The administration of delta9-tetrahydrocannabinol (THC), the principle psychoactive ingredient in marijuana, or the endogenous cannabinoid anandamide, has been shown to impair recent memory. The purpose of the present investigation was to determine if the cannabinoid CB1 receptor antagonist SR141716A could attenuate THC- or anandamide-induced memory impairment, and to assess the effects on memory of SR141716A alone. Memory was assessed in rats well-trained in a two-component instrumental discrimination task, consisting of a conditional discrimination, and a non-match-to-position to assess recent or working memory. SR141716A (0.0-2.0 mg/kg) had no effect on either the conditional discrimination or the non-match-to-position. However, SR141716A (0.0-2.0 mg/kg) attenuated the memory impairment produced by THC (2.0 or 4.0 mg/kg) as indexed by an enhancement of performance in the non-match-to-position. When administered to rats pretreated with anandamide (2.0 mg/kg), SR141716A (0.0-2.5 mg/kg) impaired performance in the conditional discrimination at the highest dose. This was interpreted as a deficit in some capacity unrelated to memory (e.g., motor impairment). However, lower doses of SR141716A (0.1 and 0.5 mg/kg) attenuated the anandamide-induced impairment of performance in the non-match-to-position without affecting the conditional discrimination. This is the first report that the memory impairment produced by anandamide can be attenuated by a cannabinoid antagonist; results suggest that anandamide-induced memory disruption is mediated by CB receptors.
The nucleus accumbens (NAc) plays a role in conditioned place preference (CPP). The authors tested the hypothesis that inhibition of mitogen-activated protein kinases (MAPKs) would inhibit NAc-amphetamine-produced CPP. Results confirmed that NAc amphetamine increased levels of the MAPK extracellular signal-regulated kinase (ERK). In CPP studies, NAc injections (0.5 microl per side) of the ERK inhibitor PD98059 (1.0-2.5 microg) or the p38 kinase inhibitor SB203580 (15-500 ng) dose dependently impaired CPP. The c-Jun-N-terminal kinase (JNK) inhibitor SP600125 (1.0-2.5 microg) failed to block the CPP effect. The drugs did not block amphetamine-induced motor activity. Results suggest that ERK and p38, but not JNK, MAPKs may be necessary for the establishment of NAc amphetamine-produced CPP and may also mediate other forms of reward-related learning dependent on NAc.
Animals with a history of receiving daily injections of +-amphetamine in a specific environment showed a placebo effect (enhanced activity) when injected with saline and placed there; control animals with similar but dissociated drug histories and experience with the test chamber failed to show the effect. The dopamine receptor blocker pimozide antagonized the establishment of conditioning. However, the same dose of pimozide, when given to previously conditioned animals on the placebo test day, failed to antagonize the expression of conditioned activity. Thus, during conditioning dopaminergic neurons mediated a change that subsequently influenced behavior even when dopaminergic systems were blocked. Although schizophrenia may be related to hyperfunctioning of dopamine, neuroleptic drugs, which block dopamine receptors on their first administration, do not have therapeutic effects for a number of days. The results of the pimozide experiments may resolve this paradox.
A high incidence of depressive symptoms has been observed in patients with Parkinson's disease (PD). PD involves a loss of central monoamines, and a decrease of monoamines has been implicated in depression; therefore, it is possible that depressive symptoms in PD result from the loss of endogenous neurotransmitters. However, it is equally possible that depressive symptoms represent a reaction to the chronic disabling course of PD. By comparing depressive symptoms in PD patients to those in matched patients with other chronic disabling diseases not involving a loss of central monoamines, it may be possible to decide between these alternatives. Thus, depressive symptoms were assessed in 45 patients with PD and 24 disabled controls that did not differ from the PD subjects on a measure of functional disability. Results showed that PD subjects obtained significantly higher total scores on the Beck Depression Inventory (BDI) than controls. PD subjects scored significantly higher than controls on BDI items grouped to reflect cognitive-affective and somatic depressive symptoms. The BDI scores of PD subjects were not reliably related to age, sex, duration of PD, or clinical ratings of PD symptom severity or functional disability. Self-rated disability and the number of recent medical problems were the greatest predictors of depressive symptoms. These findings supported the hypothesis that depressive symptoms in PD may not represent solely a reaction to disability.
Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 g) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 g i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 g) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.Opioid drugs such as morphine are widely used in the treatment of severe pain; however, their chronic administration results in the development of tolerance to their analgesic effects, limiting their clinical usefulness in pain management. Although the mechanisms underlying the development of opioid tolerance are poorly understood, recent studies have suggested that alterations in the coupling of opioid receptors to G protein-linked effectors may play a significant role (Crain and Shen, 2000). Morphine and related agonists are recognized to produce their characteristic acute and chronic effects by activating spinal and supraspinal -, ␦-, and -opioid receptors. Classically, morphine activates G i protein-coupled -opioid receptors to inhibit adenylyl cyclase activity and decrease neuronal cAMP levels (Uhl et al., 1994). At the presynaptic level, -opioid receptor activation inhibits voltage-sensitive Ca 2ϩ channels (Tallent et al., 1994) and reduces neurotransmitter release, whereas at the postsynaptic level, it opens potassium channels and hyperpolarizes neurons (North and Williams, 1983;Ikeda et al., 1995). The net result of th...
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