Induction Of Stereotypy Research Articles

Can the Stereotypy‐Inducing Effects of Atypical Dopamine Uptake Inhibitors Account for Their Blockade of Cocaine Self Administration?

Several N‐substituted benztropine (BZT) analogs with high dopamine transporter (DAT) affinity decreased cocaine (Coc) self‐administration (SA) relative to food‐maintained behavior in rats. Further these BZT analogs failed to increase rates of responding greater than saline injections, when substituted for Coc (JPET:329;677). The present study examined if BZT analogs enhance the stereotypy‐inducing effects of Coc, which in turn interferes with continued Coc SA. Standard DAT inhibitors (WIN35,428, methylphenidate) maintained responding greater than saline injections when substituted for Coc, whereas responding maintained by BZT analogs (AHN1‐055, AHN2‐005, JHW007, JHW013, GA1‐69, GA2‐50, GA2‐99) was not different from vehicle. Additionally the DAT inhibitors shifted the Coc SA dose‐effect curve leftward, whereas the BZT analogs dose‐dependently decreased maximum SA of Coc SA. Administered alone, standard DAT inhibitors like Coc dose‐dependently increased stereotypy and enhanced the stereotypy‐induction produced by Coc. The BZT analogs, however, were inactive alone and did not significantly change the effects of Coc. Thus it appears that the induction of stereotypy does not account for the decreases in Coc SA produced by BZT analogs. The present study further supports the development of N‐substituted BZT analogs as medications to treat Coc abuse. Supported by NIDA IRP.

Pharmacological profile of a chromanamine analogue (DP-6OH-3CA) of the selective presynaptic dopamine agonist N,N-dipropyl-7-hydroxy-2-aminotetralin.

The pharmacological profile of an oxygen isostere of the selective presynaptic dopamine agonist DP-7OH-AT, i.e. dipropyl-6-hydroxy-3-chromanamine (DP-6OH-3CA) has been evaluated in various receptor binding, neurobiochemical and behavioural experiments. The chromanamine displaced the 3H-labelled dopamine ligands, 5,6-DPAT and N-0437, with Ki values of 106 and 143 nM, respectively. In in-vivo biochemical models for presynaptic activity the chromanamine induced a half-maximal effect in the gamma-butyrolactone reversal test at 6.8 mumol kg-1 and had an ED70 value of 40 mumol kg-1 for HVA decrease in the striatum. In behavioural models for postsynaptic dopaminergic activity a half-maximal effect for the induction of stereotypy was reached at 100 mumol kg-1 and reversal of the effects of reserpine to a level of 200 counts was induced at 11 mumol kg-1. On comparison of these results with the results obtained with the carbon analogue of DP-6OH-3CA, i.e. DP-7OH-AT, it is apparent that the chromanamine has a reduced potency for dopamine D2 receptors in in-vitro and in-vivo models. The selectivity for presynaptic dopamine receptors was lower than with DP-7OH-AT and the isomeric chromanamine, DP-8OH-3CA, indicating that the optimal position of the hydroxyl group for presynaptic selectivity is in the 8 and not in the 6 position for the chromanamines.

Acute Effects of Cocaine on Movement-Related Firing of Dorsolateral Striatal Neurons Depend on Predrug Firing Rate and Dose

To investigate striatal mechanisms underlying the acute effects of stimulants on motor behavior, firing rates (FRs) of striatal neurons related specifically to vertical head movement were studied exclusively during vertical head movements. Precocaine FRs were recorded after intraperitoneal saline injection (time 1; T1), and rats performed conditioned vertical head movements (>10,000) similar to those induced by stimulants. After cocaine injection (0, 5, 10, or 20 mg/kg; T2), animals continued in the task. The proportion of long head movements was increased by low doses but decreased by the high dose, which induced stereotypic head movements. Comparing each neuron's FR during movements that were matched between T1 and T2 (e.g., regarding direction, distance), cocaine's effects depended on predrug FR and dose. Plots regressing T2FR on T1FR showed dose-dependent, "clockwise" rotations of regression lines in plots of all the neurons' average FRs and of individual neurons' FRs during different movements. All three doses elevated normally low FRs; the high dose also suppressed many higher FRs. Enhancement of a neuron's FR associated with weak and suppression of FR associated with strong corticostriatal inputs contradict several current theories of dopamine (DA) function. Induction of stereotypy by a single, high-dose injection suggests that this cocaine level exceeded that in other studies using cocaine self-administration, in which stereotypy develops only after several sessions. Suppressive effects observed only at the high dose and in numerous electrophysiological studies of DA agonist effects may be unrepresentative of uniform elevations in lateral striatal firing related to movement observed at lower cocaine levels.

