Neonatal Isolation Stress Inhibits Pre-Weaning Weight Gain and Mild-Stressor Induced Locomotor Activity in Early Adolescent Male and Female Rats

The present study looked at the effects of neonatal isolation, an early life stress experience, in male and female early adolescent rats, an age which is underrepresented in the early stress literature. Four stress-sensitive indices were assessed: weight gain during the pre-weaning period, open field activity, and locomotor activity in response to two mild stressors: exposure to a novel environment, and a single IP saline injection. Rats in the neonatal isolation condition were removed from dam and littermates on postnatal days 2-9 in accord with the procedure used by Kehoe et al. (1995); behavioral testing occurred on PN25-PN30 during the early adolescent period. It was found that neonatally isolated pups weighed less than non-isolate controls on each of three measurement days (PN7, PN14, PN21) throughout the pre-weaning period. Further, neonatal isolation experience consistently reduced horizontal locomotor activity measured in the open field, in a novel environment, and following a single mild acute stressor. On some measures, behavior reflected greater impact of NI in males compared with NI females, suggesting that the effects of NI in early adolescent rats may be sexually dimorphic

Extinction of Fear-potentiated Startle: Blockade by Infusion of an NMDA Antagonist into the Amygdala

Data derived from in vitro preparations indicate that NMDA receptors play a critical role in synaptic plasticity in the CNS. More recently, in vivo pharmacological manipulations have suggested that an NMDA-dependent process may be involved in specific forms of behavioral plasticity. All of the work thus far has focused on the possible role of NMDA receptors in the acquisition of responses. However, there are many examples in the behavioral literature of learning-induced changes that involve the reduction or elimination of a previously acquired response. Experimental extinction is a primary example of the elimination of a learned response. Experimental extinction is well described in the behavioral literature, but has not received the same attention in the neurobiological literature. As a result, the neural mechanisms that underlie this important form of learning are not at all understood. In the present experiments, the fear-potentiated startle paradigm was employed to begin to investigate neural mechanisms of extinction. The results show that infusion of the NMDA antagonist D,L-2-amino-5-phosphonovaleric acid (AP5) into the amygdala, a limbic structure known to be important for fear conditioning, dose-dependently blocked extinction of conditioned fear. Control experiments showed that the blockade of extinction was neither the result of the permanent disruption of amygdaloid function nor the result of decreased sensitivity of the animals to the conditioned stimulus. Infusion of AP5 into the interpositus nucleus of the cerebellum, a control site, did not block extinction. Finally, intra-amygdala infusion of a selected dose of the non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione did not block extinction of conditioned fear. These results, together with a previous report from our laboratory (Miserendino et al., 1990), demonstrate the importance of the amygdala in the elaboration of conditioned fear and suggest that an NMDA-dependent process might underlie the extinction of conditioned fear

Blocking of Acquisition But Not Expression of Conditioned Fear-Potentiated Startle by NMDA Antagonists in the Amygdala

Assessed the role of N-methyl-{d}-aspartate (NMDA) receptors in the amygdala in associative fear conditioning. 132 rats were implanted with cannulae aimed at the basolateral amygdaloid nuclei, while 13 controls had cannulae aimed at the interpositus nuclei of the cerebellum. NMDA antagonists infused into the amygdala blocked the acquisition, but not the expression, of fear conditioning measured with a behavioral assay mediated by a defined neural circuit (fear-potentiation of the acoustic startle reflex). This effect showed anatomical and pharmacological specificity, and was not attributable to reduced salience of the stimuli of light or shock used in training. An NMDA-dependent process in the amygdala was critical for associative fear conditioning

Lesions of the Perirhinal Cortex but Not of the Frontal, Medial Prefrontal, Visual, or Insular Cortex Block Fear-Potentiated Startle Using a Visual Conditioned Stimulus

