. The densities of dopamine D 1 receptor binding sites, dopamine transporter binding sites and β adrenergic receptor binding sites were significantly decreased in caudate nucleus to 51%, 17% and 61% of control, respectively, two weeks after repeated cocaine injections. There were no differences in D 2 receptor binding site densities in the caudate, nor were there differences in binding sites between groups in the other brain regions examined: prefrontal cortex (D 1, D 2, dopamine transporter, β), nucleus accumbens (D 1, D 2, dopamine transporter) and substantia nigra (D 2). Behavioral observation showed that the cocaine-treated monkeys became sensitized to the repeated injections. Early in the regimen, these animals displayed stereotypic grooming, buccal movements and visual checking after each injection that differed significantly from the saline-treated animals. As the regimen progressed, the frequency of grooming decreased while the frequencies of visual tracking and splayed legs increased in a manner consistent with the development of behavioral sensitization. Together, these findings suggest that the caudate nucleus may be more sensitive than other dopamine-containing brain regions to long-lasting pre- and post-synaptic effects of repeated cocaine administration, and that the changes seen in dopaminergic neurons may be related to behavioral sensitization.

Possible role for G-proteins in behavioral sensitization to cocaine

The role of G-proteins in behavioral sensitization to cocaine was examined by injecting pertussis toxin (PTX) into the A10 dopamine cell group. The capacity of acute cocaine to increase motor activity and dopamine release in the nucleus accumbens was significantly augmented in rats pretreated 14 days earlier with PTX. These data suggest that injection of PTX into the A10 dopamine cell group produces a long-term alteration in mesolimbic dopamine function, and implicates A10 dopamine neurons and G-proteins in the development of behavioral sensitization.

Effects of chronic methamphetamine treatment on the binding parameters of [ 3H]SCH 23390, a selective D 1-dopamine receptor ligand, in the rat brain

Following the determination of the binding characteristics of [ 3H]SCH 23390 using slide-mounted tissue sections of molded minced forebrain, the effects of chronic methamphetamine (MAP) treatment (at a dose of 4 mg/kg for 14 days) on D 1 receptors in the rat brain were studied using quantitative receptor autoradiography. There were no differences in both Kd(app) and Bmax values between vehicle- and MAP-treated rats, indicating that D 1 receptors might not be involved in the development of behavioral sensitization in chronically MAP-treated rats.

Possible involvement of supersensitivity in cerebral β-adrenergic and dopaminergic receptors in the occurrence of sensitization to d-methamphetamine in mice

Behavioral sensitization of mice (male STD-ddy) to d-methamphetamine (MAP) and its correlation with the neurochemical alterations in cerebral catecholaminergic systems were investigated following the repeated administration of MAP (5 mg/kg, i.p. x 2/day, 5 days). MAP-pretreated mice showed an enhancement in MAP-stimulated locomotor activity following the readministration of MAP (0.625 mg/kg). The metabolic turnovers of cerebral norepinephrine (NE) and dopamine (DA) showed a significant decrease in these sensitized mice. The activities of tyrosine hydroxylase. DOPA decarboxylase, monoamine oxidase and catechol-O-methyltransferase, however, showed no change under the same experimental conditions. On the other hand, the repeated MAP pretreatment induced the enhancement of the specific bindings of [(3)H]dihydroalprenolol and [(3)H]spiperone to cerebral synaptic membrane, which resulted from the increase of B(max) values. Furthermore, pretreatments of mice with propranolol (10 mg/kg) and haloperidol (0.1 mg/kg) inhibited the development of behavioral sensitization to MAP. These results suggest that the supersensitivity in cerebral ?-adrenergic and dopaminergic receptors may be involved in behavioral sensitization to MAP.

Continuous and intermittent levodopa differentially affect basal ganglia function.

The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.

The cellular analog of sensitization in Aplysia emerges at the same time in development as behavioral sensitization

Recent studies examining the development of learning and memory in the gill and siphon withdrawal reflex of Aplysia have shown that different forms of learning emerge according to very different developmental timetables. For example, in the previous paper, Rankin and Carew (1988) showed that, whereas habituation and dishabituation emerge early in juvenile development (in stages 9 and 10, respectively), sensitization emerges at least 60 d later (in late stage 12). This developmental separation of different learning processes provides the opportunity to examine the unique contribution of specific cellular mechanisms to each form of learning. As a first step in this cellular analysis, in the present paper we have examined the development of the cellular analog of sensitization (facilitation of nondecremented EPSPs) in the identified giant neuron R2, which can serve as a monitor of the afferent input in the gill and siphon withdrawal reflex (Rayport and Camardo, 1984). We have found 2 striking parallels between the development of behavioral sensitization and the development of its cellular analog: (1) Behavioral sensitization, produced by tail shock, emerges very late in juvenile development (stage 12), and the cellular analog of sensitization (produced by activation of the tail pathway) emerges by exactly the same late juvenile stage; (2) prior to the emergence of behavioral sensitization, tail shock unexpectedly was found to produce significant reflex depression (Rankin and Carew, 1988), and prior to the emergence of the cellular analog of sensitization, activation of the tail pathway was found to produce significant depression of the synaptic input in the reflex pathway. Thus, the cellular analog of sensitization in the CNS develops and matures in close temporal register with the development of behavioral sensitization in juvenile Aplysia.

Differential effects of carbamazepine and lithium on sensitization and kindling

Abstracto1.Lithium carbonate appears to inhibit the development of cocaine-induced behavioral sensitization while it does not inhibit the development of amygdala kindling. Lithium chloride did not inhibit kindled seizures.2.Carbamazepine does not inhibit cocaine-induced motor activity or the development of behavioral sensitization in the rat.3.Carbamazepine is highly effective in blocking completed amygdala-kindled seizures, but does not block their development in the rat.4.Lithium carbonate and carbamazepine, two drugs of use in the prophylactic treatment of affective illness, appear to have differential effects on sensitization and kindling. Lithium carbonate appears to inhibit the development of cocaine-induced behavioral sensitization while it does not inhibit the development of amygdala kindling. Lithium chloride did not inhibit kindled seizures. Carbamazepine does not inhibit cocaine-induced motor activity or the development of behavioral sensitization in the rat. Carbamazepine is highly effective in blocking completed amygdala-kindled seizures, but does not block their development in the rat. Lithium carbonate and carbamazepine, two drugs of use in the prophylactic treatment of affective illness, appear to have differential effects on sensitization and kindling.

Differential effects of carbamazepine and lithium on sensitization and kindling

Lithium carbonate appears to inhibit the development of cocaine-induced behavioral sensitization while it does not inhibit the development of amygdala kindling. Lithium chloride did not inhibit kindled seizures. Carbamazepine does not inhibit cocaine-induced motor activity or the development of behavioral sensitization in the rat. Carbamazepine is highly effective in blocking completed amygdala-kindled seizures, but does not block their development in the rat. Lithium carbonate and carbamazepine, two drugs of use in the prophylactic treatment of affective illness, appear to have differential effects on sensitization and kindling.