Vertical shifts in dose?injection curves reflect reward allostasis, not sensitization

In 1998, we reported that increasing access time to cocaine (from 1 h to 6 h per day) precipitates a rapid escalation of intake that is associated with a vertical upward shift in the dose–injection curve, without detectable parallel shifts to the right or to the left (Ahmed and Koob 1998, 1999). Zernig et al. (2003) have suggested that this post-escalation vertical shift may result from tolerance to the rate-suppressing effects of the drug (e.g. “sedation, induction of stereotypy, aversion, etc”) and not—as suggested by other researchers—from tolerance to its rewarding effects or sensitization to its incentive effects (references in Zernig et al.). Unfortunately, Zernig et al. misinterpret our own hypothesis of drug intake escalation and misrepresent it as another version of the sensitization hypothesis of drug addiction. Briefly, according to our reward allostasis hypothesis, prolonged drug exposure induces a chronic decrease in baseline reward sensitivity, a process called reward allostasis (Koob and Le Moal 1997, 2001). As a result, the user becomes both increasingly motivated to seek the reward-facilitating effects of the drug (to avoid anhedonia and recover initial sensitivity) and increasingly tolerant to these effects (due to the shift in baseline sensitivity). In the following comments, we explain why the model offered by Zernig et al. fails to provide a more parsimonious explanation of our data than our reward allostasis hypothesis. According to the model by Zernig et al., dose–response rate functions for drug self-administration represent the net effect of two antagonistic, S-shaped dose-dependent processes (with same efficacy but different potency), one increasing, the other suppressing responding for the drug. The resulting dose–response rate curve is an inverted U. For Zernig et al., the ascending limb of the dose–response curve “is easy to interpret”: the reinforcing effects of the drug increase with the unit dose and “thus leads to an increase in the rate of responding.” In the model by Zernig et al., simulating tolerance to the rate-suppressing effects of the drug results in both an upward and a rightward shift of the theoretical inverted U (Fig. 2C of Zernig et al.). They consider this complex shift as a theoretical approximation of our experimental data, although we did not observe any shift of the dose– injection curve to the right after escalation of cocaine selfadministration (compare Fig. 1C with Fig. 2C of Zernig et al.). Despite its apparent simplicity, the model by Zernig et al. misses the target. Escalation of cocaine intake and associated vertical shifts in dose–injection curves were observed under a schedule of continuous reinforcement (Ahmed and Koob 1998, 1999). Under this type of schedule, the dependent variable is the rate of injections, not the (inter-reinforcement) rate of responses, as wrongly assumed by Zernig et al. The rate of injections decreases with the duration of the rewarding effects of the drug which increases with the unit dose. Resulting dose– injection curves are predominantly characterized by a descending limb that covers the largest and most meaningful range of doses (Fig. 1C, D of Zernig et al.). Ascending limbs are rarely observed and difficult to interpret. In contrast, the descending limb of the dose– injection curve “is easy to interpret”: it reflects the behavioral regulation which allows the individual user to maintain the cumulative effect of the drug above some set level, at least down to a certain threshold dose, below which the rate of injections breaks down (Fig. 1C of Zernig et al.). At this threshold dose, the required rate of injections is probably higher than the maximum rate This reply refers to the letter http://dx.doi.org/10.1007/s00213-0031601-0

Neuropharmacological profile of a new series of dopamine agonists: N-n-propyl-hexahydronaphthoxazines