The present study is part of an ongoing series of experiments aimed at delineation of the neural pathways that mediate fear-potentiated startle, a model of conditioned fear in which the acoustic startle reflex is enhanced when elicited in the presence of a light previously paired with shock. A number of cortical areas that might be involved in relaying information about the visual conditioned stimulus (the light) in fear-potentiated startle were investigated. One hundred thirty-five rats were given 10 light-shock pairings on each of 2 consecutive days, and l-2 d later electrolytic or aspiration lesions in various cortical areas were performed. One week later, the magnitude of fear-potentiated startle was measured. Complete removal of the visual cortex, medial prefrontal cortex, insular cortex, or posterior perirhinal cortex had no significant effect on the magnitude of fear-potentiated startle. Lesions of the frontal cortex attenuated fear-potentiated startle by approximately 50%. However, lesions of the anterior perirhinal cortex completely eliminated fear-potentiated startle. The effective lesions included parts of the cortex both dorsal and ventral to the rhinal sulcus and extended from approximately 1.8 to 3.8 mm posterior to bregma. Lesions slightly more posterior (2.3-4.8 mm posterior to bregma) or lesions that included only the perirhinal cortex dorsal to the rhinal sulcus had no effect. The region of the perirhinal cortex in which lesions blocked fear-potentiated startle projects to the amygdala, and thus may be part of the pathway that relays the visual conditioned stimulus information to the amygdala, a structure that is also critical for fear-potentiated startle. In addition, the present findings are in agreement with numerous studies in primates suggesting that the perirhinal cortex may play a more general role in memory

NMDA and Non-NMDA Antagonists Infused into the Nucleus Reticularis Pontis Caudalis Depress the Acoustic Startle Reflex

Male rats chronically implanted with bilateral cannulae aimed at the nucleus reticularis pontis caudalis were tested to assess effects of γ-{d}-glutamylglycine, {d},{l}-2-amino-5-phosphonopentanoic acid (AP5), and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) on the amplitude of the acoustic startle reflex. Local infusion of each of the 3 compounds significantly reduced startle amplitude by as much as 70–80%. AP5 and CNQX attenuated startle over a dose range that indicated that the reticularis pontis caudalis may be much more sensitive to these compounds than other nuclei along the primary startle pathway. Results suggest that at the level of the nucleus reticularis pontis caudalis an excitatory amino acid neurotransmitter may mediate acoustic startle and that both N-methyl-D-aspartate (NMDA) and non-NMDA receptor subtypes may be important for the expression of the acoustic startle reflex

Electrical Stimulation of the Medial Prefrontal Cortex Supports Both \u27Pure Reward\u27 and \u27Reward-Escape\u27 Behavior in Rats

In female Sprague-Dawley rats, 8 of 12 medial prefrontal cortex (MPFC) sites that yielded criterion self-stimulation behavior supported only self-stimulation, i.e. were ‘pure reward’ in type. The remaining 4 sites supported behavior to escape from experimenter-administered stimulation of the same parameter as well, i.e. were ‘reward-escape’ in type. ‘Pure reward’ and ‘reward-escape’ sites in the MPFC were distinguished by both the magnitude and temporal form of the escape response functions generated, and by the prevalence of ‘pounce-back’, a vigorous and repetitive barpressing during the 3-s MPFC stimulation-escape interval produced by an effective barpress. The finding that both ‘pure reward’ and ‘reward-escape’ patterns of behavior can be elicited by stimulation on the MPFC provides a basis for futher assessment of similarities and differences in medial prefrontalcortical and lateral hypothalamic (LH) ‘reward’ systems. It is suggested that ‘reward-escape’ in the MPFC may be mediated by the activity of ‘reward’ neurones which respond to stimulus offset, rather than by a secondary aversive process as is proposed to underlie ‘reward-escape’ in the LH

Behavioral Sensitization to Cocaine: Modulation by the Cyclic AMP System in the Nucleus Accumbens

