Neurotensin microinjection into the nucleus accumbens antagonizes dopamine-induced increase in locomotion and rearing

Neurotensin is an endogenous neuropeptide with neuronal perikarya or fibers distributed in the vicinity of the mesolimbic dopamine system. This observation, plus behavioral data showing that neurotensin injection into the nucleus accumbens blocks some behavioral effects of amphetamine, indicates that neurotensin may modulate the mesolimbic dopamine system. In this study it was shown that neurotensin given into the nucleus accumbens produces a dose-dependent blockade of locomotion and rearing initiated by dopamine injection into the nucleus accumbens. This effect is not mimicked by inactive neurotensin analogue nor some other endogenous neuropeptides. Since dopamine acts on postsynaptic dopamine receptors in the nucleus accumbens, neurotensin is acting, not on dopamine terminals, but on neurons or neuronal systems which are modulated by the mesolimbic dopamine system. This conclusion is supported by the facts that intra-accumbens injection of neurotensin does not alter accumbens levels of dopamine or its metabolites, nor does it affect the increase in dopamine metabolites produced by injection of neurotensin into the ventral tegmental area. Further, neurotensin was also found to block the dopamine-independent increase in locomotion and rearing produced by the injection of d-Ala 2-Met- 5enkephalinamide into the nucleus accumbens. These data indicate that neurotensin acts on neurons in the nucleus accumbens to counteract the motor stimulant effects of dopamine or enkephalin. Therefore, in the nucleus accumbens, neurotensin is not acting to modulate the mesolimbic dopamine system, but rather appears to antagonize behavioral hyperactivity, regardless of the neurochemical initiation

Behavioral and neurochemical effects of neurotensin microinjection into the ventral tegmental area of the rat

The ventral tegmental area of the rat brain has been shown to possess high densities of neurotensin- and dopamine-containing neuronal perikarya. We recently demonstrated that microinjection of neurotensin into the ventral tegmental area produces behavioral hyperactivity similar to amphetamine-induced increase in exploratory behaviors, but lacking stereotypies. In this study, we report that the threshold dose for neurotensin-induced hyperactivity is 0.10–0.25 μg neurotensin/side. Either intracerebroventricular injection of haloperidol (5.0 μg/lateral ventricle) or destruction of the mesolimbic dopamine system by 6-hydroxydopamine abolishes the behavioral hyperactivity produced by intraventral tegmental injection of neurotensin (2.5 μg/side). Using high pressure liquid chromatography with electrochemical detection, we show that neurotensin injection into the ventral tegmental area increases the concentration of dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid in the nucleus accumbens and olfactory tubercles, but not in the striatum. This effect is especially profound in the nucleus accumbens where the threshold dose is less than 0.025 μg/side. The ratio of 3,4-dihydroxyphenylacetic acid to dopamine increased in the nucleus accumbens and olfactory tubercles in a dosedependent fashion (0.025 μg–2.50 μg/side). Neurotensin-induced behavioral hyperactivity correlates positively with neurotensin-induced changes in the ratio of 3,4-dihydroxyphenylacetic acid to dopamine. This study indicates that neurotensin acts in the ventral tegmental area to activate the mesolimbic dopamine system. Further, this activation produces behavioral hyperactivity characterized by an increase in exploratory behaviors. The fact that both immunoreactive neurotensin and neurotensin receptors are found in high concentration in the ventral tegmental area supports the possible physiological significance of this peptide-catecholamine interaction

Psychological Interventions as They Relate to Intrusive Thinking: Intrusive, Emotional Mental Imagery after Traumatic and Negative Events

Common across psychological disorders, intrusive, emotional mental images are sensory-perceptual representations that intrude involuntarily into the mind. Mental health treatments typically focus on entire disorders with multiple symptoms. This chapter suggests focusing on core clinical symptoms (i.e., intrusive imagery). Existing psychological therapy techniques (e.g., imagery rescripting) are promising, but underlying treatment mechanisms need to be better understood. Precise treatments and preventions are required. Using the example of psychological trauma, this chapter argues that psychological interventions can be developed in the laboratory: eff ective experimental analogues of trauma can generate intrusions so that putative interventions that modulate intrusions can be explored at various mechanistic levels (e.g., molecular, cognitive, social). Examples of targeting “new” (i.e., Day 1 of the traumatic event) memories include a simple cognitive interference intervention that holds promise for preventing intrusive images after trauma (a behavioral protocol including Tetris game play). This intervention specifi cally targets intrusive involuntary memories while leaving voluntary memory intact. Work on targeting “old” (as of Day 2) memories is at an earlier stage. Research on reconsolidation update mechanisms appears valuable in reducing older trauma memories via interference interventions, again with a behavioral task interference technique. To understand mechanisms across diff erent levels (e.g., molecular, cognitive, or social), mathematical models can aid the identifi cation of causal mechanisms involved in memory formation. Questions are posed to instigate discussion of future science-driven psychological interventions for intrusive images