It has been demonstrated that within the series of hydroxylated (7-OH, 9-OH) and non-hydroxylated (N-0498) hexahydronaphthoxazines the 9-OH (N-0500) analogue is a very potent centrally acting DA receptor agonist. In in vitro [ 3H]DP-5,6-ADTN binding experiments, reflecting D-2 dopaminergic activity, N-0500 was equipotent with apomorphine and RU-29717, whereas both the 7-OH (N-0499) and N-0498 were much less effective. In in vivo tests related to DA receptor stimulation N-0500 was found to be the most active compound. In the γ-butyrolactone model, a test for DA autoreceptor activation, N-0500 was 10 times as potent as apomorphine, but 3 times less active than RU-29717. The locomotor activity of mice was inhibited more strongly by N-0500 than by N-0499. Striatal concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid were rapidly reduced by N-0500 both after intraperitoneal and oral administration, indicating that this compound is well absorbed from the gastrointestinal tract and passes the blood-brain barrier to activate DA autoreceptors. In models for postsynaptic DA receptor stimulation (induction of stereotypy in rats, reversal of reserpine-induced immobility of mice) N-0500 was found to be as effective as RU-29717 in inducing stereotyped behaviors in rats, but was much less effective than RU-29717 in restoring the mobility of reserpinized mice, suggesting a selectivity for D-2 DA receptors by N-0500 in contrast to the mixed D-1/D-2 receptor activity of RU-29717. In in vitro binding experiments for evaluating the affinity towards other receptor types, N-0500 exhibited only a weak affinity towards 5-HT 1 and α 2 binding sites and possessed a very weak affinity for 5-HT 2 and α 1 receptor sites. It was concluded from these in vitro binding experiments that N-0500, has not only a very high affinity for D-2 DA receptors, but is more selective than RU-29717 and much more selective than the ergot bromocriptine. On the basis of its very potent in vivo central D-2 dopamine receptor activities and its in vitro selectivity, N-0500, being the most potent compound within the series, is a much more specifically acting drug than many of the dopaminergic ergolines and might therefore be a good candidate for the treatment of Parkinson's disease.

Behavioral and neurophysiological evidence for a facilatory interaction between co-existing transmitters: cholecystokinin and dopamine

Cholecystokinin (CCK) and dopamine (DA) co-exist in ventral tegmental neurons which project via the mesencephalic pathway to the nucleus accumbens of the rat. CCK and DA are located in separate neurons in the substantia nigra which projects via the nigrostriatal pathway to the caudate nucleus in the rat. The functional significance of this peptide-amine co-localization was investigated using behavioral and neurophysiological techniques. CCK injected directly into the nucleus accumbens potentiated apomorphine-induced stereotypy and dopamine-induced hyperlocomotion. CCK injected directly into the caudate nucleus had no effect on apomorphine-induced stereotypy or dopamine-induced hyperlocomotion CCK injected alone into either site did not induce stereotypy or hyperlocomotion. The dose-response curve to apomorphine induction of stereotypy was shifted to the left by CCK, indicating increased sensitivity to the dopaminergic agonist. Neurophysiological analysis of the firing rate of ventral tegmental neurons demonstrated that CCK produced a left-shift in the dose-response curve of apomorphine on inhibition of neuronal firing. These data suggest that CCK acts as a modulator of dopamine, increasing neuronal responses to dopaminergic agonists. The potentiation of dopamine by CCK may be specific to the mesolimbic neurons, where CCK and DA co-exist in the rat.

Neurochemical and behavioural profiles of five dopamine analogues.

The dopaminergic actions of five hydroxylated dopamine analogues have been examined for: i) Ability to induce stereotypy, ii) Effects upon dopamine metabolism, iii) Ability to antagonise the rise in striatal dopamine caused by gammabutyrolactone. With the exception of the resorcinol derivative 2-(3,5-dihydroxyphenyl)-N,N-dipropylethylamine, all of the compounds tested exhibited dopamine-like actions, and similarities were found in the induction of stereotypy and in the reduction of dopamine metabolism. For example, 2-(3-hydroxyphenyl)-N,N-dipropylethylamine had a short duration of action as far as reducing dopamine metabolism and inducing stereotypy were concerned. On the other hand, 2-(3-hydroxyphenyl)-N-n-propyl-N-phenyl-ethyl-ethylamine (e) and also 5-hydroxy-2-(N-n-propyl-N-phenylethyl)-aminotetralin had a long duration of agonist-like effects upon both parameters, the aminotetralin derivative being the more potent of the two. Thus, in going from the simple dopamine-like structure to the aminotetralin compound there has been an increase in dopamine agonist-like activity. The differences in dopamine agonist potency of the drugs used are discussed in relation to the structure of these compounds, and are compared with the potencies or related compounds. Also, the potencies of the compounds under investigation upon presynaptic dopamine receptors (using the gammabutyrolactone model as a test system) were investigated, and the ester, 2-(3-benzoyloxyphenyl)-N-n-propyl-N-phenylethyl-ethylamine was the most potent. This ester, which is probably converted to (e) in the brain, also had a long duration of action in the stereotypy and dopamine metabolism tests. The results suggest that certain of the compounds might be useful leads for the design of dopamine agonists of possible clinical use.