Examined the involvement of the cyclic adenosine monophosphate (cAMP) system at the level of the nucleus accumbens (NAc) in cocaine-induced locomotor activity and sensitization. 36 male rats were pretreated on 3 consecutive days with cocaine concurrently with intraaccumbens infusion of saline, 8-bromo-cAMP, or RP-CPT-cAMP. Ss and controls were tested for locomotor activity on pretreatment days and following an additional cocaine challenge on a subsequent day. Over pretreatment days, Ss given 8-bromo-cAMP showed greater cocaine-induced activity, while Ss given RP-CPT-cAMP tended to be less active. When subsequently challenged with cocaine, Ss pretreated with 8-bromo-cAMP showed greater locomotor activity. Data suggest that protein kinase activation at the level of the NAc may have a facilitative role with respect to acute and long-term stimulant-induced locomotor activity

Dissociation of Novelty- and Cocaine-Conditioned Locomotor Activity from Cocaine Place Conditioning

igh locomotor response to novelty is associated with ease of drug self-administration but does not predict greater place conditioning effects of drugs. Yet, the latter reflects context conditioning and high responders (HR), compared to low responders (LR), show greater conditioned locomotor effects. Conditioned locomotor effects may occur in place conditioning, perhaps confounding its measure. To examine whether conditioned locomotor effects occur in place conditioning, the present study classified rats as HR vs LR. The place conditioning and locomotor sensitizing effects of cocaine were tested. In Exp 1, HR rats exhibited more crossings between compartments but did not differ from LR rats in cocaine place conditioning. Further, both groups showed increased crossings at test compared to baseline, indicative of a conditioned locomotor effect. In Exp 2, HR rats showed greater acute locomotor activation to cocaine, whereas LR rats tend to show greater locomotor sensitization. Finally, in Exp 3, HR rats showed habituation in locomotor responses, whereas LR rats did not. Results of these studies suggest that inherent and conditioned locomotor activity levels are dissociated from place conditioning effects

Hedonic Interactions of Medial Prefrontal Cortex and Nucleus Reticularis Gigantocellularis

It has been shown that ‘pure reward’ and ‘reward-escape’ sites in the lateral hypothalamus (LH) of rats respectively ameliorate and exacerbate nucleus reticularis gigantocellularis (NGC) stimulation-induced aversion52. Conversely, the present studies found that ‘rewarding’ medial prefrontal cortex (MPFC) stimulation increased escape from NGC stimulation regardless of whether the MPFC site tested was ‘pure reward’ or ‘reward-escape’ in type. This suggested that a simple algebraic summation model of positive and negative affective processes may not adequately describe the NGC-MPFC interaction. In a subsequent study, rats were observed both to barpress less to obtain, and more to escape from, ‘rewarding’ MPFC stimulation during continuous NGC stimulation, supporting the hypothesis that the observed MPFC stimulation-mediated increase in NGC stimulation escape reflected an exacerbation of aversion. Finally, NGC stimulation was seen to increase barpressing to obtain ‘subreward’ MPFC current trains, indicating a potentiation of the reward value of such current. Results of this series of studies suggests a hedonic interaction model of NGC and MPFC characterized by reciprocal neuromodulation. The model is conceptuallized as a ‘neural opponent process’ subserving affective ‘balance’ and ‘feature enhancement’, and its possible relevance to the putative role of the MPFC in cocaine use is discussed

Enhanced Acquisition of Cocaine Self-Administration in Adult Rats With Neonatal Isolation Stress Experience

Examined the acquisition of self-administered cocaine addiction in adult male rats with neonatal isolation stress experience. Some Ss underwent neonatal isolation for 1 hr daily on postnatal days 2–9. At approximately 100 days of age, 4 escalating cocaine doses were administered for 5 days each, continuing with the highest dose until acquisition occurred. Results indicate that isolated Ss acquired operant conditioning for cocaine in fewer days and at lower doses than did non-isolated Ss. No differences between the 2 groups were observed in locomotor activity, acquisition of operant responding for food, or in number of days to extinguish self-administration. Findings suggest that neonatal isolation stress increases rats\u27 vulnerability to cocaine addiction; findings have important implications for the role of early childhood stress in human vulnerability to cocaine addiction