Deletion of the 5-HT(3A)-receptor subunit blunts the induction of cocaine sensitization

Serotonin (5-HT) receptors are classified into seven groups (5-HT1–7), comprising at least 14 structurally and pharmacologically distinct receptor subtypes. Pharma-cological antagonism of ionotropic 5-HT3 receptors has been shown to modulate both behavioral and neuro-chemical aspects of the induction of sensitization to cocaine. It is not known, however, if specific molecular subunits of the 5-HT3 receptor influence the development of cocaine sensitization. To address this question, we studied the effects of acute and chronic intermittent cocaine administration in mice with a targeted deletion of the gene for the 5-HT3A-receptor subunit (5-HT3A ?/?). 5-HT3A (?/?) mice showed blunted induction of cocaine-induced locomotor sensitization as compared with wild-type littermate controls. 5-HT3A (?/?) mice did not differ from wild-type littermate controls on measures of basal motor activity or response to acute cocaine treatment. Enhanced locomotor response to saline injection following cocaine sensitization was observed equally in 5-HT3A (?/?) and wild-type mice suggesting similar conditioned effects associated with chronic cocaine treatment. These data show a role for the 5-HT3A-receptor subunit in the induction of behavioral sensitization to cocaine and suggest that the 5-HT3A molecular subunit modulates neurobehavioral adaptations to cocaine, which may underlie aspects of addiction

Psychological and neural mechanisms of relapse

Relapse, the resumption of drug taking after periods of abstinence, remains the major problem for the treatment of addiction. Even when drugs are unavailable for long periods or when users are successful in curbing their drug use for extended periods, individuals remain vulnerable to events that precipitate relapse. Behavioural studies in humans and laboratory animals show that drug-related stimuli, drugs themselves and stressors are powerful events for the precipitation of relapse. Molecular, neurochemical and anatomical studies have identified lasting neural changes that arise from mere exposure to drugs and other enduring changes that arise from learning about the relationship between drug-related stimuli and drug effects. Chronic drug exposure increases sensitivity of some systems of the brain to the effects of drugs and stressful events. These changes, combined with those underlying conditioning and learning, perpetuate vulnerability to drug-related stimuli. Circuits of the brain involved are those of the mesocorticolimbic dopaminergic system and its glutamatergic connections, and the corticotropin-releasing factor and noradrenergic systems of the limbic brain. This paper reviews advances in our understanding of how these systems mediate the effects of events that precipitate relapse and of how lasting changes in these systems can perpetuate vulnerability to relapse

Neuropsychological Mechanisms of Intrusive Thinking

A classic definition of intrusive thinking is “any distinct, identifiable cognitive event that is unwanted, unintended, and recurrent. It interrupts the flow of thought, interferes in task performance, is associated with negative affect, and is difficult to control” (Clark 2005:4). While easy to understand and applicable to many cases, this definition does not seem to encompass the entire spectrum of intrusions. For example, intrusive thoughts may not always be experienced as unpleasant or unwanted, and may in some situations even be adaptive. This chapter revisits the definition of intrusive thinking, by systematically considering all the circumstances in which intrusions might occur, their manifestations across health and disorders, and develops an alternative, more inclusive definition of intrusions as being “interruptive, salient, experienced mental events.” It proposes that clinical intrusive thinking differs from its nonclinical form with regard to frequency, intensity, and maladaptive reappraisal. Further, it discusses the neurocognitive processes underlying intrusive thinking and its control, including memory processes involved in action control, working memory and long-term memory encoding, retrieval, and suppression. As part of this, current methodologies used to study intrusive thinking are evaluated and areas are highlighted where more research and/or technical innovation is needed. It concludes with a discussion of the theoretical, therapeutic, and sociocultural implications of intrusive thinking and its contro